Triple-Negative Breast Cancer: An Update on Neoadjuvant Clinical Trials

Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC

Biology, Metastatic Patterns, and Treatment of Patients with Triple-Negative Breast Cancer

Of the estimated 1 million cases of breast cancer diagnosed annually worldwide, it is estimated that over 170,000 will harbor the triple-negative (estrogen receptor/progesterone receptor/HER2–negative) phenotype. Most, though not all, triple-negative breast cancers will be basal-like on gene expression micorarrays. The basal-like molecular subtype exhibits a unique molecular profile and set of risk factors, aggressive and early pattern of metastasis, limited treatment options, and poor prognosis. Large population-based studies have identified a higher proportion of triple-negative breast tumors among premenopausal African American women, and a suggestion that increased parity, younger age at first-term pregnancy, shorter duration of breast feeding, and elevated hip-to-waist ratio might be particular risk factors. When BRCA1 mutation carriers develop breast cancer, it is usually basal-like; given the central role of BRCA1 in DNA repair, this could have profound therapeutic implications. When diagnosed, triple-negative breast cancers illustrate preferential relapse in visceral organs, including the central nervous system. Although initial response to chemotherapy might be more profound, relapse is early and common among triple-negative breast cancers compared with luminal breast cancers. The armamentarium of “targeted therapeutics” for triple-negative breast cancer is evolving and includes strategies to inhibit angiogenesis, epidermal growth factor receptor, and other kinases. Finally, the positive association between triple-negative breast cancer and BRCA mutations makes inhibition of poly(adenosine diphosphate-ribose) polymerase–1 an attractive therapeutic strategy that is in active study

The management of early-stage and metastatic triple-negative breast cancer: A review

Triple negative breast cancer (TNBC) defined as lacking expression of the estrogen receptor, progesterone receptor and HER2, comprises approximately 15% of incident breast cancers and is over-represented among those with metastatic disease. It is increasingly clear that TNBC is heterogeneous and that there are several biologically distinct subtypes within TNBC, in particular the basal-like subtype but also the claudin-low, among others. While the incidence of BRCA mutations across all subsets of breast cancer is quite low (~5%), BRCA mutations are more common among those with TNBC (~20%) and may have therapeutic implications. The general principles guiding the use of chemotherapy and radiation therapy do not differ dramatically between early stage TNBC and non-TNBC. There is a trend, however, to treat TNBC at a lower stage with chemotherapy as this is the only way to systemically reduce recurrence risk. In the metastatic setting, while cytotoxic chemotherapy is the mainstay of treatment for advanced TNBC, there are many promising targeted therapies in development in both the preclinical and early phase clinical trial settings. While the treatment of TNBC remains a challenge, coordinated efforts between clinician/scientist partnerships providing a comprehensive understanding of TNBC genomic, proteomic and other biologic processes may result in individualized therapy for TNBC faster than other subtypes -- driven by both the heterogeneity we know exists within this clinical entity and the intense need for improved treatment

Gravity vs radiation model: on the importance of scale and heterogeneity in commuting flows

We test the recently introduced radiation model against the gravity model for the system composed of England and Wales, both for commuting patterns and for public transportation flows. The analysis is performed both at macroscopic scales, i.e. at the national scale, and at microscopic scales, i.e. at the city level. It is shown that the thermodynamic limit assumption for the original radiation model significantly underestimates the commuting flows for large cities. We then generalize the radiation model, introducing the correct normalisation factor for finite systems. We show that even if the gravity model has a better overall performance the parameter-free radiation model gives competitive results, especially for large scales.Comment: in press Phys. Rev. E, 201

Stratifying triple-negative breast cancer: which definition(s) to use?

Triple-negative breast cancers (TNBC) have increased rates of pathologic complete response following neoadjuvant chemotherapy, yet have poorer prognosis compared with non-TNBC. Known as the triple-negative paradox, this highlights the need to dissect the biologic and clinical heterogeneity within TNBC. In the present issue, Keam and colleagues suggest two subgroups of TNBC exist based on the proliferation-related marker Ki-67, each with differential response and prognosis following neoadjuvant chemotherapy. To place results into context, we review several definitions available under the TNBC umbrella that may stratify TNBC into clinically relevant subgroups

Breast Cancer Before Age 40 Years

Approximately 7% of women with breast cancer are diagnosed before the age of 40 years, and this disease accounts for more than 40% of all cancer in women in this age group. Survival rates are worse when compared to those in older women, and multivariate analysis has shown younger age to be an independent predictor of adverse outcome. Inherited syndromes, specifically BRCA1 and BRCA2, must be considered when developing treatment algorithms for younger women. Chemotherapy, endocrine, and local therapies have the potential to significantly impact both the physiologic health—including future fertility, premature menopause, and bone health—and the psychological health of young women as they face a diagnosis of breast cancer

Endocrine therapy and urogenital outcomes among women with a breast cancer diagnosis

Endocrine therapy for breast cancer can exacerbate menopausal symptoms. The association between endocrine therapy and common pelvic floor disorders including urinary incontinence has rarely been evaluated. We examined urogenital and sexual side effects among women with a breast cancer diagnosis, comparing endocrine therapy users to nonusers

Multidisciplinary Management of Breast Cancer During Pregnancy

Although breast cancer during pregnancy (BCDP) is rare (occurring with only 0.4% of all BC diagnoses in female patients aged 16–49 years), management decisions are challenging to both the patient and the multidisciplinary team

Race, response to chemotherapy, and outcome within clinical breast cancer subtypes

The effect of race on breast cancer outcome is confounded by tumor and treatment heterogeneity. We examined a cohort of women with stage II–III breast cancer treated uniformly with neoadjuvant chemotherapy to identify factors associated with racial differences in chemotherapeutic response and long-term survival. Using a prospective database, we identified women with stage II-III breast cancer treated with neoadjuvant chemotherapy from 1998 to 2011. Race was categorized as African-American (AA) or non-AA. Preplanned subtype analyses were stratified by hormone receptor (HR) and HER2. Pathologic response to chemotherapy (pCR), time to recurrence (TTR), and overall survival (OS) were assessed using logistic regression, Kaplan–Meier method, and Cox proportional hazards regression analyses. Of 349 women identified, 102 (29 %) were AA, who were younger (p = 0.03), more obese (p < 0.001), and less likely to have HR+/HER2–tumors (p = 0.01). No significant differences in pCR rate by race were found. At median follow-up of 6.5 years, AA had worse TTR (hazard ratio 1.51, 95 % CI 1.02–2.24), which was attenuated in multivariable modeling, and there was no significant difference in OS. When stratified by HR, worse outcomes were limited to HR+AA (TTR hazard ratio 1.85, 95 % CI 1.09–3.14; OS hazard ratio 2.42 95 % CI 1.37–4.28), which remained significant in multivariable analysis including pCR rate and BMI. With long-term follow-up, racial disparity in outcome was limited to HR+ breast cancer, with no apparent contribution of chemotherapy sensitivity. This suggests that disparity root causes may be driven by HR+ factors such as unmeasured molecular differences, endocrine therapy sensitivity, or adherence