Molecular Landscape of Tp53 Mutations in Breast Cancer and Their Utility for Predicting Response to HER-Targeted Therapy in HER2 Amplification-Positive and HER2 Mutation-Positive Amplification-Negative Patients

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer

npj Breast Cancer ◽

10.1038/s41523-020-00201-9 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Zongbi Yi ◽

Guohua Rong ◽

Yanfang Guan ◽

Jin Li ◽

Lianpeng Chang ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Targeted Therapy ◽

Partial Response ◽

Objective Response ◽

Metastatic Breast ◽

Complete Response ◽

Her2 Amplification ◽

Cox Regression Analysis ◽

Molecular Landscape

Abstract Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%, P < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25–5.65, P = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.

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HER2-Positive Neuroendocrine Breast Cancer: Case Report and Review of Literature

Breast Care ◽

10.1159/000453572 ◽

2016 ◽

Vol 11 (6) ◽

pp. 424-426 ◽

Cited By ~ 2

Author(s):

Arpine Gevorgyan ◽

Giacomo Bregni ◽

Giulia Galli ◽

Elisa Zanardi ◽

Filippo de Braud ◽

...

Keyword(s):

Breast Cancer ◽

Case Report ◽

Targeted Therapy ◽

Neuroendocrine Carcinoma ◽

Immunohistochemical Analysis ◽

Breast Cancer Case ◽

Cancer Case ◽

Review Of Literature ◽

Her2 Amplification ◽

Her2 Positive

Background: Neuroendocrine carcinoma is an uncommon histology for breast cancer. Case Report: Our patient underwent right quadrantectomy for a neuroendocrine carcinoma in 1984 and had a bone relapse 30 years later. After thorough pathological and immunohistochemical analysis the diagnosis was confirmed and HER2 amplification was observed. Here we discuss the management, rationale and results of HER2-targeted therapy in advanced neuroendocrine breast carcinoma.

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Clinical relevance of comprehensive genomic profiling for advanced cancers in India.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e18718 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e18718-e18718

Author(s):

Serena Elizabeth Joseph ◽

Aju Mathew ◽

Senthill J. Rajappa ◽

Nitesh Rohatgi ◽

Bhawna Sirohi ◽

...

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Targeted Therapy ◽

Genetic Alteration ◽

Insertion Mutation ◽

Study Cohort ◽

Genomic Profiling ◽

Her2 Amplification ◽

Low Middle Income Countries ◽

Comprehensive Genomic Profiling

e18718 Background: Comprehensive genomic profiling (CGP) assay, a next-generation sequencing (NGS) based technique generates a large amount of genomic information about a cancer. While CGP is increasingly used in low-middle income countries (LMIC), little is known about the extent to which these benefits patients. Here we describe the proportion of patients with advanced cancer in India who eventually receive targeted therapy for an actionable genetic alteration identified on CGP assays. Methods: This was a multicenter, retrospective cohort study in adult patients with advanced non-hematological malignancies who underwent a CGP test. We excluded patients who were identified to have a genetic alteration that has a well-validated targeted standard-of-care therapy (e.g.; EGFR exon 18, 19, 21 mutations for lung cancer, HER2 amplification for breast cancer). Participating oncologists provided anonymized information of consecutive CGP test reports through an online data capture form. Descriptive statistics were used to describe the proportion of patients with subsequent targeted therapy. Results: During 2019-20, 12 medical oncologists provided CGP reports for 297 patients; 235 met the inclusion criteria. Fourteen different testing panels were used by the oncologists. Among the study cohort, 45% were male. Eighty nine percent underwent tumor tissue biopsy and 11% had liquid biopsy. The most common cancers were lung (19%), breast (18%), pancreatobiliary (9%) and colorectal (6%). Patients received a median of 2 lines (range: 0-5) of prior systemic therapy. Based on the CGP assay, 35 patients (15%) received targeted therapy. Among them, 29% was for HER2 amplification (non-breast cancer), 26% for PIK3CA mutation, 11% for HER2 or EGFR exon 20 insertion mutation (lung cancer), 5% each for BRAF mutation (non-melanoma), EGFR mutation (non-lung cancer) and MET mutation. Conclusions: In a LMIC setting, 15% patients received a targeted therapy based on CGP assay. This is comparable to reports from high income countries. Considering the limited access to new drugs and clinical trials, this finding requires further analysis.

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Targeted Therapy in Brain Metastases: Ready for Primetime?

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_100006 ◽

2016 ◽

pp. e123-e130 ◽

Cited By ~ 6

Author(s):

Vyshak A. Venur ◽

Manmeet S. Ahluwalia

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Targeted Therapy ◽

Brain Metastases ◽

Targeted Therapies ◽

Future Directions ◽

Anaplastic Lymphoma ◽

Cancer Breast ◽

Current State ◽

Her2 Mutation

Brain metastasis is a serious complication of cancer that causes significant morbidity for patients. Over the last decade, numerous new driver somatic mutations have been recognized and targeted therapies are changing the landscape of treatment in lung cancer, breast cancer, and melanoma, which are also the three most common cancers that result in brain metastases. The common actionable mutations include the EGFR mutation and anaplastic lymphoma kinase (ALK) translocations in non–small cell lung cancer, the HER2 mutation in breast cancer, and the BRAF mutation in melanoma. However, most of the early trials with targeted agents excluded patients with brain metastases. With a better understanding of the biology, several recent trials of targeted therapy that focus on brain metastases have been reported and others are ongoing. Novel agents with better penetration across the blood–brain barrier are currently being investigated for patients with brain metastases. In this review, we discuss the current state of use and future directions of targeted therapies in brain metastases.

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Automated, IHC/FISH-free, H&E histopathology image-based HER2 amplification, tumor infiltrating lymphocyte (TIL) and tumor heterogeneity profiling in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.593 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 593-593

Author(s):

Satabhisa Mukhopadhyay ◽

Tathagata Dasgupta ◽

Nicolas M Orsi ◽

Michele Cummings ◽

Angelene Berwick

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Tumor Heterogeneity ◽

Breast Biopsy ◽

Real Life ◽

Hazard Ratio ◽

Her2 Status ◽

Her2 Amplification ◽

Tumor Infiltrating Lymphocyte ◽

Diagnostic Time

593 Background: Digital pathology has fostered the development of automated diagnostic solutions. However, current technologies in breast cancer remain unable to determine HER2 amplification status, which is established by immunohistochemistry (IHC) and/or fluorescent in situ hybridization (FISH). These ancillary tests carry a significant cost, prolong diagnostic time and fail to capture HER2 tumor heterogeneity and tumor infiltrating lymphocyte (TIL) burden, both of which determine the effectiveness anti-HER2 targeted therapy. Methods: This study describes the real-life clinical context development and validation of a patented novel, universal, automated, white-box, scanning platform agnostic solution that determines HER2 amplification status, prognostically significant TIL levels and tumor heterogeneity index (HI) from hematoxylin and eosin (H&E) stained malignant breast biopsy whole slide images (WSIs) alone. Unlike conventional artificial intelligence-based approaches, the underlying proprietary algorithm’s prediction criteria are explainable and are based on deterministic, hard-coded observational relationships of scale constructed from image morphological features mapped to observables representing underlying tumor-related perturbations in biological pathways/mitotic checkpoints.This includes G1/S deregulation signatures reflecting oncogenic HER2-neu. Results: Blinded validation of HER2 status prediction (n = 197 WSIs; 118 independent cases/patients) showed excellent diagnostic performance (κ = 0.85) relative to existing standard-of-care methodologies. This was independent of WSI file format, background histology, tumor subtype/grade or hormone receptor status. The device also displayed good accuracy (92%) in determining TIL profiles, and its combined HER2-TIL and HER2-HI prediction scales both exhibited a significant association with progression-free survival (CoxPH hazard ratio: 1.856; 95% CI: 1.002-3.438; p = 0.049 and CoxPH hazard ratio: 3.45; 95% CI: 0.95-12.55; p = 0.060). Conclusions: This technology opens up the future possibility of bypassing existing ancillary HER2 profiling investigations, thus potentially reducing laboratory workloads/healthcare costs while accelerating diagnostic turnaround times for patient benefit. In the interim, if used as an adjunct tool, this device could provide an objective HER2 testing reference scale while the robustness of its prediction of patient response to anti-HER2 targeted therapy is fully explored.

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Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Science Signaling ◽

10.1126/scisignal.aat9773 ◽

2018 ◽

Vol 11 (551) ◽

pp. eaat9773 ◽

Cited By ~ 19

Author(s):

Emiliano Cocco ◽

F. Javier Carmona ◽

Pedram Razavi ◽

Helen H. Won ◽

Yanyan Cai ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Xenograft Model ◽

Growth Factor Receptor ◽

Poor Response ◽

Breast Cancer Patients ◽

Her2 Amplification ◽

Sequencing Data ◽

Her2 Positive ◽

Her2 Mutation

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

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