Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling.

BACKGROUND: Triple negative breast cancer (TNBC) is characterized by lack of expression of both estrogen and progesterone receptor as well as lack of overexpression or amplification of HER2. Despite an increased probability of response to chemotherapy, many patients resistant to current chemotherapy regimens suffer from a worse prognosis compared to other breast cancer subtypes. However, molecular determinants of response to chemotherapy specific to TNBC remain largely unknown. Thus, there is a high demand for biomarkers potentially stratifying triple negative breast cancer patients for neoadjuvant chemotherapies or alternative therapies. METHODS: In order to identify genes correlating with both the triple negative breast cancer subtype as well as response to neoadjuvant chemotherapy we employed publicly available gene expression profiles of patients, which had received neoadjuvant chemotherapy. Analysis of tissue microarrays as well as breast cancer cell lines revealed correlation to the triple negative breast cancer subtype. Subsequently, effects of siRNA-mediated knockdown on response to standard chemotherapeutic agents as well as radiation therapy were analyzed. Additionally, we evaluated the molecular mechanisms by which SFRP1 alters the carcinogenic properties of breast cancer cells. RESULTS: SFRP1 was identified as being significantly overexpressed in TNBC compared to other breast cancer subtypes. Additionally, SFRP1 expression is significantly correlated with an increased probability of positive response to neoadjuvant chemotherapy. Knockdown of SFRP1 in triple negative breast cancer cells renders the cells more resistant to standard chemotherapy. Moreover, tumorigenic properties of the cells are modified by knockdown, as shown by both migration or invasion capacity as well reduced apoptotic events. Surprisingly, we found that these effects do not rely on Wnt signaling. Furthermore, we show that pro-apoptotic as well as migratory pathways are differentially regulated after SFRP1 knockdown. CONCLUSION: We could firstly show that SFRP1 strongly correlates with the triple negative breast cancer subtype and secondly, that SFRP1 might be used as a marker stratifying patients to positively respond to neoadjuvant chemotherapy. The mechanisms by which tumor suppressor SFRP1 influences carcinogenic properties of cancer cells do not rely on Wnt signaling, thereby demonstrating the complexity of tumor associated signaling pathways.

Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer.

PURPOSE: Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. PATIENTS AND METHODS: Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). RESULTS: A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. CONCLUSION: The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.

Genomic grade index is associated with response to chemotherapy in patients with breast cancer.

PURPOSE The genomic grade index (GGI) is a 97-gene measure of histological tumor grade. High GGI is associated with decreased relapse-free survival in patients receiving either endocrine or no systemic adjuvant therapy. Herein we examined whether GGI predicts pathologic response to neoadjuvant chemotherapy in patients with HER-2-normal breast cancer. METHODS Gene expression data (gene chips) was generated from fine-needle aspiration biopsies (n = 229) prospectively collected before neoadjuvant paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. Pathologic response was quantified using the residual cancer burden (RCB) method. The association between the GGI and pathologic response was assessed in univariate and multivariate analyses. The performance of a response predictor combining clinical variables and GGI was evaluated under cross-validation. Results Eighty-five percent of grade 1 tumors had low GGI, 89% of grade 3 tumors had high GGI, and 63% of grade 2 tumors had low GGI. Among both estrogen receptor (ER)-positive and -negative cancers, high GGI score was associated with pathologic complete response (RCB-0) or minimal residual disease (RCB-1). A multivariate model combining GGI and clinical parameters had an overall accuracy of 71%, compared with 58% for the GGI alone, for prediction of pathologic response. However, high GGI score was also associated with significantly worse distant relapse-free survival in patients with ER-positive cancer (P = .005), and was not associated with survival in patients with ER-negative cancer. CONCLUSION High GGI is associated with increased sensitivity to neoadjuvant paclitaxel plus fluorouracil, adriamycin, and cyclophosphamide chemotherapy in both ER-negative and ER-positive patients, but it remains a predictor of worse survival in ER-positive patients.

Evaluation of biological pathways involved in chemotherapy response in breast cancer.

INTRODUCTION: Our goal was to examine the association between biological pathways and response to chemotherapy in estrogen receptor-positive (ER+) and ER-negative (ER-) breast tumors separately. METHODS: Gene set enrichment analysis including 852 predefined gene sets was applied to gene expression data from 51 ER- and 82 ER+ breast tumors that were all treated with a preoperative paclitaxel, 5-fluoruracil, doxorubicin, and cyclophosphamide chemotherapy. RESULTS: Twenty-seven (53%) ER- and 7 (9%) ER+ patients had pathologic complete response (pCR) to therapy. Among the ER- tumors, a proliferation gene signature (false discovery rate [FDR] q = 0.1), the genomic grade index (FDR q = 0.044), and the E2F3 pathway signature (FDR q = 0.22, P = 0.07) were enriched in the pCR group. Among the ER+ tumors, the proliferation signature (FDR q = 0.001) and the genomic grade index (FDR q = 0.015) were also significantly enriched in cases with pCR. Ki67 expression, as single gene marker of proliferation, did not provide the same information as the entire proliferation signature. An ER-associated gene set (FDR q = 0.03) and a mutant p53 gene signature (FDR q = 0.0019) were enriched in ER+ tumors with residual cancer. CONCLUSION: Proliferation- and genomic grade-related gene signatures are associated with chemotherapy sensitivity in both ER- and ER+ breast tumors. Genes involved in the E2F3 pathway are associated with chemotherapy sensitivity among ER- tumors. The mutant p53 signature and expression of ER-related genes were associated with lower sensitivity to chemotherapy in ER+ breast tumors only.