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Review
. 2021 Oct:59:339-350.
doi: 10.1016/j.breast.2021.07.019. Epub 2021 Aug 5.

Dissecting the biological heterogeneity of HER2-positive breast cancer

Francesco Schettini  1 , Aleix Prat  2
Affiliations
Review

Dissecting the biological heterogeneity of HER2-positive breast cancer

Francesco Schettini et al. Breast. 2021 Oct.

Abstract

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.

Keywords: Breast cancer; HER2; HER2-enriched; Intrinsic subtypes; PAM50; TILs.

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Conflict of interest statement

Declaration of competing interest F.S. declares no conflict of interest. A.P. declares an immediate family member being employed by Novartis; fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g. speakers' bureaus); personal honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly and Daiichi Sankyo; travel, accommodations and expenses paid by Daiichi Sankyo; research funding from PUMA, Nanostring Technologies, Roche and Novartis; consulting/speaker/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer, PUMA, Seattle Genetics, AstraZeneca, Guardant Health, Foundation Medicine and Bristol-Myers Squibb; patent PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY and HER2DX (filed); founder of Reveal Genomics.

Figures

Fig. 1
Fig. 1
Intrinsic subtype distribution in cHER2+ tumors.Legend. HR: hormone receptors; +: positive; -: negative. Number of samples: 3390 HR+/HER2+ tumors and 2567 HR-/HER2+ tumors.
Fig. 2
Fig. 2
HER2-dependent pathway for proliferation and survival in HER2+ breast cancer.Legend. cHER2+: clinically HER2-positive; HER2-E: HER2-Enriched. The red cone visually suggests a higher activation of the HER2-related pathway in cHER2+/HER2-E tumors, compared to cHER2+/non-HER2-E.
Fig. 3
Fig. 3
Mutational spectrum of cHER2+ primary tumors.Legend. cHER2+: clinically HER2-positive.
Fig. 4
Fig. 4
Representative sections of TILs in early-stage HER2+ breast tumors.Legend. TILs: tumor-infiltrating lymphocytes. TILs levels increase from left to right.
Fig. 5
Fig. 5
HER2 protein levels detected by immunohistochemistry and ERBB2 mRNA levels according to HER2 IHC status.Legend. Representative pathological images of cHER2+ and cHER2-negative tumors courtesy of the Hospital Clinic of Barcelona Pathology Department and ERBB2 mRNA expression levels (log2 values) across HER2 IHC categories, as observed in 146 metastatic samples analyzed at the Translational Genomics and Targeted Therapies in Solid Tumors laboratory at IDIBAPS. HER2 protein and mRNA levels increase from left to right. HER2+: HER2-positive; IHC immunohistochemistry.
Fig. 6
Fig. 6
Personalized medicine in cHER2+ breast cancer.Legend. TILs: tumor-infiltrating lymphocytes.
See this image and copyright information in PMC

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