Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer

Bidard, François-Clément; Ng, Charlotte K.Y.; Cottu, Paul; Piscuoglio, Salvatore; Escalup, Laurence; Sakr, Rita A.; Reyal, Fabien; Mariani, Pascale; Lim, Raymond S.; Wang, L.; Norton, Larry; Servois, Vincent; Sigal, Brigitte; Vincent‐Salomon, Anne; Weigelt, Britta; Pierga, Jean‐Yves; Reis‐Filho, Jorge S.

doi:10.1093/annonc/mdv217

Cited by 23 publications

(20 citation statements)

References 18 publications

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“…The validity of the ERBB3 sequencing method was successfully checked by sequencing the ERBB3 -mutated breast cancer case (G284R) mentioned in the introduction [19] and used as a positive control.…”

Section: Resultsmentioning

confidence: 99%

“…ERBB3 being unable to initiate an intracellular signal on its own, Jaiswal and colleagues demonstrated that ERBB3 mutants signal through heterodimerization with ERBB2, and that anti-ERBB2 therapies efficiently blocked ERBB3-initiated oncogenic signaling in cell lines. Our group reported a few months ago the first case of a patient who was treated by trastuzumab and lapatinib as third line regimen for ERBB2-negative metastatic breast cancer on the basis of an activating ERBB3 mutation retrieved by all-exome sequencing in both the primary tumor and liver metastases [19]. After only two weeks of dual ERBB2 blockade, the patient exhibited a complete metabolic response followed by a 20 months progression-free interval, although no chemotherapy was used.…”

Section: Introductionmentioning

confidence: 99%

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ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

et al. 2016

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ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

et al. 2016

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“…For Cases 2 and 3, no FFPE biopsies were available (Supplementary Table S2). Previous genomics analyses of case 5 were reported elsewhere (16) (Supplementary Methods). …”

Section: Methodsmentioning

confidence: 99%

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Bidard

Piscuoglio

et al. 2017

Clinical Cancer Research

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Purpose Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy. Experimental Design Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Results Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%–95%) of shared somatic mutations. Whilst mutations in known driver genes including TP53, PIK3CA and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intra-tumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2 and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Conclusion Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intra-tumor genetic heterogeneity.

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“…46 Raw data files were loaded into Nexus Express for OncoScan analysis software (BioDiscovery) and analyzed using ASCAT 47 as implemented in the Nexus Express for OncoScan software. Regions of copy number gains/losses, amplifications and homozygous deletions were generated based on the ploidy and purity adjusted modal copy numbers from ABSOLUTE (v1.0.6), 48 where segments of modal copy number 0 were considered homozygously deleted, modal copy number >0 and ≤ ploidy−1 considered lost, modal copy number ≥ ploidy considered gained and modal copy number ≥ ploidy considered amplified.…”

Section: Methodsmentioning

confidence: 99%

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

et al. 2016

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Adenoid cystic carcinoma of the breast is a rare histologic type of triple-negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple-negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Whilst the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intra-tumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple-negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by MYB-NFIB fusion gene, and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/ or the acquisition of additional genetic alterations.

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Response to dual HER2 blockade in a patient with HER3-mutant metastatic breast cancer

Abstract: This is the first-in-man evidence that anti-HER2 therapies are likely effective in breast cancers harboring HER3 activating mutations.

Cited by 23 publications

References 18 publications

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

ERBB2 mutations associated with solid variant of high-grade invasive lobular breast carcinomas

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer

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