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PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications.

ABSTRACT: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role. RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (n = 140) included in a prospective study (NCT01322893). Gene expression analyses were performed using the Breast Cancer 360 (BC360) assay from Nano-String. The subtype shifts were evaluated using McNemar and symmetry tests, and clinical outcomes were evaluated with log-rank tests and Cox regression. The PAM50 subtype changed in 25/59 of paired samples between PTs and LNMs (Psymmetry = 0.002), in 31/61 between PTs and DMs (Psymmetry < 0.001), and in 16/38 between LNMs and DMs (Psymmetry = 0.004). Shifts toward subtypes with worse outcomes were the most common. Patients with shifts from the luminal PT to non-luminal DM subtypes had worse progression-free survival compared to patients with a stable subtype (hazard ratio (HR): 2.3; 95% confidence interval (CI): 1.14-4.68, p = 0.02). Strong evidence of PAM50 subtype shifts toward unfavorable subtypes were seen between PTs and metastatic samples. For patients with a shift in subtype from luminal PT to non-luminal DM, a worse prognosis was noted.

SUBMITTER: Jorgensen CLT

PROVIDER: S-EPMC8037951 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications.

Jørgensen Charlotte Levin Tykjær CLT Larsson Anna-Maria AM Forsare Carina C Aaltonen Kristina K Jansson Sara S Bradshaw Rachel R Bendahl Pär-Ola PO Rydén Lisa L

Cancers 20210330 7

<h4>Background</h4>PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role.<h4>Methods</h4>RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (<i>n</i> = 140) included in a prospective study (NCT01322893). Gene e ...[more]

PMID: 33808271

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Project description:BACKGROUND:The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown. MATERIALS AND METHODS:This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated. RESULTS:Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47-0.94; p = .020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07-2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p = .433). CONCLUSION:The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting. IMPLICATIONS FOR PRACTICE:Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%-30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer.

Dataset Information

PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications.

Publications

PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications.

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