PIK3CA Wild-type Patients Research Articles

Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in PIK3CA-Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant (Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

PIK3CA Mutations as a Prognostic Factor in Patients With Residual Rectal Cancer After Neoadjuvant Chemoradiotherapy.

PIK3CA mediates various cellular processes, such as transformation, tumor initiation and proliferation, and resistance to apoptosis. This study was conducted to identify the clinical significance and prognostic effect of PIK3CA mutations in patients with residual rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy (NACRT). Formalin-fixed and paraffin-embedded surgical specimens were collected from 128 patients between January 2006 and December 2011 and analyzed using real-time polymerase chain reaction for hotspot mutations in exons 9 and 20 of the PIK3CA gene. Of the 128 patients, 109 were analyzed and 19 were excluded because of poor DNA quality. Mutations in PIK3CA were identified in three patients (2.8%), all of which were detected in exon 20 of the PIK3CA gene. PIK3CA mutations significantly correlated with lymphatic invasion (p=0.016), lymph node metastasis (p=0.034), and higher pathological disease stage (p=0.040). By univariate analysis, patients with PIK3CA mutations were observed to have significantly shorter cancer-specific survival (CSS) (p=0.001) and disease-free survival (DFS) (p=0.006) than PIK3CA wild-type patients. However, PIK3CA mutations were not an independent prognostic factor for CSS (p=0.319) or DFS (p=0.219) in multivariate modeling. Our findings indicate that PIK3CA mutation plays a role in oncogenesis in rectal cancer and may be considered as a candidate therapeutic approach targeting the PIK3/Akt/mTOR pathway in patients with residual rectal cancer after NACRT.

Abstract P5-02-52: Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis

Abstract Background: PIK3CA mutations is one of the most frequent gene alterations in breast cancers, which was reported to be related to the treatment response of anti-HER2 regimens. However, the relationship between PIK3CA mutations and treatment response of a tyrosine kinase inhibitors (TKIs) is still unclear. We thus conducted a systemic review and meta-analysis to investigate the predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with TKIs. Methods: The following databases were searched from inception to July 2022: Medline, Embase and the Cochrane Library. Abstracts from conferences were also reviewed for inclusion. The critical information was extracted from eligible studies. Results: A total of 16 reports including 17 studies were assessed for eligibility, enrolling 1706 patients. Ten studies including 902 patients were in the neoadjuvant setting, the pCR rate is significantly higher in PIK3CA wild-type (WT) patients than in mutated-type (MT) patients (OR = 0.45; 95% CI: 0.31-0.65; P< 0.001). Seven studies including 804 patients were in the metastatic setting, the pooled objective response rate (ORR) is significantly higher in PIK3CA WT patients than in MT patients (OR = 0.40; 95% CI: 0.23-0.70; P = 0.001), and similarly, the clinical benefit rate (CBR) in WT patients is also higher (OR = 0.43; 95% CI: 0.19-0.98; P=0.045). A total of 4 metastasis studies reported progression free survival (PFS), and 2 of them reported overall survival (OS), revealing a marginally significant relationship between PIK3CA mutation and worse PFS (HR = 0.82; 95% CI: 0.67-1.00; P=0.052) and OS (HR=0.63, 95%CI:0.39-1.02; P=0.062). No evidence of publication bias was found in both the neoadjuvant setting and metastatic setting. Conclusion: Our findings indicate that PIK3CA mutations is significantly associated with a lower rate of pCR when treated with TKI-containing regimens in neoadjuvant chemotherapy of early-stage HER2-positive breast cancer, and is significantly associated with lower ORR and CBR in metastatic HER2-positive breast cancer. Citation Format: Qiyun Shi, Juncheng Xuhong, Hao Tian, Yi Zhang, Jun Jiang, Xiaowei Qi. Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-52.

Circulating tumor DNA profile and its clinical significance in patients with hormone receptor-positive and HER2-negative mBC.

After early-line (first- and second-line) endocrine therapy, hormone-receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancers (mBCs) become resistant to endocrine therapy. Genetic alterations may underlie resistance to endocrine therapies. This study aims to investigate the circulating tumor DNA (ctDNA) alterations and the clinical implication in hormone-receptor-positive, HER2-negative metastatic breast cancer patients with multiline endocrine therapy failure. This registered study (NCT05079074, ClinicalTrials.gov) enrolled 104 patients with hormone-receptor-positive, HER2-negative metastatic breast cancer who progressed after the early-line endocrine therapy. ctDNA alterations were analyzed by next generation sequencing (NGS). ctDNA alterations were ranked and clustered by using R 'ComplexHeatmap' and 'hclust' function. ctDNA-guided therapy was administrated. Progression-free survival (PFS) was assessed COX regression analysis, and Kaplan-Meier curves were plotted. The top ctDNA altered genes were TP53 (39%), PIK3CA (38%), BRCA1/2 (13%), ESR1 (12%), FGFR (11%), ERBB2 (11%), and GATA3 (9%). Among these genes, TP53, PIK3CA helix domain mutation (PIK3CA-HD), FGFR, ESR1 and GATA3 were related to endocrine therapy resistance. The genetic landscapes changed and tumor mutation burden increased in both TP53-altered and PIK3CA-altered patients. Both BRCA1/2 and ERBB2 alterations correlated with TP53 alterations (P=0.02 and P=0.04, respectively). However, while 93% BRCA1/2 alterations concentrated in PIK3CA-wildtype patients, 82% ERBB2 alterations concentrated in PIK3CA-altered patients. Kaplan-Meier curves showed that patients who received druggable ctDNA alteration-guided treatment (DDAT) had significantly longer PFS than those who received physician-chosen therapy, with median PFS of 6.1 months versus 4.6 months (hazard ratio = 0.53, 95% CI: 0.34-0.85, Logrank P = 0.006). Multiple genetic alterations were important reasons for the failure of endocrine therapy for HR-positive and HER2-negative mBC. Targeting these genes might restore the treatment sensitivity and benefit survival.

Genomic landscape and tumor mutation burden analysis of Chinese patients with sarcomatoid carcinoma of the head and neck

BackgroundSarcomatoid carcinoma (SC) of the head and neck (HN) is a rare disease that has both sarcomatoid and cancerous components. The genetic background and mechanisms of tumorigenesis remain largely unrevealed, and the progress of precision therapy has been limited. MethodsTargeted DNA-based next-generation sequencing (NGS) was performed by a 539 genes panel of pan-cancer in 12 patients with SC of the HN to identify their genetic alterations and investigate clinically actionable mutations for use in precision treatment. ResultsTP53 was identified as the most frequently mutated gene. Genes related to the cell cycling, chromatin remodeling and histone modification were found to be frequently mutated in patients with SC of the HN. Alterations in receptor tyrosine kinases (RTKs) were also found in six patients. In addition, four patients had mutations in members of the downstream RAS and PI3-kinase pathways, PIK3CA was identified as the most frequently mutated gene in this pathway. The tumor mutation burden (TMB) value ranged from 0.71 to 14.71 per megabase, with a median of 4.34. The TMB value of PIK3CA mutation patients was significantly higher than that of PIK3CA wild-type patients. ConclusionsThis was the first study to investigate genomic alterations specifically in Chinese patients with SC of the HN. Our research results showed that 10 out of 12 patients can match the targeted therapies or immunotherapy currently available in clinical practice or active clinical trials, suggesting precision therapy has the potential utility to improve the long-term prognosis for patients with the rare disease. Due to the small number of patients in this study, the findings need to be validated in a larger cohort.

5-Fluorouracil Enhances the Antitumor Activity of the Glutaminase Inhibitor CB-839 against PIK3CA-Mutant Colorectal Cancers

PIK3CA encodes the p110α catalytic subunit of PI3K and is frequently mutated in human cancers, including ∼30% of colorectal cancer. Oncogenic mutations in PIK3CA render colorectal cancers more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), colorectal cancers. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn upregulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant patients with colorectal cancer might derive greater benefit from this treatment strategy as compared with PIK3CA WT patients with colorectal cancer. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant colorectal cancers and warrants further clinical evaluation. SIGNIFICANCE: Preclinical and clinical trial data suggest that the combination of CB-839 with capecitabine could serve as an effective treatment for PIK3CA-mutant colorectal cancers.

Abstract 3172: Evaluation of cytotoxic T cell infiltration and clinical benefit from PD-L1 checkpoint inhibition among PIK3CA mutant microsatellite stable (MSS) metastatic adenocarcinoma patients

Abstract Background: Immunotherapy has produced durable responses in advanced cancers with microsatellite instability. However, response rates remain very low for microsatellite stable (MSS) adenocarcinomas, and biomarkers predictive of response are urgently needed. PI3K pathway alterations are known to modulate anti-tumor immune microenvironment. We previously reported increased cytotoxic T cell infiltration and greater clinical benefit from immunotherapy among PIK3CA mutant MSS colorectal cancer patients as compared to PIK3CA wild-type patients. Here, we investigated the immune repertoire and treatment outcomes with anti-PD-L1 checkpoint inhibitors in PIK3CA mutant MSS metastatic adenocarcinoma patients. Methods: We retrospectively identified metastatic adenocarcinoma patients treated with anti-PD-L1 antibody either as monotherapy or in combination with anti-PD-1 antibody in early phase clinical trials at the MD Anderson Center for Targeted Therapy. Molecular profiling was performed on archived primary or metastatic tumor tissue using CLIA certified targeted next generation sequencing (FoundationOne or Oncomine). PIK3CA mutations were annotated for functional significance by the Precision Oncology Decision Support Team. Density of cytotoxic T cells was determined using immunohistochemistry (IHC) on biopsy or resection specimens. Microsatellite status was assessed using IHC or polymerase chain reaction. Median time to treatment failure (TTF) was estimated using Kaplan and Meier method. Groups were compared using Fischer's exact, Student's T test or Log-rank test, as appropriate. Results: Twenty-seven patients with MSS metastatic adenocarcinoma (female, 20; male, 7) from 12 different sites were treated with anti-PD-L1 antibody. Breast, colon and esophageal cancers were the most common cancers with 7, 5 and 3 patients, respectively. Activating PIK3CA mutations were present in 7/27 (26%) patients (H1047R, 3; E545K, 2; E542K, 1; co-occuring R88Q and K111N, 1). Patients with activating PIK3CA mutations had trend towards longer median TTF as compared to PIK3CA wild-type patients (6.6 vs. 3.1 months, P=0.1). Similarly, 3/7 (42.9%) patients with activating PIK3CA mutations had stable disease (SD) > 6 months as compared to 2/20 (10%) patients with wild type PIK3CA (P=0.09). CD8 densities were available for 8 patients (5 PIK3CA mutant, 3 PIK3CA wild). Among PIK3CA mutant patients, mean CD8 density was higher in patients who had SD > 6 months as compared to those who did not (630.3 vs 305.1 cells/mm3; P=0.06). Conclusion: Activating PIK3CA mutations are enriched among MSS metastatic adenocarcinoma patients with prolonged SD (> 6 months) on anti-PD-L1 treatment. PIK3CA mutant patients with prolonged SD have higher CD8 densities, possibly due to high-affinity neopeptide-HLA interactions. Larger studies to validate our observations are warranted, including assessment of neopeptide load and HLA types, which may help identify an immunotherapy sensitive subset of PIK3CA mutant MSS adenocarcinoma. Citation Format: Maliha Nusrat, Coya Tapia, S. Greg Call, David S. Hong, Sarina A. Piha-Paul, Vivek Subbiah, Jordi Rodon, Apostolia M. Tsimberidou, Abha Adat, Yan Wang, Funda Meric-Bernstam, Michael J. Overman, Scott Kopetz, Filip Janku. Evaluation of cytotoxic T cell infiltration and clinical benefit from PD-L1 checkpoint inhibition among PIK3CA mutant microsatellite stable (MSS) metastatic adenocarcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3172.

Aspirin has a better effect on PIK3CA mutant colorectal cancer cells by PI3K/Akt/Raptor pathway

BackgroundAspirin, as a non-steroidal anti-inflammatory drug, can improve the survival rate of patients with colorectal cancer, while aspirin is effective in patients with PIK3CA mutant colorectal cancer (CRC). However, the mechanism of aspirin in the treatment of PIK3CA mutated CRC patients remains unclear.MethodsIn this study, immunohistochemistry was used to detect the expression levels of PI3K and Raptor in colorectal cancer patients with PIK3CA mutation and PIK3CA wild-type patients. To demonstrate that aspirin has a better effect on the CRC of PIK3CA mutations in association with the PI3K/Akt/Raptor pathway, we used aspirin to treat PIK3CA mutant CRC cells (HCT-116 and RKO). Subsequently, the CCK8 assay and flow cytometry assay were used to detect the apoptosis of PIK3CA mutant CRC cells before and after aspirin use. Western blot was used to detect the changes of PI3K/Akt/Raptor-associated protein, autophagy protein microtubule associated protein 1 light chain 3 alpha (MAP1LC3A, LC3), beclin 1 (BECN1) and apoptosis protein BCL2-associated X protein/ BCL2 apoptosis regulator (Bax/Bcl2), Caspase 3 after treatment of CRC cells with PIK3CA mutation by aspirin.ResultsPhosphoinositide-3-kinase (PI3K) and regulatory associated protein of MTOR complex 1 (Raptor) protein expression levels were higher in PIK3CA-mutant patients than in IK3CA wild-type patients. The expression of Bax/Bcl2 increased after treatment indicates that aspirin can induce apoptosis of PIK3CA-mutant CRC cells. The expression level of MAP1LC3 (LC3) in cells increases with the concentration of aspirin demonstrates that aspirin can induce autophagy in CRC cells. After 48 h of treatment with aspirin, the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase B1 (S6K1) was reduced, cell proliferation has been inhibited. After treatment with aspirin, as phosphorylation of PI3K and Protein kinase B (PKB, Akt) was decreased, Raptor expression was also decreased.ConclusionAspirin can regulate the proliferation, apoptosis and autophagy of CRC cells through the PI3K/Akt/Raptor pathway, affecting PIK3CA-mutant CRC.

Application of capture-based sequencing in predicting pathologic response to neoadjuvant therapy in HER2-positive breast cancer.

e24073 Background: Pathologic complete response (pCR) to neoadjuvant therapy correlates with significantly improved survival in early-stage HER2-positive breast cancer (BC). Early indicators of pCR could conceivably be used to optimize treatment. This study aimed to reveal pCR-related genomic characteristics in both tissues and circulating tumor DNA (ctDNA). Methods: We enrolled 31 hormonal receptor (HR)-negative HER2-positive BC patients treated with neoadjuvant chemotherapy with or without trastuzumab from a single-center prospective study between January 2014 and June 2017 (ClinicalTrials.gov, NCT02041338). Twenty-two treatment naïve tumor tissues were obtained. Baseline plasma samples were collected from all 31 patients, among whom 22 plasma after 2 cycles of neoadjuvant treatment were sampled. Target-capture deep sequencing was performed to identify somatic genomic alterations. Clonal population structures were identified using PyClone. Results: TP53 and PIK3CA were the most frequently mutated genes in tumor tissues, detected in 77.3% (17/22) and 50% (11/22) of patients, respectively. The pCR rate of PIK3CA-mutated patients (18.2%, 2/11) was significantly lower than that of PIK3CA wild-type patients (72.7%, 8/11), (P = 0.03). Among patients treated with chemotherapy plus trastuzumab, all 8 patients with clonal PIK3CA-mutated did not achieve pCR. CtDNA was successfully detected in 26 of the 31 patients (83.9%) in whom somatic genomic alterations were identified. TP53 mutation, HER2 gene amplification and PIK3CA mutation were the most frequently somatic variants in the baseline plasma samples, detected in 54.8% (17/31), 41.9% (13/31) and 32.3% (10/31) of patients, respectively. Further analysis of the post-treatment plasmas showed that the pCR rate of ctDNA-negative patients after 2-cycle therapy was 87.5%, significantly higher than that in ctDNA-positive patients (18.2%; P = 0.005). Conclusions: In this study, the PIK3CA-mutation in tumor tissues associates with an unfavorable pCR rate to neoadjuvant chemotherapy plus trastuzumab. Analysis of post-treatment ctDNA offers a promising way to predict pCR in HER2-positive BC patients.

Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol

BackgroundBreast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC. Patients and methodsGenetic profile of 146 BC patients’ tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in>3% of the tumours were selected. ResultsA total of 193 genomic rearrangements were identified, and 16 were observed in>3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6years was reported for PIK3CA mutation carriers (n=31, 21.2%) versus 9.9years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12–0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09–0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS. ConclusionPIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

Abstract OT1-03-06: LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/ HER2-negative, early-stage breast cancer

Abstract Background: Taselisib is an orally bioavailable, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the alpha isoform showing enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer (BC) treated with single-agent taselisib. Enhanced antitumor activity has been noted when taselisib is combined with either letrozole or fulvestrant in preclinical and Phase Ib clinical studies. Methods: LORELEI is a Phase II, two-arm, randomized, double-blind, multicenter, study of neoadjuvant letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable BC. Other eligibility criteria include tumor size  2 cm by magnetic resonance imaging (MRI), ECOG PS 0-1, and evaluable tumor tissue for PIK3CA genotyping. Patients treated with anti-diabetic drugs are not eligible. Patients are randomized (1:1) to receive continuous letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Stratification is based on tumor size and nodal status. The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast MRI via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all randomized patients and PIK3CA mutant patients. Secondary endpoints include ORR by centrally-assessed MRI and pCR rate in PIK3CA wild-type patients. The sample size was calculated to detect an absolute percentage increase of 24% in ORR with 80% power and an absolute percentage increase of 18% in pCR rate. An interim safety analysis will be conducted by an Independent Data Monitoring Committee. As of 1st Jun 2015, 54 of the 330 patients have been enrolled, and global enrollment is ongoing (clinicaltrials.gov NCT02273973). Contact information: Reference Study ID Numbers: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 Phone: 888-662-6728 (US Only) Email Address: global.rochegenentechtrials@roche.com Citation Format: Oliveira M, de Azambuja E, Saura C, Dubsky P, Zardavas D, Fesl C, Bardia A, Soberino J, Ciruelos Gil E, Ng V, Fredrickson J, Stout TJ, Singel SM, Hsu JY, Piccart M, Gnant M, Baselga J. LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/ HER2-negative, early-stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-06.

PIK3CA mutation analysis in Chinese patients with surgically resected cervical cancer.

The aim of this study was to evaluate the clinicopathological and prognostic relevance of PIK3CA mutations in Chinese patients with surgically resected cervical cancer. PIK3CA mutations were screened in 771 cervical cancer specimens using reverse transcription polymerase chain reaction and Sanger sequencing. In total, 13.6% (105 of 771) of patients harbored non-synonymous PIK3CA mutations. Patients harboring PIK3CA mutations were older than patients with wild-type PIK3CA (mean age: 50.7 years vs. 47.0 years, P < 0.01). PIK3CA mutations were more commonly observed in postmenopausal patients than in premenopausal patients (19.6% vs. 10.2%, P < 0.01). PIK3CA mutations were more common in squamous cell carcinomas than in non-squamous cell tumors (15.3% vs 7.3%, of P < 0.01). The 3-year relapse-free survival was 90.2% for PIK3CA mutant patients and 80.9% for PIK3CA wild-type patients (P = 0.03). PIK3CA mutation was confirmed as an independent predictor for better treatment outcome in the multivariate analyses (HR = 0.54, 95% CI: 0.29–0.99, P = 0.048). PIK3CA mutations were significantly associated with less distant metastases (mutant-type: 8/105, wild-type: 98/666, p = 0.048). Thus, patients with mutant PIK3CA had distinct characteristics in age, menopausal status, and histological subtype and have better treatment outcome and less distant metastasis after surgery-based multimodal therapy.

A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction

ObjectiveTo develop gene expression profiles that characterise KRAS-, BRAF- or PIK3CA-activated- tumours, and to explore whether these profiles might be helpful in predicting the response to the epidermal growth factor...

Abstract 4552: Utilization of pathway activation and somatic mutation analysis in combination in fine needle aspirates to identify candidate drugs for effective treatment of breast cancer

Abstract A critical hurdle in implementing prognostic and predictive biomarkers in clinical trials is our inability to perform an efficient molecular characterization of the limited amounts of available clinical samples. Here we report a comprehensive molecular analysis of fine needle aspirate (FNA) samples collected from metastatic sites of 58 breast cancer (BCA) patients. The analysis included interrogation of key receptor tyrosine kinases and their downstream signaling molecules including HER1, HER2, p95HER2, HER3, cMET, IGF1R, PI3K, Shc, AKT and ERK as well as oncogenic somatic mutational profiling. A multiplexed immunoarray CEER™ (Collaborative Enzyme Enhanced Reactive-immunoassay) platform was utilized to determine the levels of pathway protein expression and phosphorylation. All FNA collections provided sufficient materials for the combined analysis of multiplexed pathway expression/activation and somatic mutation analysis. All the FNA from metastatic sites (mFNA) collected from HER2 positive primary tumors (determined by IHC) were also CEER-HER2 positive. Over-expression of HER2 was found in 10% of mFNAs collected from BCA patients with HER2 negative primary tumors. PIK3CA mutations were found in 20% of the samples in this cohort. Statistically significant higher levels of phosphorylated AKT, ERK (downstream effector targets) as well as HER1, HER2, HER3 and IGF1R (PI3K membrane recruiter proteins) were found in mFNAs with PIK3CA mutations. Subset of PIK3CA wildtype patients also showed robust pathway signature. Hence, evaluation of biomarkers in BCA patients should include both pathway proteins as well as mutation analysis. A comprehensive disease profiling can provide insightful information on efficacy of specific agents on its intended target protein inhibition. As CEER requires minimal amount of specimen, performance of routine pathway profiling can be achieved in clinical settings. A multiplexed pathway analysis can also provide valuable information about potential drug resistance mechanisms. Furthermore, a combined mutational and pathway activation profiling can guide therapeutic strategies in clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4552. doi:1538-7445.AM2012-4552

Frequency of PIK 3CA Mutations in Chinese HER2+ Metastatic Breast Cancer Patients and Association with Clinical Benefit to Lapatinib and Capecitabine Treatment.

Abstract Background: Activating mutations in PIK3CA are frequent in breast cancer (Campbell et al. Cancer Res 2004;64:7678-7681). Previous analyses suggest that the presence of PIK3CA activating mutations were associated with poor clinical outcome (Li et al. Breast Can Res Treat 2006;96:91-95) and could confer resistance to treatment with trastuzumab (T) (Berns et al. Cancer Cell 2007;12:395-402). Lapatinib (L) is an oral tyrosine kinase inhibitor targeting EGFR and HER2 pathways. L plus capecitabine (C) has demonstrated efficacy in women with HER2+ metastatic breast cancer (MBC) previously treated with T (Geyer et al. N Engl J Med 2006;355(26):2733-2743). EGF109491 evaluated the efficacy of L+C in 52 Chinese HER2+ MBC patients. The clinical benefit rate (CBR) was 57.7% (PR 44% and SD 44%) and median progression free survival (PFS) was 6.3 months. The purpose of this analysis was to establish the frequency of PIK3CA mutations in this small cohort of Chinese patients and to determine if the presence of a PIK3CA mutation has any impact on clinical benefit to L+C.Methods: 38/52 patients provided tumor samples for biomarker analysis. Briefly, DNA was extracted from these tumor samples, amplified by PCR and sequenced by Pyrosequencing methods to identify the presence of frequent activating mutations in exons 9 and 20 in PIK3CA. Mutation status was tested for association with CBR and PFS using contingency table analysis and proportional hazards analysis respectively.Results:11/38 (29%) patients harbored a mutation in the PIK3CA gene, consistent with published frequencies. 9/11 mutations reside in the catalytic domain and 2/11 mutations reside in the accessory domain of the gene. There was no statistical association with CBR (p=0.639) or PFS (HR=1.01, p=0.989) in PIK3CA wildtype patients vs. PIK3CA mutant patients. PIK3CA wildtype n=27 (%)PIK3CA Mutation n=11 (%)CR0 (0)0 (0)PR12 (44%)4 (36%)SD13 (48%)5 (45%)PD1 (4%)1 (9%)Unknown1 (4%)1 (9%)HR1.01 (p=0.989) Conclusion: The frequency of PIK3CA mutations in this small cohort of Chinese HER2+ MBC patients is consistent with published frequencies. There was no statistically significant association between the presence of a PIK3CA mutation and clinical benefit to L+C in these patients. These results are in agreement with previous reports that mutations in PIK3CA do not seem to impact clinical outcome following L-containing treatment regimens. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1140.