Introduction: Somatic mutations in the PIK3CA/AKT/mTOR pathway are associated with resistance to first-line endocrine therapy in hormone-receptor positive (HR+) breast cancer (BC). PIK3CA and AKT1 mutations are reported in 35-40% and 4-7% of HR+ BC respectively, with less published about the rates of co-occurrence (PMID: 32983983). Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib. Prior cohort data showed limited benefit of alpelisib after everolimus (PMID:36292649). Recent data notes that AKT emergent mutations may be a resistance mechanism to PIK3CA inhibition (PMID: 37916958). As Capitello-291, BYLieve, and SOLAR-1 excluded patients with prior PIK3CA/AKT/mTOR inhibitors, minimal data exists on how to optimally select and sequence these therapies. Here we present a case of a patient with co-occurring PIK3CA and AKT1 mutations who gained clinical benefit from alpelisib and subsequently capivasertib.

Case presentation: A 64-year-old female presented with a left-sided parasternal mass. She had a prior estrogen receptor positive (ER+), human epidermal growth factor negative (HER2-) left mixed ductal and lobular carcinoma (pT2pN1a) 17 years ago, treated with lumpectomy, chemotherapy, radiation and 10 years of adjuvant endocrine therapy. 7 years later, PET-CT revealed presence of metastatic disease in the sternum and supraclavicular lymph nodes. Biopsy of the parasternal mass noted invasive ductal carcinoma, grade II, ER low+ (11-20%), progesterone receptor negative (PR-), HER2-. A second site biopsy was ER-, PR-, and HER2-. Tempus tumor sequencing of this sample noted both AKT1 E17K [variant allele fraction (VAF) 21.4%] as well as PIK3CA E545K mutation (VAF 8.1%). The patient progressed on several lines of therapy due to adverse effects and disease progression. She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned. However, the patient developed transaminitis after the first fulvestrant treatment, prior to initiation of alpelisib, which resolved with steroids. After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated. The patient had a partial metabolic response on PET/CT imaging and eventually progressed on alpelisib and exemestane after 15 months. Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months. Guardant 360 liquid biopsy testing revealed the same prior AKT1 E17K (VAF 2%) and PIK3CA E454K alteration (VAF 1.7%). She started 9th line therapy with the pan-AKT inhibitor capivasertib with fulvestrant. Guardant Response assessment after 4 weeks noted clearing of the AKT1 and PIK3CA mutations with no cfDNA detectable. 2-month follow-up PET-CT revealed significant favorable response to treatment. At 6-month follow-up, the patient continues on this treatment. We interrogated publicly available datasets in TCGA, MSK-IMPACT, METABRIC, and AURORA and note that across 7204 samples, mutation prevalence for PIK3CA and AKT1 was 39% and 5%, with significant mutual exclusivity and co-occurrence observed in only 41/7204 samples (0.6%) (PMID: 22588877).

Conclusion: This case report highlights a response of AKT1 targeted therapy with capivasertib in a patient who previously progressed on PIK3CA targeted therapy with alpelisib. Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

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