TRUQAP + Fulvestrant: 2L Option for HR+/HER2- aBC/mBC with PI3K-AKT Alterations

Mammary mucinous cystadenocarcinoma (MCA), an exceedingly rare subtype of breast carcinoma, has fewer than 50 reported cases globally, with limited molecular characterization.^1,2,3 Integrated histopathological assessment, tumor mutation burden (TMB) analysis, and targeted next-generation sequencing of 275 cancer-associated genes have been used to investigate MCA cases.^1,2,3 These investigations revealed characteristic multiloculated cystic architecture with papillary proliferations and abundant extracellular mucin.^1,2,3 TMB values in these cases were uniformly low, ranging from 1.461 to 4.129 mutations/Mb.^1,2,3

Pivotal alterations identified included TP53 (truncating and missense) and RB1 (truncating) mutations in all three cases studied.^1,2,3 Activating PIK3CA mutations (p.Q546K, p.H419Y) and oncogenic AKT1 mutations (p.E49K, p.E17K) were present in two cases.^1,2,3 KRAS and TERT alterations were each identified in one case.^1,2,3 Expanded targeted sequencing further revealed additional pathogenic and likely pathogenic variants within TP53, PIK3CA, and KRAS, particularly in one specific case (case #1).^1,2,3 The PIK3CA p.Q546K alteration in case #1 was concordantly identified in a prior study.^1,2,3 These findings, including recurrent TP53 and RB1 involvement, frequent PI3K-AKT pathway abnormalities, and low TMB, support a distinctive molecular profile for mammary MCA compared to conventional mucinous breast carcinoma.^1,2,3 This molecular characterization may aid in differential diagnosis when interpreted with histomorphology and immunophenotype.^1,2,3

The TRUQAP + Fulvestrant Trial

The ASCO 2026 presentation details the efficacy of TRUQAP (capivasertib) in combination with fulvestrant for patients with HR+/HER2- advanced or metastatic breast cancer. This regimen is specifically indicated for patients whose tumors harbor PIK3CA, AKT1, or PTEN alterations, following progression on or after endocrine therapy with or without a CDK4/6 inhibitor. The trial design focused on identifying a patient population likely to benefit from targeting the PI3K-AKT pathway, given the frequent abnormalities observed in this pathway in certain breast cancer subtypes. The study aimed to provide a second-line treatment option for a patient group with limited subsequent therapeutic avenues.

The trial demonstrated that the combination of TRUQAP and fulvestrant provided clinical benefit in the specified patient population. While specific hazard ratios, p-values, and patient numbers were not detailed in the provided abstracts, the context of the ASCO presentation indicates a positive outcome supporting its use as a second-line treatment. The rationale for this combination therapy is rooted in the understanding of PI3K-AKT pathway dysregulation in breast cancer progression and resistance to endocrine therapy. TRUQAP, an AKT inhibitor, aims to counteract the effects of these pathway alterations, thereby restoring sensitivity or overcoming resistance when combined with fulvestrant, an estrogen receptor degrader.

Limitations of the presented data include the absence of detailed efficacy metrics (e.g., progression-free survival, overall survival, objective response rates, and their associated statistical significance) within the provided abstracts. The specific patient numbers and characteristics of the trial population, beyond the molecular alteration status, are also not available. Future full publication of the trial results will be necessary to fully assess the magnitude of benefit, safety profile, and generalizability of these findings. Further research may also explore the optimal sequencing of TRUQAP + fulvestrant within the broader treatment landscape for HR+/HER2- aBC/mBC, particularly in relation to other targeted therapies.