Somatic Mutation Profiling and Trastuzumab in Breast Cancer
Somatic Mutation Profiling and Trastuzumab in Breast Cancer
Background Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.
Methods The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
Results Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (Pinteraction: DDFS P = .14; OS P = .24).
Conclusions In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
Gene expression profiling divides breast cancer into distinct molecular portraits according to the presence of the estrogen receptor (ER) and amplification/overexpression of the ERBB2/HER2/neu oncogene. Notably, HER2 amplification/overexpression (HER2-positive) predicts response to anti-HER2 therapy, suggesting that somatic alterations in breast cancer are associated with prognosis and potentially amenable to targeted therapy. This has inspired efforts to better understand the spectrum of somatic "driver" mutations and, in particular, targetable mutated kinases.
An abundance of data suggests that genetic aberrations and activation of the phosphatidylinositol 3-kinase (PI3K) pathway are important in determining breast cancer prognosis and the efficacy of standard chemo- and endocrine therapies. Furthermore, mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of the class IA PI3K, are frequent in breast cancer. These mutations have been shown to be oncogenic in mammary epithelial cells by driving constitutive, growth factor–independent PI3K pathway activation.
Despite being the focus of intense research interest, a clear association between PIK3CA mutations and a poorer prognosis has not been shown. To the contrary, PIK3CA mutations have been associated with statistically significantly better survival when compared with PIK3CA wild-type breast cancers in larger series obtained from single institutions. An association with resistance to endocrine therapy has also not been demonstrated.PIK3CA mutations have also been shown to be associated with trastuzumab resistance in preclinical models overexpressing HER2. Clinical validation of this association could have important clinical utility given the emergence of a broadening array of anti-HER2 agents and the concept of dual anti-HER2 therapy. Hence, given their frequency, oncogenic capabilities, and the potential to induce resistance to commonly prescribed breast cancer treatments, the clinical relevance of PIK3CA mutations deserves further clarification.
High levels of evidence on the clinical utility of prognostic and predictive biomarkers can be achieved from the use of archived tumor specimens from appropriate randomized clinical trial datasets. Therefore, the main purpose of this study was to clarify in a well-characterized, randomized clinical trial dataset the predictive relevance of PIK3CA mutations to trastuzumab efficacy and its prognostic abilities in both HER2-positive and HER2-negative disease. Given that PIK3CA genotyping can be performed with other somatic hotspot mutations, we also set out to determine prevalence and prognostic associations of other known cancer driver mutations. Our objective was to identify other potentially targetable genetic alterations that contribute to resistance to standard therapy in breast cancer.
Abstract and Introduction
Abstract
Background Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.
Methods The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
Results Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (Pinteraction: DDFS P = .14; OS P = .24).
Conclusions In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
Introduction
Gene expression profiling divides breast cancer into distinct molecular portraits according to the presence of the estrogen receptor (ER) and amplification/overexpression of the ERBB2/HER2/neu oncogene. Notably, HER2 amplification/overexpression (HER2-positive) predicts response to anti-HER2 therapy, suggesting that somatic alterations in breast cancer are associated with prognosis and potentially amenable to targeted therapy. This has inspired efforts to better understand the spectrum of somatic "driver" mutations and, in particular, targetable mutated kinases.
An abundance of data suggests that genetic aberrations and activation of the phosphatidylinositol 3-kinase (PI3K) pathway are important in determining breast cancer prognosis and the efficacy of standard chemo- and endocrine therapies. Furthermore, mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of the class IA PI3K, are frequent in breast cancer. These mutations have been shown to be oncogenic in mammary epithelial cells by driving constitutive, growth factor–independent PI3K pathway activation.
Despite being the focus of intense research interest, a clear association between PIK3CA mutations and a poorer prognosis has not been shown. To the contrary, PIK3CA mutations have been associated with statistically significantly better survival when compared with PIK3CA wild-type breast cancers in larger series obtained from single institutions. An association with resistance to endocrine therapy has also not been demonstrated.PIK3CA mutations have also been shown to be associated with trastuzumab resistance in preclinical models overexpressing HER2. Clinical validation of this association could have important clinical utility given the emergence of a broadening array of anti-HER2 agents and the concept of dual anti-HER2 therapy. Hence, given their frequency, oncogenic capabilities, and the potential to induce resistance to commonly prescribed breast cancer treatments, the clinical relevance of PIK3CA mutations deserves further clarification.
High levels of evidence on the clinical utility of prognostic and predictive biomarkers can be achieved from the use of archived tumor specimens from appropriate randomized clinical trial datasets. Therefore, the main purpose of this study was to clarify in a well-characterized, randomized clinical trial dataset the predictive relevance of PIK3CA mutations to trastuzumab efficacy and its prognostic abilities in both HER2-positive and HER2-negative disease. Given that PIK3CA genotyping can be performed with other somatic hotspot mutations, we also set out to determine prevalence and prognostic associations of other known cancer driver mutations. Our objective was to identify other potentially targetable genetic alterations that contribute to resistance to standard therapy in breast cancer.
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