Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers
ABSTRACT There have been no studies to date which look at the relative effectiveness of different regimens of chemotherapy in women who have breast cancer and who carry a BRCA1 germ-line mutation. We wished to compare rates of response to neo-adjuvant chemotherapy in BRCA1 mutation carriers and non-carrier controls.
From a registry of 3,479 patients, we identified 44 Polish women who carried a BRCA1 founder mutation and who had been treated with neo-adjuvant chemotherapy for breast cancer, and 41 age- and hospital-matched controls.
35 of the 44 BRCA1 mutation carriers (80%) experienced a partial or complete response to neo-adjuvant chemotherapy, compared to 39 of the 41 (95%) non-carriers (P=0.05). In the hereditary subgroup, response rates differed depending on whether or not a taxane (docetaxel) was given. Six of the 15 BRCA1 carrier women given docetaxel with doxorubicin responded (complete or partial), compared to 29 of 29 given other (DNA-damaging) therapies (P=0.001). Among the non-carriers, the rates of response to the two categories of chemotherapy were similar.
Breast cancers among BRCA1 carriers frequently do not exhibit sensitivity to docetaxel in the neo-adjuvant setting. It is likely that normal BRCA1 is required for clinical response to mitotic spindle poisons.
- SourceAvailable from: Richard D Kennedy
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- "A further explanation may be that even low levels of BRCA1 are sufficient to mediate response to taxanes and perhaps reduced taxane response is confined to patients with complete BRCA1 dysfunction. In support of this, two small studies in hereditary breast cancer have reported resistance to neo-adjuvant taxane based chemotherapy in patients with germline BRCA1 mutations  . Another point to consider is the potential dose dependent effects that may occur when both platinums and taxanes are administered in combination. "
ABSTRACT: We investigated the relationship between BRCA1 protein expression by immunohistochemistry (IHC) and clinical outcome following platinum and platinum/taxane chemotherapy in sporadic epithelial ovarian cancer (EOC). BRCA1 IHC was performed on a cohort of 292 ovarian tumours from two UK oncology centres. BRCA1 protein expression levels were correlated with overall survival (OS), progression free survival (PFS) and clinical response to chemotherapy by multivariate analysis. EOC patients with absent/low BRCA1 protein expression (41%) had a better chance of clinical response following chemotherapy as compared to patients with high BRCA1 expression (odds ratio 2.47: 95%CI 1.10-5.55, p=0.029). Patients with absent/low BRCA1 had a higher probability of clinical response following single agent platinum compared to high BRCA1 expressing patients (68.5% vs. 46.8%), while addition of a taxane increased response rates independent of BRCA1. Overall, patients with absent/low BRCA1 had a better clinical outcome compared to patients with high BRCA1 protein expression in terms of both OS (HR=0.65: 95%CI 0.48-0.88, p=0.006) and PFS (HR=0.74, 95%CI 0.55-0.98, p=0.040). We confirm that absent/low BRCA1 protein expression is a favourable prognostic marker. However, we also provide the first evidence that absent/low BRCA1 protein expression in sporadic EOC patients predicts for an improved clinical response to chemotherapy.Gynecologic Oncology 09/2011; 123(3):492-8. DOI:10.1016/j.ygyno.2011.08.017 · 3.69 Impact Factor
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- "Breast cancers of BRCA1 mutation carriers frequently show poor responses to neoadjuvant therapy with docetaxel, whereas platinum-based chemotherapy seems to be highly effective (Byrski et al, 2008, 2009). Similarly, BRCA1/2 mutation carriers with ovarian cancer show higher response rates and longer overall survival after platinum-based chemotherapy than nonhereditary patients (Ben David et al, 2002; Tan et al, 2008). "
ABSTRACT: A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions.British Journal of Cancer 11/2009; 101(10):1651-7. DOI:10.1038/sj.bjc.6605350 · 4.82 Impact Factor
Article: Molecular diagnosis in oncology[Show abstract] [Hide abstract]
ABSTRACT: Recent advances of molecular genetics have exerted a noticeable effect on some areas of clinical medicine. A comprehensive understanding of the nature of hereditary tumors is frequently heralded as the most substantial practical achievement of molecular oncology. Proper diagnostic algorithms have already been developed for the vast majority of known familial cancer syndromes. Interestingly, an unexpectedly strong founder effect has been documented at least for some hereditary cancers occurring in Russia, which significantly simplifies the detection of the corresponding disease-associated gene variants. The number of tests aimed at customizing cancer treatment continues to grow every year. The EGFR mutation test is probably the most impressive one, as it predicts the lung cancer response or nonresponse to gefitinib or erlotinib with a really unprecedented accuracy. Approaches helping to determine the individual efficacy and safety profiles for fluoropyrimidines, platinum compounds, irinotecan, etc. are currently under development. Methods detecting residual amounts of disseminated cancer cells represent another popular avenue of research. These technologies are expected to improve the quality of prediction of local and distant metastases, facilitate monitoring of the minimal residual disease, and, in the long-term perspective, provide a tool for early cancer diagnosis. It should be emphasized that molecular detection of disseminated tumor cells is currently used mainly in research settings and is not yet incorporated into routine clinical practice.Molecular Biology 10/2008; 42(5):687-698. DOI:10.1134/S0026893308050063 · 0.74 Impact Factor