Prevalence Of PIK3CA Mutations Research Articles

Prevalence of somatic PIK3CA mutations in hormone receptor-positive metastatic breast cancer: The Indian experience.

e13047 Background: The phosphatidylinositol 3-kinase (PI3K) inhibitors have been found to improve survival outcomes in hormone receptor-positive metastatic breast cancer (MBC) and are FDA-approved in this setting after progression on hormonal therapy. However, real-world data from India on the prevalence of PIK3CA mutations is scarce. Methods: This is a retrospective study including patients with hormone receptor-positive breast cancer registered at our center between January 2017- and December 2023 who developed metastatic disease on follow-up after getting appropriate treatment (adjuvant /neoadjuvant) as per institutional protocol. The PIK3CA mutation testing was done on the biopsy specimen. FDA-approved therascreen PIL3CA RGQ PCR kit from Qiagen was used and the assay is a real-time qualitative PCR test for the detection of 11 mutations phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene (Exon 7: C420R; Exon 9: E542K, E545A, E545D [1635G>T only], E545G, E545K, Q546E, Q546R; and Exon 20: H1047L, H1047R, H1047Y) using genomic DNA (gDNA) extracted from formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue. The clinical demographics of patients with PIK3CA mutations were extracted from the hospital database and represented descriptively. Results: A total of 80 consecutive patients with hormone-positive breast cancer at relapse were screened and 26 were found to have PIK3CA mutations (32.5%) of which 24 were female (92.3%). The median age of patients with mutated PIK3CA cases was 50 years (range: 31 to 72 years). The clinical stage of disease at presentation was: stage II in 11.5%, IIIA in 23.1%, and IIIB in 65.4% of cases. The median time of relapse was 21 months from diagnosis (range: 10 to 42 months). The disease sites at relapse were multiple in 23 patients (88.46%) [including central nervous system (CNS) relapse in 3 patients) and CNS (brain) only in 3 patients (11.54%). The mutations detected included H1047R (3140A>G at exon 20) in 8 cases, E545K (1633 G>A at exon 9) in 5 cases, Q546R (1637 A>G at exon 9) in 4 cases, E542K (1624 G>A at exon7) in 3 cases and synchronous mutations (E542K/E545K at Exon 7) in 3 cases and (H1047R/H1047L at exon 20 ) in 3 cases. Only eight patients received alpelisib with fulvestrant due to financial constraints. Conclusions: This is the first Indian study that describes the prevalence of PIK3CA mutations in hormone-positive breast cancer at relapse. Around one-third of patients harbor this mutation and 23.1% of cases have CNS involvement at relapse. The most common PIK3CA mutation detected was H1047R (exon 20) followed by E545K (exon 9).

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after > 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-02.

Abstract 1752: Comprehensive genomic profiling of advanced breast cancer subtypes: Insights from liquid biopsy analysis and implications for personalized therapies

Abstract Background: Breast cancer stands as the most prevalent malignancy affecting women’s health. The disease consists of three subtypes, including hormone receptor (HR) positive, HER2-positive, and triple-negative breast cancer (TNBC). In recent years, the advent of targeted therapies such as PI3K inhibitors has significantly improved the prognosis of breast cancer patients. However, the detection of relevant molecular markers, such as PIK3CA mutations, relies on tissue samples, which imposes limitations on the clinical application of these therapies. Consequently, this study presents a comprehensive analysis of genomic profiling that compares breast cancer patients across distinct pathological classifications, utilizing a liquid biopsy approach. Methods: In this retrospective study, 214 patients with advanced breast cancer were recruited. Plasma samples collected prior to first line treatment were analyzed using PredicineCARE, a targeted next-generation sequencing (NGS) liquid biopsy assay, to detect somatic alterations in ctDNA of blood, including single nucleotide variations (SNVs), gene fusions, and copy number variations (CNVs). Results: Based on the IHC classifications of tumor tissue, this cohort comprised 119 HR-positive, 61 HER2-positive, and 34 TNBC patients. The assay identified a total of 1456 mutations and 2357 gene copy number variants in plasma samples. Among these, the most frequently mutated genes and those with copy number variations (top 5) in HR-positive patients were TP53 (40%), PIK3CA (39%), ATM (22%), ERBB2 (19%), and FGFR1 (19%). In HER2-positive patients, they were TP53 (39%), PIK3CA (31%), ERBB2 (30%), NTRK1 (20%), and RAD50 (20%). For TNBC patients, the top genes were TP53 (59%), ERBB2 (44%), PIK3CA (35%), NTRK1 (35%), and BRCA2 (26%). Regarding the PIK3CA gene, the most prevalent mutation site was H1047, occurring in 12.61% of HR-positive patients, 14.75% of HER2-positive patients, and 11.76% of TNBC patients. Similarly, both E542 (4.20% in HR-positive, 3.28% in HER2-positive, and 2.94% in TNBC patients) and E545 (3.36% in HR-positive, 3.28% in HER2-positive, and 2.94% in TNBC patients) showed equivalent prevalence across the three classifications. These findings suggest the potential efficacy of PI3K inhibitors in various pathological types of breast cancer. Conclusions: This study offers insights into the genomic landscape of advanced breast cancer subtypes through liquid biopsy. The observed prevalence of PIK3CA mutations supports the potential efficacy of PI3K inhibitors across these diverse types of breast cancer, laying the groundwork for personalized therapeutic strategies and biomarker identification for prognosis and targeted therapies. Citation Format: Xiaoran Liu, Yaxin Liu, Cancan Jia, Yue Zhang, Feng Xie, Haoran Tang, Shidong Jia, Huiping Li. Comprehensive genomic profiling of advanced breast cancer subtypes: Insights from liquid biopsy analysis and implications for personalized therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1752.

Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first-line setting.

In approximately 40% of patients with HER2-negative/HR-positive breast cancer tumors, the PIK3CA gene is mutated. Despite this, clinical outcomes vary between studies in this cohort. We aimed to ascertain the prevalence of PIK3CA mutations in patients with metastatic HR+/HER2- breast in Bulgaria, as well the evaluation and comparison of progression free survival (PFS) between wild-type (WT) and mutation-positive groups in the real-world setting. Three oncology centers in Bulgaria collected 250 tissue samples between 2016 and 2022 for this multicentric retrospective study. PIK3CA mutations were identified using Real-Time qPCR. The median follow-up period was 35 months. The mean age of the mutant cohort was 57.6 ± 11.6 years, compared to 56.5 ± 12.2 years for the WT cohort (p = .52). The percentage of patients with visceral metastasis was 58.8% (n = 147). Approximately 84.3% (n = 210) of the patients had reached postmenopause. 29.2% (n = 73) of the patients had PIK3CA mutations. The predominant mutation was present in exon 20, H1047R (46.5%). We found a significant correlation only between the presence of a mutation and the metastatic diseases at diagnosis (p = .002). As first-line therapy, 67.1% of patients received endocrine therapy (ET) plus cyclin dependent kinase (CDK4/6) inhibitor, while the remainder received ET alone. The median PFS of patients in the group with the mutation was 32 months (95%, CI: 22-40) compared to 24 months in the WT cohort ((95%, CI: 21-36) (p = .45)); HR = 0.86 (95%, CI: 0.5-1.3) (p = .46). We corroborated our conclusion using propensity matching score analysis, (36 months [95% CI: 20-40] vs. 26 months [95% CI: 21-38], [p = .69]). We found that the prevalence of PIK3CA mutations in our patients was comparable to what has been reported in other nations. Our results suggest that PIK3CA mutational status has no bearing to ET efficacy in first-line setting.

Prevalence of PIK3CA Mutation Based on Tumour Locations Among Colorectal Cancer Patients in Bali

Colorectal tumour location is important in determining therapeutic strategies because the location of the tumour will affect the histological and molecular characteristics of the cancer. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a gene known to be associated with colorectal cancer location. The prevalence of PIK3CA mutations in colorectal cancer (CRC) ranges from 10-20%. Although the prevalence is small, this gene has a potential as a predictive and prognostic biomarker in the management of CRC. 80% of PIK3CA mutations occur in exon 9 (codon 542 and 545) and exon 20 (codon 1047). This study aimed to determine the prevalence of PIK3CA gene mutations based on tumour location among colorectal cancer patients in Bali, especially in Prof. dr. I G.N.G. Ngoerah Hospital, Denpasar, Bali. DNA was isolated from formalin-fixed-paraffin embedded (FFPE) blocks of colorectal cancer samples which were stored in the Department of Pathology of Prof. dr. I G.N.G. Ngoerah Hospital. Mutation was detected using polymerase chain reaction (PCR) and direct sequencing. Data on age, gender, and tumour location were recorded from patient medical records. Our findings on 31 colorectal cancer samples showed 26 samples (96.3%) were found with heterozygous mutation in exon 9 with AC genotype, but no mutation was found on exon 20. Based on tumor location, among 26 samples with mutation, 16 samples (61.5%) were left colorectal cancer and 10 samples (38.5%) were right colorectal cancer. Further studies are needed to identify the association of this mutation with colorectal cancer location and the other clinicopathological aspects of CRC. Keywords: Colorectal cancer, PIK3CA gene mutation, PIK3CA exon 9, PIK3CA exon 20, colorectal cancer location, left-sided colorectal cancer, right-sided colorectal cancer

PIK3CA mutations in cutaneous squamous cell carcinoma.

Oncogenic PIK3CA mutation activates phosphoinositide 3-kinase (PI3K) enzyme, and PI3K-AKT signaling activation induces several growth-regulatory transcription factors. PIK3CA mutations have attracted attention as biomarker in clinical trials of various inhibitors including PI3K inhibitors. About 80% of PIK3CA mutations in human cancers are observed in 'hot spot' regions: exon 9 (E542K and E545K) and exon 20 (H1047R). There were few reports about clinical significance of PIK3CA mutations in cutaneous cell carcinoma (cSCC). Thus, we investigate the prevalence of three PIK3CA hot spot mutations in 143 cases with cSCC and evaluate the correlation between the presence of these mutations and clinical characteristics by using ddPCR. The frequency of each E542K, E545K and H1047R PIK3CA mutations was 1.4% (2/143), 2.8% (4/143), and 0.7% (1/143) respectively. No significant correlation was found between PIK3CA mutations and clinical characteristics. Although additional basic researches and clinical trials are necessary, various inhibitors may be effective therapeutics for PIK3CA mutation-positive cSCC. Our study revealed the prevalence of PIK3CA mutations in cSCC.

Prevalence of PIK3CA mutations in Taiwanese patients with breast cancer: a retrospective next-generation sequencing database analysis.

Breast cancer is the most common cancer type that affects women. In hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is the most frequently mutated gene associated with poor prognosis. This study evaluated the frequency of PIK3CA mutations in the Taiwanese breast cancer population. This is a retrospective study; patient data were collected for 2 years from a next-generation sequencing database linked to electronic health records (EHRs). The primary endpoint was the regional prevalence of PIK3CA mutation. The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment. PIK3CA mutations were identified in 278 of 728 patients (38%). PIK3CA mutations were reported in 43% of patients with HR-/HER2+ subtype and 42% of patients with HR+/HER2- postmenopausal status. A lower prevalence of PIK3CA mutations was observed in triple-negative (27%) and HR+/HER2- premenopausal patients (29%). The most common mutation was at exon 20 (H1047R mutation, 41.6%), followed by exon 9 (E545K mutation, 18.9% and E542K mutation, 10.3%). Among patients treated with CDK4/6 inhibitors, the median time to treatment failure was 12 months (95% CI: 7-21 months) in the PIK3CA mutation cohort and 16 months (95% CI: 11-23 months) in the PIK3CA wild-type cohort, whereas patients receiving an mTOR inhibitor reported a median time to treatment failure of 20.5 months (95% CI: 8-33 months) in the PIK3CA mutation cohort and 6 months (95% CI: 2-9 months) in the PIK3CA wild-type cohort. A high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.

PI3KCA mutation prevalence and outcome among patients with metastatic breast cancer in Bulgaria treated with first-line endocrine therapy.

e13005 Background: There are phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations in 30-40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2) tumor samples. Nevertheless, clinical outcomes in this group vary amongst research trials. Methods: We sought to determine the incidence of PIK3CA mutations in Bulgarian patients with metastatic HR+, HER2-negative breast cancer, as well as to evaluate and compare progression-free survival (PFS) in the real world between wild-type (WT) and mutant cohorts. In this multicentric retrospective analysis, 250 tissue samples were collected between 2016 and 2022 from three Bulgarian oncology centers. Qualitative real-time PCR was used to determine the existence of PIK3CA mutations. The median follow-up time was 28 months. Results: The mean age was 57.6±11.6 years for the mutant cohort and 56.5±12.2 for the wild-type cohort (p=0.52). The percentage of patients with visceral metastatic disease was 58.8% (n=147). Postmenopausal patients were 84.3% (n=210). PIK3CA mutation prevalence was 29.2% (n=73). The most prevalent mutation was found in exon 20: H1047R (9.2%). Among all clinicopathological features, we observed only a significant relation between the presence of a mutation and a metastatic stage at diagnosis (p = 0.002). 67.1% of the patients received endocrine therapy (ET) + CDK4/6 inhibitor as first-line therapy, while the remainder receive ET monotherapy. Patients with PIK3CA mutation did not have significantly different median PFS compared to WT patients (32 months (95%, CI: 22-40) versus 24 months ((95%, CI: 21-36) (p=0.45)); HR=0.86 (95%, CI: 0.5-1.3) (p=0.46). In propensity matching score analysis (matched for treatment utilized as a first line ET, menopausal status, and locations of metastatic disease), we confirmed our finding (36 months (95%, CI: 20-40) versus 26 months (95%, CI: 21-38), p = 0.69). Conclusions: We demonstrated that the prevalence of PIK3CA mutations in Bulgarian patients is comparable to that reported in other countries. Our findings suggest that the presence of a PIK3CA mutation has no effect on the efficacy of endocrine therapy of first-line treatment. In summary, our study provides valuable insights into the topic, but limitations including the retrospective design and small sample size suggest that the findings need to be replicated by more robust studies and larger sample sizes to draw definitive conclusions.

Abstract P5-03-04: PIK3CA mutation prevalence in hormone receptor positive breast cancer patients in United Arab Emirates

Abstract Background: The Phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha (PIK3CA) gene is mutated in about 30-40% of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) breast cancer (BC) patients. For HR+/HER2- advanced breast cancer patients with disease progression following endocrine-based therapy, the NCCN guideline recommends testing for PIK3CA mutations with tumour or liquid biopsy to identify suitable patients for targeted therapy with alpelisib, an oral α-specific PI3K inhibitor in combination with fulvestrant. The primary objective of this study was to evaluate the proportion and distribution of PIK3CA mutational landscape of HR+ve BC patients at the largest cancer centre in the United Arab Emirates (UAE). Material and methods: Retrospective review of consecutive HR+ve BC patients at Tawam Hospital for whom PIK3CA testing was requested. DNA was extracted from the samples and a targeted resequencing assay was used for mutation detection in exons 7, 9 and 20 of the PIK3CA gene. Sequencing was carried out using the Next Generation Sequencing platform Ion GeneStudio S5 Prime System with a detection limit of 2-5% of the mutant allelic content. Results: 124 patients with HR+ve BC were enrolled in the present study. The pathology samples were considered unsuitable/unsatisfactory in 18 cases. The median age was 51.5 years (range 31-90). All patients were female, 54% were post-menopausal and 49% presented with de-novo metastatic disease. Of the 106 eligible patients, PIK3CA mutations were detected in 33 (31%) patients, the most common being H1047R (45%) and E545K (30%) mutations in exons 20 and 9, respectively. Other less common mutations included C420R mutations (6%) in exon 7, E542 (6%) in exon 9 and H1047Y (3%) in exon 20. 9% of patients had more than one hotspot mutations, primarily in exons 9 and 20. Of the 12 HER2 +ve patients tested, 3 had PIK3CA mutations, most commonly the H1047R mutation in exon 20. Conclusion: The prevalence of PIK3CA mutations and the presence of most common hotspot mutations in exons 20 and 9 was consistent with prior published studies. The clinical relevance of PIK3CA mutations in HER2 +ve BC patients needs further assessment. Citation Format: Fathi Azribi, Mohammad Hourani, Sulaman Magdub, Aydah Alawadhi, Ali Yousif, Emad Dawoud, Khaled Al Qawasmeh, Mouza Al Ameri, Diaeddine Trad, Nouri Bennini, Mohamed Ahmed, Jawaher Ansari. PIK3CA mutation prevalence in hormone receptor positive breast cancer patients in United Arab Emirates [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 P5-03-04.

PIK3CA mutations in breast cancer with low HER2 / neu expression

Introduction. Disturbances in the PI3K-dependent (PI3K – phosphoinositide 3‑kinase) cascade are characteristic of all types of breast cancer. In particular, 30–40 % of patients with advanced / metastatic hormone-positive HER2‑negative (HER2 – human epidermal growth factor receptor 2) breast cancer carry PIK3CA mutations in tumor cells. The detection of these mutations in patients with hormone-positive HER2‑negative breast cancer is of great clinical importance, since they are a predictor of tumor sensitivity to the PI3K inhibitor alpelisib. According to the HER2 / neu protein expression status, all patients with hormone-positive HER2‑negative breast cancer can be divided into two groups – with low expression of HER2 / neu (scores 0, 1+ or 2+ per immunohistochemical analysis and negative result of in situ hybridization) and with a complete lack of expression of this protein.Aim. To establish whether there are differences in the nature and prevalence of PIK3CA mutations in patients in these two groups.Materials and methods. The study was carried out on 32 breast cancer samples with a luminal HER2‑negative immunophenotype, which were divided into two groups – with low HER2 / neu expression (n = 15) and with a complete absence of HER2 / neu expression (n = 17). PIK3CA mutations were determined using the commercially available cobas PIK3CA MutationTest kit (Roche, Switzerland) by real-time polymerase chain reaction on paraffin block material (tissue biopsy).Results. Mutations of the PIK3CA gene were detected in 37.5 % of cases, of which p.E542K mutation was detected in 2 cases; p.E545X – in 3, p.H1047X – in 6 and p.N345K – in 1. Analysis of the mutational status of both groups revealed statistically significant differences in the quantitative distribution of PIK3CA mutations. The frequency of PIK3CA mutations was significantly higher in tumors with low expression of HER2 / neu (p = 0.0268). Thus, characteristic genetic changes have been identified for a group of patients with HER2‑low breast cancer. These changes are potential targets for therapy, which is important for clinical practice, as it opens up new therapeutic possibilities for breast cancer patients with low HER2 / neu expression.

Clinical and genomic characterization of ERBB2-altered gallbladder cancer.

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.

Single center experience with alpelisib-fulvestrant in heavily pretreated women with HR(+), HER-2 (−) metastatic breast cancer.

e13034 Background: HR-positive, Her2-negative metastatic breast cancer patients harboring PIK3CA mutations are associated with resistance to endocrine therapy and worse prognosis. Results from the phase III SOLAR-1 trial demonstrate improved PFS for patients treated with Alpelisib-Fulvestrant after failure on first or second line treatment with aromatase inhibitor. Methods: Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations. New generation sequencing (NGS) was the preferred technique to identify carriers with PIK3CA mutations on soft tissue or liquid biopsy. Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy. Results: Among 32 patients (pts) screened, 13 (40,6%) had a PIK3CA mutation. In total, 11 pts received alpelisib. Median age at diagnosis was 57.5 years (range, 39-69). Eight pts (72.7%) had been operated for early-stage breast cancer, 6 (54.5%) had received adjuvant chemotherapy and 5 (45.5%) had received adjuvant radiotherapy. Of 11 pts with evaluable histology, 3 pts (27.3%) had high grade tumors at diagnosis. Ten pts (90.9%) had PR positive tumors. Median Ki67 was 20% (range, 2-80). Eight pts (72.7%) had PIK3CA exon 20 and 3 (27.3%) had exon 9 mutations. Six pts (54.5%) had received prior chemotherapy in the metastatic setting and 10 (90.9%) prior CDK4/6 inhibitor. Three pts (27.3%) received Alpelisib as 2nd line and all remaining patients received alpelisib beyond 3rd line treatment. All pts (100%) had metastasis to the bones, 8 pts (72.7%) to the liver, 6 pts (54.5%) to the lungs and 2 pts (18.2%) to the brain. Until the date of last assessment, Alpelisib was administered for a median of 5.1 months (range, 0.4-21.3). Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response. Median duration of disease control was not reached. Baseline characteristics were not associated with disease control. Adverse events noticed were thrombocytopenia grade II (1/11), diarrhea grade II (2/11), skin rash grade I &II (4/11), weakness grade III (1/11) and hyperglycemia (3/11). Conclusions: Prevalence of PIK3CA mutations is consistent with published data. Furthermore, combination of Alpelisib-Fulvestrant is a highly active line of therapy even in heavily pretreated patients.

Characterizing the genomic landscape of PIK3CA alterations from 121,221 adult patients with cancer: The next tissue-agnostic target?

3088 Background: The PI3K–AKT–mTOR signaling pathway is frequently dysregulated in cancer and small molecule inhibitors targeting various nodes in the pathway have been pursued for decades. Activating mutations in PIK3CA are recognized potent drivers of oncogenesis, though the landscape of PIK3CA fusions and amplifications has yet to be well-defined. The field has been hampered by issues such as resistance and poor tolerance, however several isoform-specific PI3K inhibitors have now received regulatory approval and allosteric pan-mutant and specific mutant selective Inhibitors of PI3Kα are being investigated in early phase clinical trials. Here, we present a comprehensive analysis of PIK3CA alterations in pan-cancer adult malignancies. Methods: We analyzed 136096 samples from 121221 patients available from AACR Project GENIE v.11 database for the prevalence of PIK3CA mutations, fusions and copy number alterations in a range of cancer types. Results: 15712 alterations in PIK3CA were detected in profiled tumor samples (12%), in 14774 of patients profiled (12%), most frequently in endometrial (44% of 4135 cases), anal (35% of 286 cases), breast (35% of 14218 cases), cervical (27% of 761 cases) and colorectal cancer (20% of 3743 cases). PIK3CA alterations identified included 17740 mutations (11%) (including duplicate mutations in patients with multiple samples). 16685 missense mutations were identified (12%);14953 were identified as missense in driver mutation (likely oncogenic)(90% of missense); 1,732 were missense of variants of uncertain significance (VUS) using OncoKB database (11%). Missense mutations most frequently involved codons 545(3347, 20% of missense), codon 1047 (3644, 22%) and codon 542 (1881, 11%). 237 truncating mutations were identified (0.2%), 442 in-frame deletions, 29 in-frame insertion mutations. PIK3CA fusions were observed in 0.06% of tumor samples and were most identified in breast, colorectal, lung, GBM and ovarian cancer (24%, 17%, 13%, 7% and 6% of identified PIK3CA fusions respectively). PIK3CA fusions were most commonly intragenic fusions(36%);common fusion partners included TBL1XR1, FNDC3B and NAALADL2(17%, 7%, 5% of identified PIK3CA fusions, respectively). PIK3CA fusions were identified as VUS, aside from KMT2C-PIK3CA (2%) . PIK3CA amplification high level gain occurred in 0.5% of samples tested(662), deletion occurred in 0.16%(21). Conclusions: Activating PIK3CA mutations occur frequently across cancer types and could be considered for tissue-agnostic drug development. PIK3CA fusion and amplification events are extremely rare. Most PIK3CA missense mutation variants are described as oncogenic, while fusions are described as VUS, which may limit the impact of precision oncology for patients with this alteration. Further functional characterization of PIK3CA variants and basket trial enrollment are warranted.

High Mutation Burden in ER-Positive/HER2-Negative/Luminal Breast Cancers.

Background: Tumor mutation burden (TMB) is arising as a useful marker of checkpoint inhibitors’ effectiveness in cancer patients in general and has been proposed as predictive in breast cancers. Despite the initial success of checkpoint inhibitors in triple-negative breast cancer, ER-positive breast cancers are less amenable to immunotherapy treatments due to the lower immunogenicity of this subset, associated with lower TMB and less pronounced inflammatory cell infiltration. However, a minority of ER-positive breast cancers do have a higher TMB and could be targets of immune checkpoint inhibitors. Methods: This investigation uses publicly available genomic data to examine ER-positive/HER2-negative or luminal breast cancers with high mutation numbers and compare them with cancers of the same subtype and low mutation numbers. Clinical characteristics and molecular correlates according to mutation numbers are described. Results: ER-positive/HER2-negative and luminal breast cancers with high mutation numbers have a higher prevalence of PIK3CA mutations and in some of the series examined mutations in TP53 and CDH1. A significant proportion of cancers with high mutation numbers carry mutations in microsatellite instability genes and genes involved in DNA damage response. Despite these differences, the prognosis of ER-positive/HER2-negative and luminal breast cancers with high mutation numbers is not significantly different compared to counterparts with lower mutation counts. Conclusions: These data may inform the potential suitability of these cancers for immunotherapy and could guide the development of rational combination therapies based on immune checkpoint inhibitors with other targeted drugs.

Abstract P3-09-18: The association between genomic alterations and body mass index in patients with early breast cancer

Abstract Background: High body mass index (BMI) is an established risk factor for developing breast cancer (BC), especially estrogen receptor (ER)-positive, and also has been associated with adverse survival. Still, patients with BC are currently treated independently of their BMI given limited understandings of the association between BC biology and patient adiposity. In this study, using retrospective data retrieved from two large BC studies, we aimed to identify genomic alterations of primary BC that are associated with BMI in the most common histological BC subtype - invasive carcinoma of no special type (NST). Patients, Data and Methods: Clinicopathological and genomic alteration data were retrieved from two study cohorts: METABRIC (Pereira et al. 2016) and ICGC (Nik-Zainal et al. 2016), with BMI recorded at the time of diagnosis and represented as either a continuous variable or a categorical variable of three categories - lean, overweight and obese. Stratification according to ER and HER2 status resulted in two focused subgroups: NST ER+/HER2- (n=392) and NST ER-/HER2- (n=152). Mutations classified as oncogenic using a set of predefined criteria were used to determine gene-level mutation status. Copy number alteration (CNA) calls were distinguished into three event types: amplification, hemizygous deletion and homozygous deletion. We used multivariable Firth’s logistic regression models with the presence of a genomic alteration as the response variable, BMI as the predicting variable of interest, and data cohort (METABRIC vs ICGC), age group (≤50 vs >50) and tumor grade (I & II vs III) as covariates, to assess the associations between BMI and recurrent gene-level genomic alterations, including gene mutations and CNAs. In a similar manner, we performed multivariable linear regression analysis, adjusting for age and tumor grade, to evaluate the associations of BMI with mutational signatures (MS) and tumor mutational burden in the ICGC NST subsets where these data are available. Results: Considering BMI as a categorical variable, we observed in the NST ER+/HER2- subgroup that PIK3CA was significantly less frequently mutated in obese compared to lean patients (33% vs 46%, odds ratio (OR) = 0.57 (95% confidence interval = (0.33, 0.97)), p = .039), while PTEN and TBX3 showed an increased frequency in overweight (6% vs 1%, OR = 4.14 (1.1, 22.34), p = .034) and obese (8% vs 1%, OR = 7.41 (1.82, 70.65), p = .008) patients, respectively. Regression analyses with BMI as a continuous variable revealed an increased prevalence of mutations in CDH1 and TBX3 genes as BMI increases by 1kg/m2 (OR = 1.14 (1.05, 1.24), p = .002, and OR = 1.13 (1.04, 1.22), p = .005, respectively) in patients with NST ER+/HER2- BC. No associations between BMI and oncogenic mutations was observed in the NST ER-/HER2- subgroup. Interrogation of gene-level CNAs in both subgroups demonstrated differences according to BMI in the prevalence of CNAs affecting a number of genes, many of which are known or have been presented with evidence to be involved in regulation of or regulated by hallmark pathways of BC, such as the MAPK/ERK, JAK/STAT and Wnt/β-catenin signaling pathways. We report a strong positive association between the single-base substitution signature 1 (SBS1), an age-correlated MS, and both continuous (coefficient (coef) = 18.3 (7.7, 28.9), p < .001) and categorical BMI (obese vs lean, coef = 336.3 (187.9, 484.8), p < .001) in the ICGC NST ER+/HER2- subgroup. Conclusion: This exploratory retrospective study suggests that the genomic profiles of primary BC may differ according to BMI. Clinical implications of these differences, especially the decreased prevalence of PIK3CA mutations in obese patients in the context of alpelisib, warrant further investigation. These results however indicate that patient adiposity should be taken into account in the era of personalized medicine. Citation Format: Ha-Linh Nguyen, Tatjana Geukens, Marion Maetens, Karen Van Baelen, Maxim De Schepper, Sophia Leduc, Edoardo Isnaldi, Sam Aparicio, Ake Borg, Jane Brock, Annegien Broeks, Carlos Caldas, Andrew Green, Hazem Khout, Eyfjörð Jórunn, Stian Knappskog, Savitri Krishnamurthy, Sunil Lakhani, Anita Langerod, John WM Martens, Leigh Murphy, Serena Nik-Zainal, Colin Purdie, Emad Rakha, Andrea Richardson, Anne Salomon, Peter Simpson, Christos Sotiriou, Paul Span, Benita Kiat-Tee Tan, Alastair Thompson, Stefania Tommasi, Marc Van de Vijver, Steven Van Laere, Alain Viari, Giuseppe Floris, Elia Biganzoli, François Richard, Christine Desmedt. The association between genomic alterations and body mass index in patients with early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-18.

A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2- Metastatic Breast Cancer.

PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2– advanced (locally unresectable) or metastatic disease (HR+/HER2– mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2– mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2– mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2– mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.

Abstract CT142: Prevalence of PIK3CAmutations in patients with hormone receptor-positive, human epidermal growth factor-2-negative advanced breast cancer from the SOLAR-1 trial

Abstract Introduction: Approximately 40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) exhibit mutations in the PIK3CA gene, leading to phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation. Use of the oral α-specific PI3K inhibitor alpelisib (ALP) + fulvestrant (FUL) in SOLAR-1 significantly improved progression-free survival (HR 0.65; P<0.01) and objective response rate (measurable disease: ALP arm, 36%; placebo arm, 16%; P<0.001) in the PIK3CA mutant (mut) cohort; in the non-mut cohort, clinically relevant benefit was not observed. Here we present the prevalence of PIK3CA mutations in SOLAR-1. Methods: SOLAR-1 (N=572) is a randomized, double-blind, phase 3 study of ALP 300 mg once daily + FUL 500 mg every 28 days + Cycle 1 Day 15, in men and postmenopausal women with HR+, HER2- ABC whose disease progressed on/after an aromatase inhibitor. Tumor tissue was analyzed by PCR-based Novartis clinical trial assay or QIAGEN therascreen® PIK3CA RGQ PCR to determine PIK3CA status and assign pts to cohorts. Pts in the mut cohort had mutations in hotspots in exons 7, 9, and 20 (Table), reflecting mutations common in pts with HR+ BC and sensitive to ALP in vitro. Results: Using archival tumor tissue (92%) and fresh biopsies (8%) from randomized pts, 341 had a detectable PIK3CA mutation per primary (n=262) or metastatic (n=74) tumor or unknown (n=5); 231 had no detectable PIK3CA mutation per primary (n=174) or metastatic (n=51) tumor or unknown (n=6). Mutations in exon 20, H1047, were most prevalent (n=193; 57%); E545 (n=106; 31%), E542K (n=60; 18%), C420R (n=6; 2%), and Q546 (n=5; 1%) were also observed. Conclusions: Analysis of these data is the first step in investigating PIK3CA alterations in SOLAR-1. Further results beyond PIK3CA mutation hotspots from next-generation sequencing will be shared at the congress. NCT02437318. Table.PIK3CA MutationsExon 7C420RExon 9E542K; E545A; E545D; E545G; E545K; E545Xa; Q546E; Q546R; Q546XaExon 20H1047L; H1047R; H1047Xa; H1047YaThe Novartis clinical trial assay does not differentiate all mutations and reports E545X for E545A/D/G/K mutations, Q546X for Q546E/K/R mutations, and H1047X for H1047L/R/Y mutations. Citation Format: Hope S. Rugo, Ingrid Mayer, Pierfranco Conte, Sibylle Loibl, Mario Campone, Dejan Juric, Fabrice Andre, Marilyn Fritzemeier, Wei He, Naveen Babbar, Eva Ciruelos. Prevalence of PIK3CAmutations in patients with hormone receptor-positive, human epidermal growth factor-2-negative advanced breast cancer from the SOLAR-1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT142.

Associations of PIK3CA mutations with clinical features and prognosis in gastric cancer.

Aim: The clinical implications of PIK3CA mutations in gastric cancer (GC) are not conclusive. Materials & methods: A systematic searching of the previous publications and related studies in The Cancer Genome Atlas (TCGA) database were performed to investigate the clinical implications of PIK3CA mutations in GC. Results: Twenty-six independent cohort studies including six studies with original data were identified. Meta-analysis suggested PIK3CA mutations were associated with high T stage, poor differentiation and microsatellite instability, but not with prognosis in overall. However, PIK3CA mutation was found to be associated with favorable overall survival in subgroup of patients with low PIK3CA mutation prevalence. Conclusion: PIK3CA mutations might be involved in GC development and might be used as favorable prognostic factor in GC population with low PIK3CA mutations prevalence.

Genomic, Transcriptomic, Epigenetic, and Immune Profiling of Mucinous Breast Cancer.

Although invasive ductal breast cancer (IDC) represents the most common histological type of breast cancer, minor subtypes exist such as mucinous breast cancer (MuBC). MuBC are distinguished by tumor cells floating in extracellular mucin. MuBC patients are generally older and associated with a favorable prognosis. To unravel the molecular architecture of MuBC, we applied low-pass whole-genome sequencing and microscopic evaluation of stromal tumor infiltrating lymphocytes to 30 MuBC from a retrospective institutional cohort. We further analyzed two independent datasets from the International Cancer Genomics Consortium and The Cancer Genome Atlas. Genomic data (n = 26 MuBC, n = 535 estrogen receptor [ER] positive/HER2-negative IDC), methylation data (n = 28 MuBC, n = 529 ER-positive/HER2-negative IDC), and transcriptomic data (n = 27 MuBC, n = 467 ER-positive/HER2-negative IDC) were analyzed. MuBC was characterized by low tumor infiltrating lymphocyte levels (median = 0.0%, average = 3.4%, 95% confidence interval = 1.9% to 4.9%). Compared with IDC, MuBC had a lower genomic instability (P = .01, two-sided Mann-Whitney U test) and a decreased prevalence of PIK3CA mutations (39.7% in IDC vs 6.7% in MuBC, P = .01 in the International Cancer Genomics Consortium; and 34.8% vs 0.0%, P = .02 in The Cancer Genome Atlas, two-sided Fisher's exact test). Finally, our report identifies aberrant DNA methylation of MUC2 as a possible cause of extracellular production of mucin in MuBC.

299P - The prevalence of PIK3CA mutations in HR+/HER2– metastatic breast cancer (BELLE2, BELLE3 and BOLERO2 clinical trials)

299P - The prevalence of PIK3CA mutations in HR+/HER2– metastatic breast cancer (BELLE2, BELLE3 and BOLERO2 clinical trials)