BRCA1 protein levels and PIK3CA mutations as predictive biomarkers for response to neoadjuvant chemotherapy in locally advanced breast cancer: An exploratory analysis

Abstract

Abstract. BRCA1 overexpression and phosphoinositide 3-kinase (PIK3CA) pathway activation are involved in the resistance to DNA damaging agents. Thus, we hypothesized that BRCA1 protein expression and activating PIK3CA mutations are potential tumor biomarkers for the chemotherapeutic response to doxorubicin/cyclophosphamide plus docetaxel in locally advanced breast cancer. Informed consent was obtained and clinical, pathological and response data were collected. BRCA1 protein expression levels were assessed by immunohistochemistry of the archived tissue by two independent pathologists. The PIK3CA mutation status was assessed by nested PCR amplification and DNA sequencing. BRCA1 protein levels and the PIK3CA mutation status were correlated with pathological complete response and a partial response or better using the Chi-square test, Fisher's exact test and logistic regression. Of the 136 eligible participants, 59 samples could be analyzed. There was a trend of relatively low levels of BRCA1 protein achieving a pathological complete response (pCR), although this was not statistically significant [odds ratio (OR)=1.74; p=0.437]. Twenty-eight percent of patients had PIK3CA mutations, but no statistically significant association with pCR (OR= 0.977; p= 0.971) was noted. Neither BRCA1 protein levels (OR=1.18; p=0.818) nor PIK3CA mutations (OR=1.03; p=0.971) appeared to be associated with the likelihood of achieving a partial response or better from neoadjuvant chemotherapy. PIK3CA wild-type mutation status showed a trend towards an increased likelihood of not presenting with inflammatory disease (OR=5.34; p=0.101). In this exploratory study, neither BRCA1 protein expression levels nor the presence of PIK3CA mutations were significantly associated with chemotherapy response in locally advanced breast cancer. However, the relatively small sample size limits the overall interpretation.

The Dual Pathway Inhibitor Rigosertib Is Effective in Direct Patient Tumor Xenografts of Head and Neck Squamous Cell Carcinomas

“…In accordance with published data, our lab has identified genomic alterations of PI3K occurring in 20% of our tumor lines generally, and in 40% of HPV-positive tumors (16, 43). Furthermore, several studies have evaluated the predictive correlation of common PI3K aberrations and drug specific treatment outcome (44–46). The established importance of PI3K, as not only a therapeutic target but also a predictive biomarker, confers the relevance of a multifaceted focus on this pathway in the field of head and neck oncology.…”

Predictive value of BRCA1/2 mRNA expression for response to neoadjuvant chemotherapy in BRCA‐negative breast cancers

“…Previous studies reported the association between BRCA1 and BRCA2 expression and response to chemotherapy; however, the results shown were less consistent . Some clinical data suggested that tumors with low BRCA1 or BRCA2 mRNA expression responded better to DNA‐damaging chemotherapy, whereas some showed no relationship between BRCA1 or BRCA2 expression and chemotherapy sensitivity . However, the sample size of previous studies was relatively small.…”

“…[26][27][28] Some clinical data suggested that tumors with low BRCA1 or BRCA2 mRNA expression responded better to DNA-damaging chemotherapy, [27][28][29] whereas some showed no relationship between BRCA1 or BRCA2 expression and chemotherapy sensitivity. 28,30 However, the sample size of previous studies was relatively small. Moreover, the previous studies did not take the BRCA1/2 germline mutations into consideration when investigating the relationship between mRNA expression level of BRCA1/2 and response to neoadjuvant chemotherapy, as BRCA1 germline mutations may affect the response to some chemotherapy drugs.…”

Candidate Markers That Associate with Chemotherapy Resistance in Breast Cancer through the Study on Taxotere-Induced Damage to Tumor Microenvironment and Gene Expression Profiling of Carcinoma-Associated Fibroblasts (CAFs)

“…However, the resistance of tumor cells to a broad range of chemotherapeutic drugs and lack of useful predictive markers of response to NAC continue to be problems [21], [22], [23]. Though the precise nature and molecular mechanism of chemotherapy resistance is still unclear, many current studies have focused on identifying novel predictors of chemotherapy efficiency [24], [25]. CAFs merit attention, in consideration of frequent association with chemotherapy resistance.…”