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Previous Breast Cancer Research: 2002-2006   
The Breast Cancer File also contains summaries of past research that has shown promise and may still be standard practice among many physicians. To download earlier research findings on Breast Cancer, click HERE.
 

Latest Research on Breast Cancer
     
Hum Pathol. 2008 Sep;39(9):1295-300. Epub 2008 Jul 9.
Toker cells of the breast. Morphological and immunohistochemical characterization of 40 cases.
Di Tommaso L, Franchi G, Destro A, Broglia F, Minuti F, Rahal D, Roncalli M.
Department of Pathology, University of Milan School of Medicine & IRCCS Humanitas Clinical Institute, Rozzano, Milan, Italy.

Toker cells are epithelial cells with clear cytoplasm usually free of cytologic atypia localized within the nipple epidermis. Rarely, they can be so numerous and atypical as to require a careful distinction from malignant cells of Paget's disease. The purpose of this paper was to better define the prevalence of these atypical Toker cells and to investigate phenotypic markers that can be helpful in the differential diagnosis with Paget's disease. Forty cases containing Toker cells were identified in the nipples of 390 patients (10.2%) who underwent complete breast mastectomy. In 24 cases (60%), Toker cells were cytologically bland and benign, disappearing after a few consecutive sections ("normal Toker cells"). In 11 cases (27.5%), Toker cells were more numerous and persistent on serial sections, still retaining bland cytologic features ("hyperplastic Toker cells"). In 5 cases (12.5%), hyperplastic Toker cells also became cytologically atypical ("hyperplastic and atypical Toker cells"). On immunohistochemistry, Toker cells were positive for estrogen (25/25) and progesterone (20/23) receptors, and negative for CD138 (18/19) and p53 (14/14); some hyperplastic and atypical Toker cells (4 cases) and hyperplastic Toker cells (1 case) showed faint immunoreactivity for HER2/NEU. For comparison, Paget's disease were negative for estrogen (6/10) and progesterone (7/10) receptors, and positive for CD138 (7/10), p53 (6/10), and HER2/NEU (9/10). Both Toker cells and Paget's disease stained positive for cytokeratin 7 and epithelial membrane antigen, and negative for p63. In conclusion, Toker cells are detectable in 10% of the nipples and are usually cytologically bland, but in 10% of the cases they can be morphologically atypical. The combined use of CD138/p53 is very helpful in distinguishing these atypical Toker cells from those of Paget's disease.

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Int J Cancer. 2008 Sep 1;123(5):1146-53.
HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors.
Borgquist S, Djerbi S, Pontén F, Anagnostaki L, Goldman M, Gaber A, Manjer J, Landberg G, Jirström K.
Department of Laboratory Medicine, Center for Molecular Pathology, Malmö University Hospital, Malmö, Sweden.

Although several studies have reported on the anti-tumoural properties exerted by 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) inhibitors (statins), the in vivo expression of HMG-CoAR in human cancer has been considerably less investigated. In our study, we examined the immunohistochemical expression of HMG-CoAR in 511 incident breast cancers within the Malmö Diet and Cancer Study in order to explore its relationship to established clinicopathological and tumour biological parameters. Furthermore, the potential influence of estrogen exposure on HMG-CoAR expression was assessed by performing Cox's proportional hazards analyses of the relationship between the use of hormone replacement therapy (HRT), obesity (waist circumference) and tumour-cell specific HMG-CoAR expression. We found that HMG-CoAR was present in various fractions and intensities in the cytoplasm, sometimes with a membranous pattern, but not in the tumour cell nuclei. The expression of HMG-CoAR was associated with a smaller tumour size (p = 0.02), low histological grade (p = 0.001), low Ki67 index (p = 0.004), ERalpha+ (p = 0.02), ERbeta+ (p = 0.005), and high p27 expression (p = <0.001). The incidence of tumours with a high HMG-CoAR-expression was increased among HRT-users, although this was not statistically significant in a heterogeneity analysis. Obesity was significantly associated with a high HMG-CoAR expression assessed both as a high (>50%) fraction of positive cells (relative risk: 2.06; 95% confidence interval: 1.20-3.51), and a strong staining intensity (2.33: 1.08-5.02). In summary, we demonstrate that HMG-CoAR is differentially expressed in breast cancer and that a high expression is associated with prognostically favourable tumour parameters. Moreover, estrogen related life-style and anthropometric factors might indeed regulate HMG-CoAR expression.

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Am J Epidemiol. 2008 Aug 15;168(4):404-11. Epub 2008 Jun 13.
Proportion of invasive breast cancer attributable to risk factors modifiable after menopause.
Sprague BL, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Hampton JM, Newcomb PA.
Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI 53726, USA.

A number of breast cancer risk factors are modifiable later in life, yet the combined impact of the population changes in these risk factors on breast cancer incidence is not known to have been evaluated. The population attributable risk (PAR) associated with individual risk factors and the summary PAR for sets of modifiable and nonmodifiable risk factors were estimated by using data on 3,499 invasive breast cancer cases and 4,213 controls from a population-based study in Wisconsin, Massachusetts, and New Hampshire, conducted from 1997 to 2001. The summary PAR for factors modifiable after menopause, including current postmenopausal hormone use, recent alcohol consumption, adult weight gain, and recent recreational physical activity, was 40.7%. Of the individual modifiable factors, the highest PARs were observed for weight gain (21.3%) and recreational physical activity (15.7%), which together showed a summary PAR of 33.6%. The summary PAR for factors not modifiable after menopause, including family history of breast cancer, personal history of benign breast disease, height at age 25 years, age at menarche, age at menopause, age at first birth, and parity, was 57.3%. These findings suggest that a substantial fraction of postmenopausal breast cancer may be avoided by purposeful changes in lifestyle later in life.

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Int J Cancer. 2008 Aug 15;123(4):942-50.
A hybrid protein comprising ATF domain of pro-UK and VAS, an angiogenesis inhibitor, is a potent candidate for targeted cancer therapy.
Sun Q, Xu Q, Dong X, Cao L, Huang X, Hu Q, Hua ZC.
The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing 210093, People's Republic of China.

Directional and controllable degradation of extracellular matrix mediated by the uPA-uPA receptor (uPAR) system is ubiquitously implicated in tumor establishment, invasion and metastasis. Targeting the excessive activation of this system as well as the proliferation of the tumor vascular endothelial cell would be expected to prevent tumor neovasculature and halt the tumor development. In this study, we created a fusion protein (ALV), comprising the aminoterminal fragment (ATF) of urokinase and VAS, the antiangiogenic functional domain of vasostatin. The antitumor activity of this hybrid molecule was evaluated with both in vitro and in vivo experiments. Cell adhesion and motility assays demonstrated that ALV, owing to its ATF moiety, could interact with uPAR on the tumor cell surface with high affinity and specificity, and thereby might competitively inhibit the plasmin activation by localized urokinase and contribute to the suppression of tumor invasion. These results and speculations were validated by zymography assay and Matrigel invasion assay. In addition, ALV exhibited an improved inhibitory efficacy against endothelial cell (EC) proliferation and capillary vessel formation in a 3D angiogenesis model, proving that ATF and VAS, when fused into a chimeric molecule, cooperatively inhibited angiogenesis by targeting both the interaction of uPA and uPAR on cell surface (by ATF) and EC proliferation (mainly by VAS). Animal model confirmed that, at the same molar dose, ALV produced significantly higher therapeutic benefit than VAS and ATF in terms of tumor growth delay and mice survival prolongation. Conclusively coupling VAS with the uPAR ligand ATF resulted in an improved antineoplastic activity, which may show a novel avenue for the design of tumor therapeutic drugs. (c) 2008 Wiley-Liss, Inc.

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Int J Cancer. 2008 Aug 15;123(4):933-41.
Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy.
Flesch-Janys D, Slanger T, Mutschelknauss E, Kropp S, Obi N, Vettorazzi E, Braendle W, Bastert G, Hentschel S, Berger J, Chang-Claude J.
Department of Medical Biometry and Epidemiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. flesch@uke.uni-hamburg.de

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone- or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose. (c) 2008 Wiley-Liss, Inc.

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Br J Cancer. 2008 Aug 5;99(3):481-7.
[18F]FDG and [18F]FLT uptake in human breast cancer cells in relation to the effects of chemotherapy: an in vitro study.
Direcks WG, Berndsen SC, Proost N, Peters GJ, Balzarini J, Spreeuwenberg MD, Lammertsma AA, Molthoff CF.
Department of Nuclear Medicine & PET Research, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.

Increased 2'-deoxy-2'-[18F]fluoro-D-glucose (FDG) uptake is the most commonly used marker for positron emission tomography in oncology. However, a proliferation tracer such as 3'-deoxy-3'-[18F]fluorothymidine (FLT) might be more specific for cancer. 3'-deoxy-3'-[18F]fluorothymidine uptake is dependent on thymidine kinase 1 (TK) activity, but the effects of chemotherapeutic agents are unknown. The aim of this study was to characterise FDG and FLT uptake mechanisms in vitro before and after exposure to chemotherapeutic agents. The effects of 5-fluorouracil (5-FU), doxorubicin and paclitaxel on FDG and FLT uptake were measured in MDA MB231 human breast cancer cells in relation to cell cycle distribution, expression and enzyme activity of TK-1. At IC50 concentrations, 5-FU resulted in accumulation in the G1 phase, but doxorubicin and paclitaxel induced a G2/M accumulation. Compared with untreated cells, 5-FU and doxorubicin increased TK-1 levels by >300. At 72 h, 5-FU decreased FDG uptake by 50% and FLT uptake by 54%, whereas doxorubicin increased FDG and FLT uptake by 71 and 173%, respectively. Paclitaxel increased FDG uptake with >100% after 48 h, whereas FLT uptake hardly changed. In conclusion, various chemotherapeutic agents, commonly used in the treatment of breast cancer, have different effects on the time course of uptake of both FDG and FLT in vitro. This might have implications for interpretation of clinical findings.

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Br J Cancer. 2008 Aug 5;99(3):428-33.
Target and reality of adjuvant endocrine therapy in postmenopausal patients with invasive breast cancer.
Güth U, Huang DJ, Schötzau A, Zanetti-Dällenbach R, Holzgreve W, Bitzer J, Wight E.
Department of Gynaecology and Obstetrics, University Hospital Basel, Spitalstrasse 21, Basel CH-4031, Switzerland. ugueth@uhbs.ch

Previous research evaluating the use of adjuvant endocrine therapy among postmenopausal breast cancer patients showed with 15-50% wide ranges of non-adherence rates. We evaluated this issue by analysing an unselected study group comprising of 325 postmenopausal women, diagnosed from 1997 to 2003 with hormonal receptor-positive invasive breast cancer. The different clinical situations that led to the discontinuation of adjuvant endocrine therapy were clearly defined and differentiated: non-adherence was not simply the act of stopping medication, but rather the manifestation of an intentional behaviour of the patient. Of the 287 patients who initiated endocrine therapy, 191 (66.6%) fully completed this treatment. Thirty-one patients (10.8%) showed non-adherence to therapy. Patients who had follow-up with a general practitioner, rather than in an oncologic unit, were more likely to be non-adherent (P=0.0088). Of 25 patients who changed medication due to therapy-related adverse effects, 20 (80%) patients fully completed the therapy after drug change. In adjuvant endocrine therapy, a lowering of the non-adherence rate to 10.8%, the lowest reported in the literature, is realistic when patients are cared for by a specialised oncologic unit focusing on the individual needs of the patients.

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Biochem Biophys Res Commun. 2008 Aug 1;372(3):497-502. Epub 2008 May 27.
Luteolin as a glycolysis inhibitor offers superior efficacy and lesser toxicity of doxorubicin in breast cancer cells.
Du GJ, Song ZH, Lin HH, Han XF, Zhang S, Yang YM.
Department of Pharmacology, Pharmaceutical College of Henan University, Jinming District, Kaifeng, Henan 475001, China.

Luteolin (Lu) exhibits a wide spectrum of anti-tumor activities, the present study was to observe whether Lu can sensitize breast cancer cells to doxorubicin (Dox) and to explain the basis underlying this phenomenon. In vitro, Lu at dose less than 100 microM had only slight effect on cells growth and cytotoxicity of Dox in 4T1 and MCF-7 cells under normoxia, but it could reverse tumor resistance to Dox and promote death of tumor cells under hypoxia. In vivo, Lu alone had also no effect on tumor growth delay, however, it could offer superior efficacy and lesser toxicity of Dox in 4T1 and MCF-7 bearing mice. Further study showed that Lu was able to suppress glycolytic flux but did not affect glucose uptake, the P-glycoprotein, anti-oxidative enzymes under hypoxia in vitro, and had not also effect on the intratumor Dox level in vivo. In addition, the activity of SOD and CAT was increased in serum and was decreased in tumor by Lu in vivo. These results suggest that luteolin as a glycolytic inhibitor might be a new adjuvant agent for chemotherapy.

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Eur J Cancer Prev. 2008 Aug;17(4):323-30.
Percutaneous tissue acquisition: a treatment for breast cancer? Vacuum-assisted biopsy devices are not indicated for extended tissue removal.
Cusumano P, Polkowski WP, Liu H, Schulz-Wendtland R, Janssens J.
Breast Clinic, Cliniques St Joseph, Liège, Belgium.

Quite a number of radiologists indicate that complete removal of an imaged lesion in the breast by transdermal tissue acquisition is beneficial for the patient. Although this claim is technologically feasible with the vacuum-assisted biopsy (VAB) devices and, by virtue of a similar technology of aspiration, liposuction, there is no scientific or clinical proof that the extended procedure is indeed valuable for the patient. The optimal treatment of malignant or premalignant lesions remains open surgery with the goal to obtain pathologically free margins whenever possible. Complete removal by imaging is quite different from complete pathological removal. Hence, VAB elimination of suspect or malignant lesions can be considered less optimal and even malpractice in many cases. In addition, there is no evidence that complete removal of benign lesions is good for the patient. When benign lesions can be considered precursors for malignancy, they should be surgically removed as for other premalignant lesions. Most benign lesions can be treated medically as they are usually dispersed in the breast and hormone dependent. The rest of benign breast lesions need removal only to relieve the patient of psychological stress or because of symptoms. Evidence indicates furthermore that increase in cancer risk is related to the number and extent of breast interventions in the past. VAB and other large core biopsy devices remain a useful tool in the diagnosis of breast cancer but not for treatment purposes.

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Hum Genet. 2008 Aug;124(1):31-42. Epub 2008 Jun 25.
Hereditary breast cancer: new genetic developments, new therapeutic avenues.
Campeau PM, Foulkes WD, Tischkowitz MD.
Department of Medical Genetics, McGill University Health Centre, McGill University, Montreal, QC, Canada. philippe.campeau@mail.mcgill.ca

Six genes confer a high risk for developing breast cancer (BRCA1/2, TP53, PTEN, STK11, CDH1). Both BRCA1 and BRCA2 have DNA repair functions, and BRCA1/2 deficient tumors are now being targeted by poly(ADP-ribose) polymerase inhibitors. Other genes conferring an increased risk for breast cancer include ATM, CHEK2, PALB2, BRIP1 and genome-wide association studies have identified lower penetrance alleles including FGFR2, a minor allele of which is associated with breast cancer. We review recent findings related to the function of some of these genes, and discuss how they can be targeted by various drugs. Gaining deeper insights in breast cancer susceptibility will improve our ability to identify those families at increased risk and permit the development of new and more specific therapeutic approaches.

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Cancer Res. 2008 Jul 15;68(14):5878-87.
A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.
Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM.
Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA.

Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive HER2-amplified breast cancer. Some studies suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling.

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J Clin Oncol. 2008 Jul 10;26(20):3426-33.
Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine.
Holmes JP, Benavides LC, Gates JD, Carmichael MG, Hueman MT, Mittendorf EA, Murray JL, Amin A, Craig D, von Hofe E, Ponniah S, Peoples GE.
Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX, 78234, USA.

PURPOSE: HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4(+) T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four-amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients. PATIENTS AND METHODS: The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 microg, 500 microg, 1,000 microg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 microg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [(3)H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790). RESULTS: All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 microg; GM-CSF, 250 microg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36. CONCLUSION: The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu-specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

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J Med Chem. 2008 Jul 10;51(13):3895-904. Epub 2008 Jun 11.
Design, synthesis, and evaluation of novel mutual prodrugs (hybrid drugs) of all-trans-retinoic acid and histone deacetylase inhibitors with enhanced anticancer activities in breast and prostate cancer cells in vitro.
Gediya LK, Khandelwal A, Patel J, Belosay A, Sabnis G, Mehta J, Purushottamachar P, Njar VC.
Department of Pharmacology & Experimental Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, Maryland 21201-1559, USA.

Novel mutual prodrugs (MPs) of ATRA (all- trans-retinoic acid) and HDIs (histone deacetylase inhibitors) ( 10, 13, 17- 19) connected via glycine acyloxyalkyl carbamate linker (AC linker) or through a benzyl ester linker (1,6-elimination linker) were rationally designed and synthesized. Most of our novel MPs were potent inhibitors of growth of several hormone-insensitive/drug resistant breast cancer cell lines and the hormone-insensitive PC-3 prostate cancer cell line. The novel MPs exhibited differential antiproliferative potencies in both MDA-MB-231 and PC-3 cell lines. Whereas 19 (VNLG/124) [4-(butanoyloxymethyl)phenyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 of 10 nM was the most potent MP versus the MDA-MB-231 cells, 13 (VNLG/66) [{ N-[ N-{2-[4-{[3-pyridylmethoxy)carbonyamino]methyl}phenyl) carbonylamino]phenyl} carbamoylcarbamoyloxy}methyl(2 E,4 E,6 E,8 E)-3,7-dimethyl-9-(2,6,6-trimethyl cyclohex-1-enyl)nona-2,4,6,8-tetraenoate] with a GI 50 = 40 nM was the most potent versus the PC-3 cells. MP 19 exhibited the most benefit because its GI 50 of 10 nM versus MDA-MB-231 cells was remarkably 1085-fold lower than that of parent ATRA and over 100000-fold lower than butyric acid (BA).

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N Engl J Med. 2008 Jun 26;358(26):2796-803. Comment in: N Engl J Med. 2008 Jun 26;358(26):2760-3.
Polygenes, risk prediction, and targeted prevention of breast cancer.
Pharoah PD, Antoniou AC, Easton DF, Ponder BA.
Department of Oncology, University of Cambridge, United Kingdom. paul.pharoah@srl.cam.ac.uk

BACKGROUND: New developments in the search for susceptibility alleles in complex disorders provide support for the possibility of a polygenic approach to the prevention and treatment of common diseases. METHODS: We examined the implications, both for individualized disease prevention and for public health policy, of findings concerning the risk of breast cancer that are based on common genetic variation. RESULTS: Our analysis suggests that the risk profile generated by the known, common, moderate-risk alleles does not provide sufficient discrimination to warrant individualized prevention. However, useful risk stratification may be possible in the context of programs for disease prevention in the general population. CONCLUSIONS: The clinical use of single, common, low-penetrance genes is limited, but a few susceptibility alleles may distinguish women who are at high risk for breast cancer from those who are at low risk, particularly in the context of population screening. 2008 Massachusetts Medical Society

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Bull Cancer. 2008 Jun 10;95(5):495-502.
[Dual effects of androgens on mammary gland]
[Article in French]
Brettes JP, Mathelin C.
Service de gynécologie-obstétrique, CHRU, 1, place de l'Hôpital, 67091 Strasbourg.

Androgens have a dual effect on mammary cells. Indeed, they have an influence on mammary cells proliferation thanks to several possible mechanisms, including their transformation into dihydrotestosterone (5alpha-reductase pathway) or into estradiol (aromatase pathway) or their binding to the androgen receptor (AR) and/or to the estrogen receptor (ER). Androgen signaling, using 5alpha-reductase pathway, enables the control of cell proliferation, mediated by AR. So androgen signaling plays a crucial role in breast homeostasis, negating the proliferative effects of estrogen signaling in the breast. When androgens transform into estrogens (aromatase pathway), they increase cell proliferation and mammary carcinogenesis risk. High levels of androgens and estrogens in the serum are associated with increased incidence of postmenopausal breast cancers. Genetic variations in metabolic genes (CYP11, CYP19) and in the AR gene are both involved in dual effects of androgens. Since mammary cells metabolic enzymes vary with time, aging increases the risk of breast cancer induced by estrogens and androgens. In addition, AR function can be perturbed by low doses of synthetic progestin, acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. In the future, the determination of AR expression in infiltrative breast cancer specimens and circulating androgens levels could provide additional information about hormonal dependency and prognosis of breast carcinomas.

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J Clin Oncol. 2008 Jun 10;26(17):2846-53.
"Stemness" genomics law governs clinical behavior of human cancer: implications for decision making in disease management.
Glinsky GV.
Translational & Functional Genomics Laboratory, Ordway Research Institute, Ordway Cancer Center, Center for Medical Science, 150 New Scotland Ave, Albany, NY 12208, USA. gglinsky@ordwayresearch.org

One of the most significant accomplishments of translational oncogenomics is a realistic promise of efficient diagnostic tests that would facilitate implementation of the concept of individualized cancer therapies. Recent discovery of the BMI1 pathway rule indicates that gene expression signatures (GESs) associated with the "stemness" state of a cell might be informative as molecular predictors of cancer therapy outcome. We illustrate a potential clinical utility of this concept using GESs derived from genomic analysis of embryonic stem cells (ESCs) during transition from self-renewing, pluripotent state to differentiated phenotypes. Signatures of multiple stemness pathways (signatures of BMI1, Nanog/Sox2/Oct4, EED, and Suz12 pathways; transposon exclusion zones and ESC pattern 3 signatures; signatures of Polycomb-bound and bivalent chromatin domain transcription factors) seem informative in stratification of cancer patients into low- and high-intensity treatment groups on the basis of prediction of the long-term therapy outcome. A stemness cancer therapy outcome predictor (CTOP) algorithm combining scores of nine stemness signatures outperforms individual signatures and demonstrates a superior prognostic accuracy in retrospective supervised analysis of large cohorts of breast, prostate, lung, and ovarian cancer patients. Our analysis suggests that stemness genomics law governs clinical behavior of human malignancies and defines epigenetic boundaries of therapy-resistant and -sensitive tumors within distinct stemness/differentiation programs. One of the main conclusions of our analysis is that near-term progress in practical implementation of the concept of personalized cancer therapies would depend on timely delivery to practicing physicians of relevant scientific information regarding the outcome of prospective trials validating prognostic performance of CTOP tests in a clinical setting.

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J Clin Oncol. 2008 Jun 10;26(17):2839-45.
Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis.
Eyler CE, Rich JN.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, PO Box 2900, Durham, NC 27710, USA.

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs), or tumor-initiating cells, have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemotherapy and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation- and chemotherapy-induced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/beta-catenin and Notch signaling. Novel targeted therapies against the DNA damage checkpoint or stem-cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are antiangiogenic and vascular targeting agents, which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of antiangiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

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J Clin Oncol. 2008 Jun 10;26(17):2813-20.
Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy.
Kakarala M, Wicha MS.
University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109-5942, USA.

Recent research in breast biology has provided support for the cancer stem-cell hypothesis. Two important components of this hypothesis are that tumors originate in mammary stem or progenitor cells as a result of dysregulation of the normally tightly regulated process of self-renewal. As a result, tumors contain and are driven by a cellular subcomponent that retains key stem-cell properties including self-renewal, which drives tumorigenesis and differentiation that contributes to cellular heterogeneity. Advances in stem-cell technology have led to the identification of stem cells in normal and malignant breast tissue. The study of these stem cells has helped to elucidate the origin of the molecular complexity of human breast cancer. The cancer stem-cell hypothesis has important implications for early detection, prevention, and treatment of breast cancer. Both hereditary and sporadic breast cancers may develop through dysregulation of stem-cell self-renewal pathways. These aberrant stem cells may provide targets for the development of cancer prevention strategies. Furthermore, because breast cancer stem cells may be highly resistant to radiation and chemotherapy, the development of more effective therapies for this disease may require the effective targeting of this cell population.

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J Clin Oncol. 2008 Feb 4 [Epub ahead of print]
Absolute Risk Reductions for Local Recurrence After Postoperative Radiotherapy After Sector Resection for Ductal Carcinoma In Situ of the Breast.
Holmberg L, Garmo H, Granstrand B, Ringberg A, Arnesson LG, Sandelin K, Karlsson P, Anderson H, Emdin S.
Department of Surgical Sciences and Regional Oncologic Center, Uppsala University Hospital, Uppsala; Department of Plastic and Reconstructive Surgery, University Hospital MAS, Malmö; Department of Surgery, University Hospital, Linköping; Department of Surgery, Karolinska University Hospital, Stockholm; Department of Oncology, Sahlgrenska University Hospital, Gothenburg; Department of Cancer Epidemiology, Lund University, Lund; Sweden Department of Surgery, Umeå University Hospital, Umeå, Sweden; and King’s College London, Division of Cancer Studies, London, United Kingdom.

PURPOSE: Evaluate the effects of radiotherapy after sector resection for ductal carcinoma in situ of the breast (DCIS) in patient groups as defined by age, size of the lesion, focality, completeness of excision and mode of detection. PATIENTS AND METHODS: A total of 1,067 women in Sweden were randomly assigned to either postoperative radiotherapy (RT) or control from 1987 to 1999, and 1,046 were followed for a mean of 8 years. The main outcome was new ipsilateral breast cancer events and distant metastasis-free survival analyzed according to intention to treat. RESULTS: There were 64 ipsilateral events in the RT arm and 141 in the control group corresponding to a risk reduction of 16.0 percentage points at 10 years (95% CI, 10.3% to 21.6%) and a relative risk of 0.40 (95% CI, 0.30 to 0.54). There was no statistically significant difference in distant metastasis-free survival. There was an effect modification by age, yielding a low effect of RT in women younger than 50, but substantial protection in women older than 60 years. The age effect was not confounded by focality, lesion size, completeness of excision, or detection mode. There was no group as defined by our stratification variables that had a low risk without radiotherapy. CONCLUSION: Our results indicate that younger women have a low protective effect of conventional RT after sector resection. Older women benefit substantially. We caution that the age effect was seen in a subgroup analysis. Further search with conventional clinical variables for a low risk group that does not need RT does not seem fruitful.

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J Clin Oncol. 2008 Feb 4 [Epub ahead of print]
Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L.
Departments of Breast Medical Oncology, Biostatistics and Applied Mathematics, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Gynecology and Obstetrics, University of Münster, Münster, Germany; Department of Obstetrics and Gynecology, Marseille Public Hospital System, Marseille; and Breast Cancer Unit and Translational Research Unit UPRES03535, Institut Gustave Roussy, Villejuif, France.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

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Cancer Radiother. 2008 Feb 1 [Epub ahead of print]
[Should chest wall irradiation be included after mastectomy and negative node breast cancer?]
[Article in French]
Ben Ammar CN, Kochbati L, Chraeit N, Amrouche A, Gargouri W, Frikha H, Besbes M, Abdallah MB, Maalej M.
Service de radiothérapie-oncologie, institut Salah-Azaiz, boulevard du 9 avril, 1006 Bab-Saadoun, Tunis, Tunisie.

PURPOSE: This study aims to evaluate local failure patterns in node negative breast cancer patients treated with post-mastectomy radiotherapy including internal mammary chain only. PATIENTS AND METHODS: Retrospective analysis of 92 internal or central-breast node-negative tumours with mastectomy and external irradiation of the internal mammary chain at the dose of 50 Gy, from 1994 to 1998. RESULTS: Local recurrence rate was 5 % (five cases). Recurrence sites were the operative scare and chest wall. Factors associated with increased risk of local failure were age </= 40 years and tumour size greater than 20mm, without statistical significance. CONCLUSION: Post-mastectomy radiotherapy should be discussed for a sub-group of node-negative patients with predictors factors of local failure such as age </= 40 years and larger tumour size.

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Cancer Radiother. 2008 Jan 7 [Epub ahead of print]
[How to combine hormonotherapy and radiation treatment in adjuvant breast cancer?]
[Article in French]
Azria D, Ozsahin M, Gligorov J, Zaman K, Llacer Moscardo C, Lemanski C, Jacot W, Belkacémi Y.
Département d’oncologie-radiothérapie, Inserm U860, CRLC Val d’Aurelle–Paul-Lamarque, rue Croix-Verte, 34298 Montpellier cedex 5, France.

Combined radiation and hormone therapies have become common clinical practice in recent years for locally-advanced prostate cancers. The use of such concomitant therapy in the treatment of breast disease has been infrequently reported in the literature, but seems justified given the common hormonal dependence of breast cancer and the potential synergistic effect of these two treatment modalities. As adjuvant therapy, two strategies are used in daily clinical practice: upfront aromatase inhibitors or sequentially after a variable delay of tamoxifen. These molecules may, thus, interact with radiotherapy. Retrospectives studies recently published did not show any differences in terms of locoregional recurrences between concurrent or sequential radiohormonotherapy. Lung and skin fibroses due to concurrent treatment are still under debate. Nevertheless, late side effects appeared to be increased by such a treatment, particularly in hypersensitive patients identified at risk by the lymphocyte predictive test. Concurrent radiohormonotherapy should, thus, be delivered cautiously at least for these patients. This article details the potent advantages and risks of concurrent use of adjuvant hormonotherapy and radiotherapy in localized breast cancers.

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Int J Radiat Oncol Biol Phys. 2008 Jan 28 [Epub ahead of print]
Radiation Use and Long-Term Survival in Breast Cancer Patients with T1, T2 Primary Tumors and One to Three Positive Axillary Lymph Nodes.
Buchholz TA, Woodward WA, Duan Z, Fang S, Oh JL, Tereffe W, Strom EA, Perkins GH, Yu TK, Hunt KK, Meric-Bernstam F, Hortobagyi GN, Giordano SH.
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

BACKGROUND: For patients with Stage II breast cancer with one to three positive lymph nodes, controversy exists about whether radiation as a component of treatment provides a survival benefit. METHODS AND MATERIALS: We analyzed data from patients with Stage II breast cancer with one to three positive lymph nodes diagnosed from 1988-2002 in the Surveillance, Epidemiology, and End Results registry and compared the outcome of 12,693 patients treated with breast-conservation therapy with radiation (BCT + XRT) with the 18,902 patients treated with mastectomy without radiation (MRM w/o XRT). RESULTS: Patients treated with BCT + XRT were younger, were more likely to be treated in recent years of the study period, more commonly had T1 primary tumors, and had fewer involved nodes compared with those treated with MRM w/o XRT (p < 0.001 for all differences). The 15-year breast cancer-specific survival rate for the BCT + XRT group was 80% vs. 72% for the MRM w/o XRT group (p < 0.001). Cox regression analysis showed that MRM w/o XRT was associated with a hazard ratio for breast cancer death of 1.19 (p < 0.001) and for overall death of 1.25 (p < 0.001). The survival benefit in the BCT + XRT group was not limited to subgroups with high-risk disease features. CONCLUSIONS: Radiation use was independently associated with improved survival for patients with Stage II breast cancer with one to three positive lymph nodes. Because multivariate analyses of retrospective data cannot account for all potential biases, these data require confirmation in randomized clinical trials.

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Cancer Treat Rev. 2008 Jan 29 [Epub ahead of print]
Dose-escalation of filgrastim does not improve efficacy: Clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel.
Liu MC, Demetri GD, Berry DA, Norton L, Broadwater G, Robert NJ, Duggan D, Hayes DF, Henderson IC, Lyss A, Hopkins J, Kaufman PA, Marcom PK, Younger J, Lin N, Tkaczuk K, Winer EP, Hudis CA; for the Cancer and Leukemia Group B.
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007-2198, USA.

PURPOSE: To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5mcg/kg/day) in this setting. PATIENTS AND METHODS: Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000mg/m(2)/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175mg/m(2) by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. RESULTS: One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). CONCLUSION: The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.

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Oncology (Williston Park). 2007 Dec;21(14):1727-34; discussion 1737, 1740.
Management of the frail elderly with breast cancer.
Dittus K, Muss HB.
University of Vermont, Hematology Oncology Unit, Burlington, Vermont 05405, USA. kim.dittus@vtmednet.org

By the year 2030 most patients with breast cancer will be aged 65 years or more and many will be frail. Frailty implies diminished physiologic reserve; contributors include diminished organ function, comorbidities, impaired physical function, and geriatric syndromes. Time-efficient tools for assessing frailty are being developed and, once validated, can be used to identify frail cancer patients and help direct therapy. Screening mammography in frail patients is questionable, and a clinical breast exam is likely to identify breast cancers that warrant intervention. Hormonal therapy may be a reasonable primary therapy in older frail women with hormone receptor-positive lesions. For estrogen receptor--and progesterone receptor-negative lesions, excision of the primary tumor may be adequate. Adjuvant hormonal therapy may be appropriate in frail elders with high-risk hormone receptor-positive breast cancer; chemotherapy is rarely indicated regardless of tumor status. The majority of frail elders with metastases will have hormone receptor-positive breast cancers, and endocrine therapy should be considered; those with receptor-negative tumors may be treated with single-agent chemotherapy or supportive care measures. Oncologists need to acquire the skills to appropriately identify frail elders so they select appropriate therapies that will minimize toxicity and maintain quality of life.

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Eur J Cancer. 2007 Nov 20; [Epub ahead of print]
Invasive lobular carcinoma of the breast: Response to hormonal therapy and outcomes.
Rakha EA, El-Sayed ME, Powe DG, Green AR, Habashy H, Grainge MJ, Robertson JF, Blamey R, Gee J, Nicholson RI, Lee AH, Ellis IO.
Department of Histopathology, School of Molecular Medical Sciences, Nottingham University Hospitals NHS Trust, University of Nottingham, Hucknall Road, Nottingham NG5 1PB, UK.

Invasive lobular carcinoma (ILC) comprises approximately 5-15% of breast cancers and appears to have a distinct biology. It is less common than invasive ductal carcinoma (IDC) and few large studies have addressed its biologic characteristics and behaviour with respect to long-term clinical outcome and response to adjuvant therapy. METHODS: This study is based on a large and well-characterised consecutive series of invasive breast carcinomas with a long-term follow-up (up to 25 years). This series included 415 (8%) patients with pure ILC and 2901 (55.7%) with IDC (not otherwise specified) identified from a consecutive cohort of 5680 breast tumours presented to our Breast Unit that were treated in a similar conventional manner. Clinicopathological, therapy and outcome information as well as data on a large panel of biomarkers were available. RESULTS: Compared to IDC, patients with ILC tended to be older and present with tumours which are more frequently lower grade (typically, grade 2 [84%]), hormone-receptor positive (86% compared to 61% in IDC), of larger size, and with the absence of vascular invasion. A higher frequency of ILC was placed in the good Nottingham Prognostic Index group (40% compared to 21% in IDC). ILC showed indolent but progressive behavioural characteristics with nearly linear survival curves which crossed those of IDC after approximately 10years of follow-up, thus eventually exhibiting a worse long-term outcome. Importantly, ILC showed a better response to adjuvant hormonal therapy (HT) with improvement in survival in patients who received HT compared with matched patients with IDC. CONCLUSION: ILC is a distinct entity of breast cancer that responds well to adjuvant HT. These data add important clinical information for assessing the long-term benefits of adjuvant HT use in ILC.

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Expert Rev Anticancer Ther. 2007 Nov;7(11):1651-64.
Progression of endocrine therapies for breast cancer: where are we headed?
Arnedos M, Smith I.
The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. monica.arnedos@rmh.nhs.uk , Breast Unit, The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. ian.smith@rmh.nhs.uk.

Endocrine therapy remains a key part of the management of patients with hormone receptor-positive breast cancer. Tamoxifen has been the gold standard for 25 years and remains a very effective treatment. The third generation aromatase inhibitors (anastrozole, letrozole and exemestane), however, have shown slightly greater efficacy in both metastatic and early breast cancer with a different side-effect profile and no major toxicities identified to date. In premenopausal women, the role of ovarian suppression is being assessed in addition to other therapies. Experimental studies suggest synergy between endocrine therapy and signal transduction inhibitors, and these are being explored in clinical trials. A key question for all forms of endocrine therapy remains optimal duration. Evidence is emerging to suggest that, for some women, treatment should be continued for many years and perhaps lifelong.

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Breast Cancer Res Treat. 2007 Nov 18; [Epub ahead of print]
A retrospective review with long term follow up of 11,400 cases of pure mucinous breast carcinoma.
Di Saverio S, Gutierrez J, Avisar E.
Department of Surgery, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, UM/SCCC 1475 NW 12th Avenue, Rm. 3550, Miami, FL, ZIP 33136, USA, salo75@inwind.it.

Background Pure mucinous breast carcinoma (PMBC) is a rare histologic type of mammary neoplasm. It has been associated with a better short-term prognosis than infiltrating ductal carcinoma (IDC) but identical long-term survival curves have been reported. The value of tumor size for TNM staging has been challenged because of the mucin content of the lesions. This study presents a large PMBC series with 20 years follow up as compared to IDC. The relative significance of a variety of common prognostic factors is calculated for this uncommon histology. Materials and methods A retrospective analysis of all PMBC cases reported in the SEER database between 1973 and 2002 was conducted. Overall survival (OS) and disease specific survival (DSS) were calculated at 5, 10, 15 and 20 years of follow up. Those curves were compared with all the IDC cases reported into the database during the same period. The prognostic significance of gender, race, laterality, age at diagnosis, T and N status, estrogen and progesterone receptors and administration of radiation therapy was calculated by univariate and multivariate analysis. Results There were 11,422 PMBC patients reported. The median age at diagnosis was 71 years (Range 25-85). Fifty three percent of the tumors were well differentiated, 38% were moderately differentiated and the remaining 9% were poorly differentiated or anaplastic. The majority of the tumors were located in the upper outer quadrant (44%) the other 56% were roughly evenly divided between the upper inner, lower inner, lower outer and central quadrants. Eighty six percent of the patients had only localized disease at the time of surgery without nodal or distant disease while 12% had regional nodal involvement and 2% had distant metastases. The PMBC cases showed a better differentiation with lesions of lesser grade and more frequent ER/PR expression, smaller size and lesser nodal involvement when compared to the IDC cases of the same period. Kaplan Meier survival curves revealed a 5 years. breast cancer specific survival rate of 94%. Although slowly decreasing with time, 10, 15 and 20 years survival were 89%, 85% and 81% respectively compared to 82% (5 year), 72% (10 year), 66% (15 year) and 62% (20 year) for IDC. There were no significant differences in overall survival. Multivariate analysis by Cox regression revealed the nodal status (N) to be the most significant prognostic factor followed by age, tumor size (T), progesterone receptors and nuclear grade. Disease specific survival curves stratified for nodal status revealed a highly significant difference between node negative and node positive patients. The addition of radiation therapy after surgery did not significantly improve overall survival. Conclusions This large retrospective comparative analysis confirms the less aggressive behavior of PMBC compared to IDC. This favorable outcome is maintained after 20 years. This tumor presents typically in older patients and is rarely associated with nodal disease. Positive Nodal status appears to be the most significant predictor of worse prognosis.

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J Clin Oncol. 2007 Nov 19; [Epub ahead of print]
Randomized Trial of High-Dose Chemotherapy with Autologous Peripheral-Blood Stem Cell Support Compared with Standard-Dose Chemotherapy in Women with Metastatic Breast Cancer: NCIC MA.16.
Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, Dancey J, O'Reilly S, Shore T, Couban S, Girouard C, Marlin S, Shepherd L, Pritchard KI.
National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada.

PURPOSE: We conducted a multicenter, randomized trial to compare progression-free survival (PFS), overall survival (OS), and quality of life in women with metastatic breast cancer (MBC) receiving high-dose chemotherapy plus autologous stem-cell transplantation (ASCT; HDCT) compared with standard-dose therapy. Patient and METHODS: Between April 1997 and December 2000, 386 women with MBC and no prior chemotherapy for metastatic disease were registered. After initial response to anthracycline- or taxane-based induction chemotherapy, 224 patients were randomly assigned: 112 to high-dose cyclophosphamide, mitoxantrone, and carboplatin chemotherapy and ASCT (HDCT), and 112 to standard therapy (ST). Median age was 47 years (range, 25 to 67 years). Thirty two percent of women randomly assigned had estrogen and progesterone receptor-negative breast cancer, 42% had visceral metastases, and 58% had bone metastases. Complete remission rates before random assignment were 11% for those receiving HDCT and 12% for those receiving ST. RESULTS: After a median follow-up of 48 months, 79 deaths were observed in the HDCT arm and 77 deaths were observed in the ST arm; seven patients (6%) in the HDCT arm died as a result of toxicity. The median OS was 24 months for the HDCT arm (95% CI, 21 to 35 months) and 28 months for ST (95% CI, 22 to 33 months; hazard ratio [HR], 0.9; 95% CI, 0.6 to 1.2; P = .43). PFS was 11 months for HDCT and 9 months for ST (HR, 0.6 in favor of HDCT; 95% CI, 0.5 to 0.9; P = .006). CONCLUSION: HDCT did not improve OS in women with MBC when used as consolidation after response to induction chemotherapy.

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Breast. 2007 Nov 14; [Epub ahead of print]
Completion mastectomy after breast conserving surgery.
O'Donnell ME, Salem A, Badger SA, Sharif MA, Lioe T, Spence RA.
Multidisciplinary Breast Unit, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK.

BACKGROUND: Breast conserving surgery (BCS) is increasingly offered to suitable patients diagnosed with early stage breast cancer. Occasionally the pathological margins on specimens following BCS are positive. The objective of this study is to assess the proportion of patients within our unit who required completion mastectomy after BCS and to determine if predictive factors could be identified to assist the breast surgeon identifying those patients at risk of positive margins following BCS. METHODS: All patients diagnosed with breast cancer between 2001 and 2005 were reviewed. Patients undergoing BCS had their histopathological specimens examined for any evidence of residual tumour at the margins of the resected specimen. These patients then proceeded to completion mastectomy if these margins were positive for residual tumour. Multinominal logistic regression was then performed on clinico-pathological factors for each of these patients to determine if predictive factors existed for determination of residual disease in the mastectomy specimen following BCS. RESULTS: Logistic regression demonstrated that size of the initial tumour was the only significant predictor for the presence of completion mastectomy residual carcinoma (CMRC) (p=0.014) and that tumours with an initial size>2.5cm were 15 times more likely to have a CMRC than tumours <1.5cm. This prediction model based on the initial tumour size had an 89.5% specificity and 52.2% sensitivity. The odds ratio for CMRC based on histological tumour type for each additional 1cm increase in size of the initial tumour was 2.82 for ductal carcinoma in situ, 2.60 for infiltrating ductal carcinoma and 2.26 for other tumours. CONCLUSION: This study demonstrates that residual disease in total mastectomy specimens following BCS increases significantly with increasing original tumour size. With current data, surgeons can inform patients of the risks of residual cancer associated with BCS with a view to increase the rate of primary mastectomies in those patients with presenting tumours greater than 2.5cm.

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Clin Breast Cancer. 2007 Oct;7(10):764-74.
The Use of Taxanes in the Neoadjuvant Treatment of Breast Cancer: A Review of Randomized Phase II/III Trials.
Tusquets I, Estévez LG, Alvarez I, Muñoz M, Adrover E, Albanell J, Rodríguez C, Seguí MA, Rodríguez-Lescure A, Ruiz-Borrego M, García-Mata J, Lluch A.
Hospital del Mar-IMAS, Barcelona, Spain. itusquets@imas.imim.es.

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.

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Clin Breast Cancer. 2007 Oct;7(10):779-83.
Bevacizumab and albumin-bound Paclitaxel treatment in metastatic breast cancer.
Link JS, Waisman JR, Nguyen B, Jacobs CI.
Breastlink Medical Group, Barbara K Robinson Breast Cancer Research Program, Todd Cancer Institute, Long Beach Memorial Medical Center, Long Beach, CA.

Background: Miller et al demonstrated that the combination of bevacizumab and paclitaxel has significant activity in metastatic breast cancer (MBC). Because albumin-bound paclitaxel has been shown to have less toxicity, a better tumor delivery, and possibly better response for MBC, we combined it with bevacizumab to treat women with MBC. Patients and Methods: This is a retrospective analysis. Billing records from March 2005 through December 2006 were reviewed to identify all patients treated with a combination of albumin-bound paclitaxel/bevacizumab. A total of 40 women were identified. They received a minimum of 2 courses. Patients with measurable disease were monitored for response using Response Evaluation Criteria in Solid Tumors. Women with bone-only disease were monitored with positron emission tomography (PET)/computed tomography/magnetic resonance imaging and tumor markers. All response data were confirmed by independent review. Results: Of 33 women with measurable disease, 16 had objective responses to the albumin-bound paclitaxel/bevacizumab regimen (3 complete responses and 13 partial responses) for an overall response rate (ORR) of 48.5%. Median time to progression for responders was 128 days. Another 5 women had stable disease (SD) with a median duration of 135 days. Of 7 patients with bone-only disease, 2 had almost complete resolution of PET activity and 4 had SD (median, 148 days). Toxicity was acceptable with fatigue, neuropathy, pain, and hypertension being the most common complaints. Conclusion: In our limited series of women with advanced, heavily pretreated MBC treated with albumin-bound paclitaxel/bevacizumab, we saw a 48.5% ORR. The regimen was well tolerated. Randomized studies are needed to confirm efficacy and safety of this combination in treating breast cancer.

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Expert Rev Anticancer Ther. 2007 Aug;7(8):1117-1122.
Contralateral prophylactic mastectomy for patients with unilateral breast cancer.
Tuttle T, Habermann E, Abraham A, Emory T, Virnig B.
University of Minnesota, Department of Surgery, Division of Surgical Oncology, 420 Delaware St SE, Minneapolis, MN, USA. tuttl006@umn.edu , Division of Health Policy & Management, University of Minnesota, School of Public Health, 420 Delaware St SE, Minneapolis, MN, USA, University of Minnesota, Department of Surgery, 420 Delaware St SE, Minneapolis, MN, USA, University of Minnesota, Department of Surgery, 420 Delaware St SE, Minneapolis, MN, USA, University of Minnesota, Department Health Policy & Management, 420 Delaware St SE, Minneapolis, MN, USA.

Patients with unilateral breast cancer are at increased risk of developing a second cancer in the contralateral breast. Some women choose contralateral prophylactic mastectomy (CPM) to prevent cancer in the contralateral breast. Several studies have demonstrated that CPM significantly decreases the occurrence of contralateral breast cancer. However, the effectiveness of CPM at reducing breast cancer mortality is not as clear. Moreover, CPM is not risk free and patients may need to undergo additional surgical procedures, especially if reconstruction is performed. Nevertheless, most patients are satisfied with their decision to undergo CPM. Alternatives to CPM include close surveillance with clinical breast examination, mammography and possibly breast magnetic resonance imaging. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces the risk of contralateral breast cancer and may be more acceptable than CPM for some patients. The decision to undergo CPM is complex and many factors likely contribute to its use. Future prospective studies are critically needed to evaluate the decision-making processes leading to CPM.

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Expert Rev Anticancer Ther. 2007 Aug;7(8):1089-94.
The ATAC trial: the vanguard trial for use of aromatase inhibitors in early breast cancer.
Cuzick J.
Cancer Research UK, Centre for Epidemiology, Mathematics & Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London, EC1M 6BQ, UK. jack.cuzick@cancer.org.uk.

The Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial was the first trial to explore the use of aromatase inhibitors in post-menopausal women with early breast cancer and is the largest published cancer treatment trial in breast cancer. The main results have been published at 33-, 47- and 68-month median follow-up, and further analyses are planned for the end of 2007 and in 2010. This trial demonstrated that 5 years of treatment with anastrozole was generally better tolerated than 5 years of treatment with tamoxifen, and led to lower recurrence rates, especially in receptor-positive women (26% reduction). The side-effect profile was different than that for tamoxifen, with fewer hot flushes, gynecologic symptoms, endometrial cancers, strokes and thromboembolic events; however, an increased incidence of fractures, joint symptoms and carpal tunnel syndrome was observed. Future analyses will determine whether benefits and fracture rates persist after stopping treatment, and the extent to which currently marginal benefits on late end points, such as distant recurrence and death after recurrence, are sustained or improved.

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J Eur Acad Dermatol Venereol. 2007 Jul;21(6):771-6.
Impact of cosmetic care on quality of life in breast cancer patients during chemotherapy and radiotherapy: an initial randomized controlled study.
Titeca G, Poot F, Cassart D, Defays B, Pirard D, Comas M, Vereecken P, Verschaevec V, Simon P, Heenen M.
Erasme University Hospital, Free University of Brussels, Belgium, and Notre Dame de Grâce Clinic, Gosselies, Belgium.

Background Breast cancer is the most common cancer in women and therefore represents a major problem in public health. Data from patients' self-report questionnaires provide valuable information about the side-effects that patients may view as having a significantly detrimental impact on their quality of life (QOL) and yet are not always recognized as important by healthcare professionals. Cosmetology is a specific care for patients and there is actually no scientific evidence regarding effects on QOL for women with breast cancer. Objective The purpose of this study is to assess the impact of cosmetic care on QOL in breast cancer patients during chemotherapy and radiotherapy. Methods We developed a prospective, multicentre, randomized, controlled study including 27 patients. All the patients had to fill in a French-validated dermatologic specific quality-of-life questionnaire to compare the QOL of the two groups, the cosmetic group and the control group, at three different times of the adjuvant treatment. Results The results show a statistically significant difference between the cosmetic group and the control group in two areas of QOL: mood state and self-perception of the disease. Conclusion This study emphasizes the interest of cosmetic care in breast cancer patients. However, further larger trials are needed to confirm this study.

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Breast. 2007 Jun 11; [Epub ahead of print]
A nonrandomized follow-up comparison between standard axillary node dissection and sentinel node biopsy in breast cancer.
Konstantiniuk P, Schrenk P, Reitsamer R, Koeberle-Wuehrer R, Tausch C, Roka S, Riedl O, Poestlberger S, Hecke D, Janauer M, Haid A.
University Hospital, Graz, Austria.

INTRODUCTION: In many countries sentinel node biopsy (SNB) has become the standard of care in breast cancer based on a large number of observational studies but without results from prospective randomized trials. The goal of our study was to evaluate the oncological safety of the SNB in breast cancer in a multicenter, nonrandomized setting with comparable groups. PATIENTS AND METHODS: Between 1996/05 and 2004/11, 2942 patients from 14 departments in Austria with unicentric, unilateral, invasive disease without neoadjuvant therapy were collected in a database. The recommendations of the Austrian Sentinel Node Study Group were to complete a training period (phase I) with 50 cases of SNB followed by axillary lymph node dissection (ALND) to prove a detection rate of 90% and a false-negative rate of 5%. In the executing period (phase II), SNB was followed by ALND only if the sentinel node (SN) contained metastases. We compared the results on disease-free survival, local recurrence rates, distant recurrence rates and overall survival of both groups. Cases from phases I and II generated groups I (n=671) and 2 (n=2271 cases), respectively. RESULTS: Overall mean follow-up time: 34.41 months CONCLUSION: SNB followed by ALND only in cases with metastases in the SN is a safe procedure and at least equal to ALND in all cases.

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Invest New Drugs. 2007 Jun 12; [Epub ahead of print]
A phase II clinical trial of ZD1839 (Iressatrade mark) in combination with docetaxel as first-line treatment in patients with advanced breast cancer.
Dennison SK, Jacobs SA, Wilson JW, Seeger J, Cescon TP, Raymond JM, Geyer CE, Wolmark N, Swain SM.
Walter Reed Army Medical Center, 6900 Georgia Ave. NW, Washington, DC, 20307, USA, dennisonsk@mail.nih.gov.

This was a phase II multi-institutional trial to determine the efficacy and tolerability of gefitinib (Iressatrade mark) and docetaxel as first-line treatment in patients with metastatic breast cancer. All patients had histologically confirmed breast cancer with metastatic disease. They were permitted to have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m(2) every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Thirty-three patients were enrolled and received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5-69.2%). There were 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9-57.9%). Four patients had stable disease for >/=24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0-17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (ten patients). Toxicities were mainly attributable to docetaxel, including >/=grade 3 neutropenia in 43% of patients. The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer, with a clinical benefit rate and toxicity profile in the range of that reported for docetaxel alone.

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Bone Marrow Transplant. 2007 Jun 11; [Epub ahead of print]
Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-gamma after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer.
Vahdat LT, Cohen DJ, Zipin D, Lo KS, Donovan D, Savage D, Tiersten A, Nichols G, Troxel A, Hesdorffer CS.
1Weill Medical College of Cornell University, New York, NY, USA.

High-risk primary breast cancer patients treated with high-dose chemotherapy (HDC) and stem cell support (SCS) have shown prolonged disease-free survival (DFS) in many studies; however, only one trial has demonstrated an overall survival benefit (OS). We hypothesize that the period following myeloablative therapy is ideal for immunologic manipulation and studied the effects of two different methods of immunotherapy following HDC with SCS aimed at the window of immune reconstitution. Seventy-two women with high-risk stage II or III breast cancer were randomized following HDC to receive either interleukin 2 (IL-2) at 1 million units/m(2) SQ daily for 28 days or combined cyclosporine A (CsA) at 1.25 mg/kg intravenously daily from day 0 to +28 and interferon gamma (IFN-gamma) 0.025 mg/m(2) SQ every 2 days from day +7 to +28. At a median follow-up of 67 months, no significant difference was observed in DFS or OS between the two treatment groups. The IL-2 arm had a 59% DFS (95% CI (0.45, 0.78)) and a 72% OS (95% CI (0.58, 0.88)) at 5 years. The CsA/INF-gamma arm had a similar outcome with a 55% DFS (95% CI (0.40, 0.76)) and a 78% OS (95% CI (0.65, 0.94)) at 5 years. Treatment was well tolerated, without increased toxicity.Bone Marrow Transplantation advance online publication, 11 June 2007; doi:10.1038/sj.bmt.1705692.

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J Clin Oncol. 2007 Jun 11; [Epub ahead of print]
Improved Overall Survival in Postmenopausal Women With Early Breast Cancer After Anastrozole Initiated After 2 Years of Treatment With Tamoxifen Compared With Continued Tamoxifen: The ARNO 95 Study.
Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G.
J.W. Goethe-University of Frankfurt, Frankfurt am Main; University of Kiel, Kiel; Henriettenstift, Hannover; University of Magdeburg, Magdeburg; and the Institute of Statistics SKM, Wiesbaden, Germany.

PURPOSE: In postmenopausal women with estrogen receptor-positive early breast cancer, surgery is usually followed by a 5-year course of tamoxifen. This report presents results of a prospective, open-label, randomized study, designed to evaluate the benefits of switching to anastrozole after 2 years of tamoxifen treatment, compared with continuing on tamoxifen for 5 years. PATIENTS AND METHODS: After receiving tamoxifen treatment for 2 years, eligible patients (n = 979) were randomly assigned to switch to anastrozole (1 mg/d) or continue tamoxifen (20 or 30 mg/d) for an additional 3 years. Patients were monitored every 6 months during years 1 to 3 and annually thereafter. The primary efficacy variable was disease-free survival, including local or distant recurrence, new contralateral breast cancer, or death. Secondary variables were overall survival and assessment of safety. RESULTS: Switching to anastrozole resulted in a significant reduction in the risk of disease recurrence (hazard ratio [HR], 0.66; 95% CI, 0.44 to 1.00; P = .049), and improved overall survival (HR, 0.53; 95% CI, 0.28 to 0.99; P = .045) compared with continuing on tamoxifen. Fewer patients who switched to anastrozole reported serious adverse events (22.7% v 30.8%) compared with those who continued on tamoxifen, mainly due to more patients in the tamoxifen group with endometrial events. The overall safety profile for anastrozole was consistent with previous reports and no new safety issues were identified. CONCLUSION: Postmenopausal women who have taken tamoxifen for 2 years as adjuvant therapy are less likely to experience a recurrence of breast cancer and have improved overall survival if they switch to anastrozole compared with continuing to receive tamoxifen.

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Eur J Surg Oncol. 2007 Jun 7; [Epub ahead of print]
The role of radiotherapy in treating small early invasive breast cancer.
Varghese P, Gattuso JM, Mostafa AI, Abdel-Rahman AT, Shenton KC, Ryan DA, Jones JL, Wells CA, Mair G, Kakkar AK, Carpenter R.
Breast Unit, St Bartholomew's Hospital, Queen Mary University of London, London, UK.

AIM: The aim of the study was to identify if radiotherapy can be safely avoided in a selected subgroup of largely screening detected small invasive breast cancer. METHODS: One hundred and eighty-eight patients with node negative invasive early breast cancer </=1cm (</=T1b) treated in our centre between 1990 and 2004 were retrospectively followed for local, regional and distant recurrences. Treatment involved adequate local excision by breast conserving surgery (BCS). Axillary staging was performed by a four node axillary sampling until 2000, following which sentinel lymph node sampling was employed. All sections were assessed histologically by haematoxylin and eosin stained sections. The inked margins were reported as being involved, close and clear. Radiotherapy (RT) was employed only if the resected margins were inadequate, and in those with involved axillary nodes who refused further completion axillary clearance. RESULTS: Ninety-four patients (Group A) had BCS alone and 79 patients (Group B) had both BCS and RT. There was no ipsilateral breast tumour recurrence (IBTR) in 88 patients in Group A, corresponding to an actuarial freedom from IBTR of 96%, 91% and 88.1% at 5years, 8years and 9years. In Group B, there was no IBTR in 75 patients corresponding to an actuarial freedom from IBTR of 97%, 94.9% and 90.6% at 5years, 8years and 10years. CONCLUSION: Our experience over 14years has shown that it is possible to safely avoid radiotherapy in a selected subgroup of small invasive breast cancer.

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J Cancer Educ. 2007;22(1):10-14.
Should Menopausal Women at Increased Risk for Breast Cancer Use Tamoxifen, Raloxifene, or Hormone Therapy?: A Framework for Personalized Risk Assessment and Counseling.
Matloff ET, Shannon KM, Moyer A, Col NF.
Cancer Genetic Counseling, Yale Cancer Center/Yale School of Medicine.

Background: Menopausal women with a family history of breast cancer have several treatment options, including tamoxifen, raloxifene, and hormone therapy. This complex decision should be based on each woman's risk to develop breast cancer, menopausal symptoms, preferences, and risks for other conditions. Current models in use do not include pedigree analysis, personalized risk assessment, or genetic testing in this process. Methods: We created a personalized risk assessment and genetic counseling intervention for healthy women with a first-degree relative with breast cancer. Participants were given a personalized risk assessment for breast cancer, heart disease, osteoporosis, and uterine cancer based on family history and personal health data. Counseling Model: The effectiveness of this novel genetic counseling intervention was demonstrated in a randomized trial and these results are published elsewhere. The framework for this counseling model, with case examples from the clinical trial, is outlined in this article. Conclusions: As more menopausal therapies are developed, each with its own risks and benefits, it will become even more critical to have a personalized counseling model for use in this process. Clinicians and educators can utilize the framework presented here for counseling women with a family history of breast cancer.

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Oncology (Williston Park). 2007 May;21(6):673-9; discussion 679-80, 686-7.
What progress have we made in managing inflammatory breast cancer?
Dawood S, Cristofanilli M.
Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Inflammatory breast cancer (IBC) is a rare and aggressive form of the disease. It is diagnosed based on clinical signs of a rapidly enlarging, tender, erythematous, edematous breast that often presents without an underlying breast mass. IBC historically was considered a uniformly fatal disease. With the advent of multimodality treatments including primary systemic chemotherapy, surgery, and radiation therapy, approximately one-third of women diagnosed with IBC will become long-term survivors. This review examines the limitations of the current definition of IBC, explores our current understanding of the biology of IBC, and reviews the many exciting advances in locoregional and systemic treatment of IBC.

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J Clin Oncol. 2007 Feb 12; [Epub ahead of print]
Phase II Study of Neoadjuvant Docetaxel, Vinorelbine, and Trastuzumab Followed by Surgery and Adjuvant Doxorubicin Plus Cyclophosphamide in Women With Human Epidermal Growth Factor Receptor 2-Overexpressing Locally Advanced Breast Cancer.
Limentani SA, Brufsky AM, Erban JK, Jahanzeb M, Lewis D.
Carolinas Hematology-Oncology Associates; The Blumenthal Cancer Center, Charlotte, NC; Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Magee-Womens Hospital, Pittsburgh, PA; Department of Medicine, Tufts-New England Medical Center, Boston, MA; and Division of Hematology-Oncology, University of Tennessee College of Medicine, Memphis, TN.

PURPOSE: To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2) -overexpressing breast cancer. PATIENTS AND METHODS: Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2) administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast. RESULTS: Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). CONCLUSION: With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.

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Cancer. 2007 Feb 12; [Epub ahead of print]
Multidisciplinary frontiers in breast cancer management: a surgeon's perspective.
Singletary SE.
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

The current paradigm of breast cancer management may be altered significantly over the coming years by the adoption of new treatment schema and devices outside of the surgical arena. New advances in breast cancer imaging will improve our ability to detect early-stage disease but also will assist in monitoring treatment outcomes and support the development of nonsurgical ablation techniques. These advances, some already in use, include a 3-dimensional adaptation of digital mammography, color Doppler ultrasonography that can visualize neovascularization in growing tumors, contrast-enhanced magnetic resonance imaging with improved accuracy for the detection of occult cancers, a specialized approach to positron emission tomography designed for use on the breast, and the development of nanoparticle contrast agents that can be visualized with near-infrared light. Systemic therapy, which revolutionized breast cancer management in the last half of the 20th century, is being reconceptualized, with attention turning to adjusting the timing of chemotherapy. Dose-dense regimens are being tested, and there also is interest in so-called metronomic chemotherapy in which very low doses are given on a very frequent schedule, resulting in reduced toxicity and treatment outcomes that reflect an antiangiogenic mode of action. Finally, the possibility of a breast cancer vaccine continues to intrigue and excite physicians and patients alike, with the promise of enlisting the body's own immune system to seek out and destroy cancer cells and/or prevent the development of future disease. It will be important for surgeons to stay aware of all developments that may improve the care of their patients and to be true surgical oncologists rather than merely surgical technicians. Cancer 2007. (c) 2007 American Cancer Society.

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Cancer. 2007 Feb 12; [Epub ahead of print]
Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma : pooled analysis of 2 consecutive trials.
Boccardo F, Rubagotti A, Aldrighetti D, Buzzi F, Cruciani G, Farris A, Mustacchi G, Porpiglia M, Schieppati G, Sismondi P.
University and National Cancer Research Institute, Genoa, Italy.

BACKGROUND: The superiority of new generation aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast carcinoma has emerged from several randomized trials. However, until now not all previous studies have shown a mortality benefit. METHODS: A pooled analysis of 2 prospective multicentric trials, sharing the same study design and nearly identical inclusion criteria, was performed. In both trials, women treated previously with tamoxifen for 2 or 3 years were randomly assigned to either continuing tamoxifen for an additional 2 or 3 years or to having their treatment switched to aminoglutethimide or anastrozole for a comparable time period. Mortality was analyzed according to allocated treatment and other patient and tumor variables. RESULTS: In all, 828 postmenopausal women, mostly with estrogen receptor (ER)-positive and node-positive tumors who had been monitored for a median time of 78 months (range, 6-141 months) were analyzed. Of these women, 415 were randomly selected to continue tamoxifen and 413 switched to aminoglutethimide or anastrozole. All-cause mortality and breast cancer-specific mortality were significantly improved by the switch: all-cause mortality: hazard ratio (HR) = 0.61 (0.42-0.88) P = .007; breast cancer-specific mortality: HR = 0.61 (0.39-0.94) P = .025. No increase was recorded in breast cancer-unrelated mortality in women after switching. Multivariate analysis showed that patient age, tumor size, allocated treatment, and nodal status, in that order, were independent mortality predictors. CONCLUSIONS: Switching to an aromatase inhibitor after 2 or 3 years of tamoxifen therapy significantly improves survival compared with continuing 2 or 3 years of additional tamoxifen treatment. Cancer 2007. (c) 2007 American Cancer Society.

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Ann Surg Oncol. 2007 Feb 13; [Epub ahead of print]
Eighteen Sensations After Breast Cancer Surgery: A 5-Year Comparison of Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection.
Baron RH, Fey JV, Borgen PI, Stempel MM, Hardick KR, Van Zee KJ.
Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York, 10021, USA, baronr@mskcc.org.

BACKGROUND: The aim of this study is to evaluate prevalence, severity, and level of distress of 18 sensations at baseline (3-15 days) and 5 years after breast cancer surgery, and compare sensations after sentinel lymph node biopsy (SLNB) with those after SLNB plus immediate or delayed axillary lymph node dissection (ALND). METHODS: A total of 187 patients with breast cancer completed the Breast Sensation Assessment Scale at baseline and at 3, 6, 12, 24, and 60 months after surgery to assess prevalence, severity, and level of distress of sensations. Of these, 133 had SLNB, and 54 had SLNB and ALND. Additionally, of the 187 patients, 141 had breast-conservation therapy and 46 had total mastectomy. RESULTS: Sensations were less prevalent, severe, and distressing after SLNB compared with ALND at baseline and at 5 years. This difference was most evident in those who had breast-conservation therapy. Most sensations after SLNB and ALND, even if prevalent, were not severe or distressing. Some sensations remained notably prevalent at 5 years, including tenderness and twinges after SLNB, and tightness and numbness after ALND. Phantom sensations were frequently reported by mastectomy patients. CONCLUSIONS: Prevalence, severity, and level of distress of sensations were lower after SLNB compared with ALND, but some morbidity existed after SLNB. Certain sensations remained highly prevalent in both groups for up to 5 years.

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Breast Cancer Res Treat. 2007 Feb 13; [Epub ahead of print]
Racial differences in breast cancer survival in women under age 60.
Sarker M, Jatoi I, Becher H.
Department of Tropical Hygiene and Public Health, University of Heidelberg, INF 324, 69120, Heidelberg, Germany, malabika.sarker@urz.uni-heidelberg.de.

INTRODUCTION: There is a known difference in breast cancer survival between races in the US for which several factors such as social, lifestyle and genetic factors may be relevant. METHOD: This is a retrospective study among women entitled to free treatment in the US department of defense health care system. Within this group, we investigated the temporal trend of absolute survival of 13,793 of White and African American aged 20-59 years and diagnosed between 1980 and 1999 with breast cancer. RESULT: There is a 3% overall improvement in survival in whites which can be explained by an earlier detection, and a two percent decrease in AA with a distinct pattern by age group. In the 40-49 year age group, the survival in white increases from 84.5% in the year 1980-1984 to 87.4 % in the year 1995-1999, in AA we estimate a decrease from 79.7% to 78.5%. When accounting for stage at diagnosis a slight reduction in survival in whites and a strong reduction in AA indicates a significant interaction between race and calendar period. The differences in survival patterns between blacks and whites are mainly caused by breast cancer and not by other causes. CONCLUSION: The gap in survival which strongly increased with calendar period cannot be explained by unequal access to health care. Possible explanations include a lower participation of early detection programs for breast cancer in AA and an increasing prevalence of obesity over time which is more pronounced in AA than in whites.

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Ann Oncol. 2007 Feb 10; [Epub ahead of print]
Inclusion of taxanes, particularly weekly paclitaxel, in preoperative chemotherapy improves pathologic complete response rate in estrogen receptor-positive breast cancers.
Mazouni C, Kau SW, Frye D, Andre F, Kuerer H, Buchholz T, Symmans W, Anderson K, Hess K, Gonzalez-Angulo A, Hortobagyi G, Buzdar A, Pusztai L.
Department of Breast Medical Oncology.

BACKGROUND: We examined if inclusion of a taxane and more prolonged preoperative chemotherapy improves pathologic complete response (pCR) rate in estrogen receptor (ER)-positive breast cancer compared with three to four courses of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC). PATIENTS AND METHODS: Pooled analysis of results from seven consecutive neo-adjuvant chemotherapy trials including 1079 patients was carried out. These studies were conducted at MD Anderson Cancer Center from 1974 to 2001. Four hundred and twenty-six (39.5%) patients received taxane-based neo-adjuvant therapy. pCR rates and survival times were analyzed as a function of chemotherapy regimen and ER status. Multivariate logistic and Cox regression analysis were carried out to identify variables associated with pCR and survival. RESULTS: Patients with ER-negative cancer had higher overall pCR rate than patients with ER-positive tumors (20.1% versus 4.9%, P < 0.001). In ER-negative patients, the pCR rates were 29% and 15% with and without a taxane (P < 0.001). In ER-positive patients, the pCR rates were 8.8% and 2.0% with and without a taxane (P < 0.001). In multivariate analysis, clinical tumor size (P < 0.001), ER-negative status (P < 0.001) and inclusion of a taxane (P = 0.01) were independently associated with pCR. For patients with pCR, survival was similar regardless of ER status or the type of regimen that induced pCR. CONCLUSION: pCR rates increased for patients with both ER-positive and ER-negative tumors as regimens started to include a taxane and became longer. This indicates that a subset of patients with ER-positive breast cancer benefits from more aggressive chemotherapy, similarly to patients with ER-negative tumors.

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Med Oncol. 2006;23(4):479-88.
Adjuvant Dose-Dense Sequential Chemotherapy with Epirubicin, CMF, and Weekly Docetaxel Is Feasible and Safe in Patients with Operable Breast Cancer.
Fountzilas G, Pectasides D, Christodoulou C, Timotheadou E, Economopoulos T, Papakostas P, Papadimitriou C, Gogas H, Efstratiou I, Skarlos D.
"Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.

Currently, randomized phase III trials have demonstrated that docetaxel is an effective strategy in the adjuvant treatment of breast cancer. However, previous attempts to incorporate docetaxel with an anthracycline in a dosedense regimen have been unsuccessful. Therefore, new schedules containing both drugs should be explored. Forty-four patients with high-risk operable breast cancer entered this feasibility study. They were treated with three cycles of epirubicin 110 mg/m2 every 2 wk with G-CSF followed by three cycles of "intensified" CMF (840 mg/m2 cyclophosphamide; 57 mg/m2 methotrexate; 840 mg/m2 fluorouracil) every 2 wk with G-CSF followed 3 wk later by nine weekly cycles of 35 mg/m2 docetaxel (E-CMF-doc). Totally, 39 patients (89%) received all cycles of chemotherapy. The vast majority (92%) of cycles were administered at full dose. Therefore, dose intensity was sufficiently maintained for all drugs. Toxicity was generally mild to moderate. Most frequently recorded side effects apart from alopecia were neutropenia (54%) and nausea/vomiting (89%). Infection developed in nine patients. Two cases of febrile neutropenia were reported. The E-CMF-doc regimen, as used in this study, is feasible and well tolerated. Its impact on survival should be evaluated in phase III trials.
  
Previous Breast Cancer Research: 2002-2006   
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