Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations

Ross, Jeffrey S.; Ali, Siraj M.; Wang, Kai; Khaira, Depinder; Palma, Norma Alonzo; Chmielecki, Juliann; Palmer, Gary A.; Morosini, Deborah; Elvin, Julia A.; Fernandez, Sandra V.; Miller, Vincent A.; Stephens, Philip J.; Cristofanilli, Massimo

doi:10.1007/s10549-015-3592-z

Cited by 77 publications

(66 citation statements)

References 57 publications

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“…Ross et al reported a comprehensive genomic profiling on 53 IBC, formalin-fixed, paraffin-embedded specimens using the hybrid capture-based, FoundationOne™ assay [39]. The 53 sequenced IBC cases harbored a total of 266 genomic alterations (GA) with an average of 5.0 GA/tumor (range 1–15).…”

Section: Genomic Aberrations In Ibc Vs Non-ibcmentioning

confidence: 99%

“…In the TNBC subset of IBC, 8/19 (42%) showed MYC amplification (median copy number 8X, range 7–20) as compared to 9/32 (28%) in non-TNBC IBC (median copy number 7X, range 6–21). Although at 32%, the MYC amplification in IBC appeared to represent enrichment in this tumor type, comparison with the 24% MYC amplification rate in the non-IBC breast cancers did not reach statistical significance ( p = 0.26) [39]. While these small studies offer some insights in novel molecular differences, larger studies are needed to confirm and validate differences.…”

Section: Genomic Aberrations In Ibc Vs Non-ibcmentioning

confidence: 99%

“…In addition, patients with invasive, previously treated non-IBC also showed equally elevated rates of mTOR activation. Ross et al recently reported the results of a cross-sectional study involving patients with metastatic IBC that had a diagnostic biopsy of primary tumor or metastatic lesion and subsequent NGS by Foundation One™ panel [39]. The analysis of 53 IBC tumor samples revealed a total of 266 genomic alterations were observed.…”

Section: Mtor/akt Pathwaymentioning

confidence: 99%

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Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Costa¹,

Santa-Maria

Rossi

et al. 2016

Oncotarget

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Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, which accounts for approximately 3% of cases of breast malignancies. Diagnosis relies largely on its clinical presentation, and despite a characteristic phenotype, underlying molecular mechanisms are poorly understood. Unique clinical presentation indicates that IBC is a distinct clinical and biological entity when compared to non-IBC. Biological understanding of non-IBC has been extrapolated into IBC and targeted therapies for HER2 positive (HER2+) and hormonal receptor positive non-IBC led to improved patient outcomes in the recent years. This manuscript reviews recent discoveries related to the underlying biology of IBC, clinical progress to date and suggests rational approaches for investigational therapies.

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Section: Genomic Aberrations In Ibc Vs Non-ibcmentioning

confidence: 99%

Section: Genomic Aberrations In Ibc Vs Non-ibcmentioning

confidence: 99%

Section: Mtor/akt Pathwaymentioning

confidence: 99%

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Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Costa¹,

Santa-Maria

Rossi

et al. 2016

Oncotarget

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“…A greater frequency of HER2 and EGFR overexpression among IBC cases has been reported, occurring in 50% and 30% of patients, respectively [8]. Genomic profiling techniques have led to the identification of genes that are potentially involved in disease development [9–11]; however, HER2-positive IBC has not been characterised through deep exome sequencing.…”

Section: Introductionmentioning

confidence: 99%

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine

et al. 2016

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BackgroundInflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy.Methods and FindingsHER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies.ConclusionsAfatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor...

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“…IBC is frequently HER2-overexpressing, and the disease’s hallmark is the clinical inflammatory symptoms on the breast skin due to numerous dermal lymphatic emboli. Like in other cancer types, genomic profiling has led to identification of multiple genes that are involved in IBC [4,5]. Assessments of molecular features and quantitative measures of intratumor heterogeneity are now in the translation phase from the research setting, and their clinical validity is being tested [6,7].…”

mentioning

confidence: 99%

Precision Cancer Diagnostics: Tracking Genomic Evolution in Clinical Trials

Beça

Beck

2016

PLoS Med

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Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations

Cited by 77 publications

References 57 publications

Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Developmental therapeutics for inflammatory breast cancer: Biology and translational directions

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine

Precision Cancer Diagnostics: Tracking Genomic Evolution in Clinical Trials

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