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Molecular Prognostic Factors for Distant Metastases in Premenopausal Patients with HR+/HER2- Early Breast Cancer.

ABSTRACT: Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2- EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7-184) months; M0, n = 49, median follow-up: 149 (121-191) months). Gene expression profiling on tumor RNA (Breast Cancer 360^TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2- EBC potentially applicable in future clinical practice.

SUBMITTER: Ni H

PROVIDER: S-EPMC8468490 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:In premenopausal patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, the gonadotoxicity of trastuzumab and lapatinib remains largely uncertain, and the prognostic effect of treatment-related amenorrhea (TRA) is unknown. Methods:In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (BIG 2-06) phase III trial, HER2-positive early breast cancer patients were randomized (1:1:1:1) to receive one year of trastuzumab, lapatinib, their sequence, or their combination. As per study protocol, menopausal status was collected in all patients at random assignment and at week 37 visit. We investigated TRA rates and whether TRA in patients with hormone receptor-positive and -negative tumors would impact disease-free survival (DFS) and overall survival (OS). Landmark and time-dependent modeling were used to account for guarantee-time bias. All statistical tests were two-sided. Results:A total of 2862 premenopausal women were included, of whom 1679 (58.7%) had hormone receptor-positive disease. Median age was 43 (interquartile range = 38-47) years. Similar TRA rates were observed in the trastuzumab (72.6%), lapatinib (74.0%), trastuzumab?lapatinib (72.1%), and trastuzumab+lapatinib (74.8%) arms (P = .64). The association between TRA and survival outcomes differed according to hormone-receptor status (Pinteraction for DFS = .007; Pinteraction for OS = .003). For hormone receptor-positive patients, the TRA cohort had statistically significantly better DFS (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.45 to 0.76) and OS (aHR = 0.63, 95% CI = 0.40 to 0.99) than the no TRA cohort. No difference was observed in hormone receptor-negative patients. Conclusions:In this unplanned analysis, no association between TRA rate and type of anti-HER2 treatment was observed. TRA was associated with statistically significant survival benefits in premenopausal hormone receptor-positive/HER2-positive early breast cancer patients.

Project description:PurposeAdvanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2- advanced breast cancer.MethodsA systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).ResultsSeventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥50% of the population were HR+/HER2-. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.ConclusionMultiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2- advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.

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Molecular Prognostic Factors for Distant Metastases in Premenopausal Patients with HR+/HER2- Early Breast Cancer.

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