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PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

ABSTRACT: The phosphoinositide 3-kinase (PI3K) pathway plays a key role in cancer, influencing growth, proliferation, and survival of tumor cells. PIK3CA mutations are generally oncogenic and responsible for uncontrolled cellular growth. PI3K inhibitors (PI3Ki) can inhibit the PI3K/AKT/mTOR pathway, although burdened by not easily manageable toxicity. Among PI3Ki, alpelisib, a selective p110α inhibitor, is approved for the treatment of hormone receptor (HR)+/HER2- PIK3CA mutant metastatic breast cancer (BC) that has progressed to a first line endocrine therapy. PIK3CA mutations are also present in triple negative BC (TNBC) and HER2+ BC, although the role of PI3K inhibition is not well established in these subtypes. In this review, we go through the PI3K/AKT/mTOR pathway, describing most common mutations found in PI3K genes and how they can be detected. We describe the available biological and clinical evidence of PIK3CA mutations in breast cancers other than HR+/HER2-, summarizing clinical trials investigating PI3Ki in these subtypes.

SUBMITTER: Ascione L

PROVIDER: S-EPMC9694420 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

Ascione Liliana L Zagami Paola P Nicolò Eleonora E Crimini Edoardo E Curigliano Giuseppe G Criscitiello Carmen C

Journal of personalized medicine 20221031 11

The phosphoinositide 3-kinase (PI3K) pathway plays a key role in cancer, influencing growth, proliferation, and survival of tumor cells. <i>PIK3CA</i> mutations are generally oncogenic and responsible for uncontrolled cellular growth. PI3K inhibitors (PI3Ki) can inhibit the PI3K/AKT/mTOR pathway, although burdened by not easily manageable toxicity. Among PI3Ki, alpelisib, a selective p110α inhibitor, is approved for the treatment of hormone receptor (HR)+/HER2- <i>PIK3CA</i> mutant metastatic br ...[more]

PMID: 36579519

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Project description:BackgroundCyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance.MethodsTissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival.ResultsNovel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C.ConclusionsWe identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET.Trial registrationClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Project description:BackgroundHER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.Patients and methodsPatients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.ResultsORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.ConclusionsThe benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Dataset Information

PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

Publications

PIK3CAMutations in Breast Cancer Subtypes Other Than HR-Positive/HER2-Negative.

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