Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer

Guarneri, Valentina; Dieci, Maria Vittoria; Frassoldati, Antonio; Maiorana, Antonio; Ficarra, Guido; Bettelli, Stefania; Tagliafico, Enrico; Bicciato, Silvio; Generali, Daniele; Cagossi, Katia; Bisagni, Giancarlo; Sarti, Samanta; Musolino, Antonino; Ellis, Catherine; Crescenzo, Rocco J.; Conte, Pierfranco

doi:10.1634/theoncologist.2015-0138

Cited by 89 publications

(124 citation statements)

References 32 publications

(24 reference statements)

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“…This TP53 mutation frequency is higher than that published for primary breast cancer and the enrichment may reflect the fact that all the patients had stage IV disease at the time of sequencing and that TP53 missense mutation is a negative prognostic factor for breast cancer . The association between PIK3CA mutations in ERBB2 amp breast cancer and the development of resistance to anti‐HER2 targeted therapy is well documented . However, to the best of our knowledge, the association between PIK3CA mutations and ERBB2 mut in breast cancer is not well known and the potential impact of PIK3CA mutations on the treatment of patients with ERBB2 mut breast cancer is currently not known.…”

Section: Discussionmentioning

confidence: 78%

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti‐HER2 targeted therapies

Ross

Gay²,

Wang

et al. 2016

Cancer

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BACKGROUND: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified. METHODS: DNA was extracted from 40 mm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (5923 mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS: Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein. CONCLUSIONS: Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016;122:2654-62. V C 2016 American Cancer Society.KEYWORDS: breast cancer, comprehensive genomic profiling, ERBB2, human epidermal growth factor receptor 2 [HER2]/neu, nextgeneration sequencing, short variants. INTRODUCTIONThe ERBB2 gene encodes a transmembrane tyrosine kinase receptor that is a member of the epidermal growth factor receptor/ human epidermal growth factor receptor (HER) family of proteins.1 ERBB2 gene amplification has been identified in 10% to 34% of invasive breast cancers, is associated with HER2 (p185 neu) protein overexpression, and has been associated with increased cell proliferation, cell motility, tumor invasiveness, progressive regional and distant metastases, accelerated angiogenesis, and reduced apoptosis.2-4 ERBB2-driven breast cancer is more frequently associated with higher histologic grade, is more often negative for estrogen receptor (ER) and p...

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Section: Discussionmentioning

confidence: 78%

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti‐HER2 targeted therapies

Ross

Gay²,

Wang

et al. 2016

Cancer

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“…To this end, we selected genes with significantly negative CARE scores, indicating that high gene expression levels correlate with lapatinib resistance. We further selected genes upregulated in lapatinib-resistant cell lines (Bailey et al, 2014; Liu et al, 2009) and negatively associated with patient response in the CHER-LOB trial (Guarneri et al, 2015). Among the 47 genes meeting these criteria, only PRKD3 and AKT3 have compound inhibitors available (Table S5A).…”

Section: Resultsmentioning

confidence: 99%

“…The gene expression profiles of pre-treatment tumors and patient clinical information were collected for vemurafenib in melanoma (Hugo et al, 2015), lapatinib in HER2+ breast cancer (Guarneri et al, 2015), pembrolizumab in melanoma (Hugo et al, 2016), and paclitaxel in breast cancer (Hatzis et al, 2011; Miyake et al, 2012; Popovici et al, 2010). In each dataset, the expression value of each gene is normalized by subtracting the mean value across all samples.…”

Section: Star Methodsmentioning

confidence: 99%

“…For example, post-treatment tumors that are resistant to drugs could be profiled for recurrent genomic and transcriptomic alterations, with pre-treatment sensitive tumors as the reference (Hugo et al, 2015). When associated with patient therapy and clinical outcome, the gene expression or mutation profiles of pre-treatment tumors could also provide insight on prognostic biomarkers (Filipits et al, 2011; Guarneri et al, 2015; van ‘t Veer et al, 2002). The ideal dataset from which to build predictive biomarkers would be systematic drug sensitivities and tumor molecular profiles (e.g., mutation, expression) across a large cohort of patients with clinical information.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Jiang

Lee

et al. 2018

Cell Systems

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Identifying reliable drug response biomarkers is a significant challenge in cancer research. We present computational analysis of resistance (CARE), a computational method focused on targeted therapies, to infer genome-wide transcriptomic signatures of drug efficacy from cell line compound screens. CARE outputs genome-scale scores to measure how the drug target gene interacts with other genes to affect the inhibitor efficacy in the compound screens. Such statistical interactions between drug targets and other genes were not considered in previous studies but are critical in identifying predictive biomarkers. When evaluated using transcriptome data from clinical studies, CARE can predict the therapy outcome better than signatures from other computational methods and genomics experiments. Moreover, the CARE signatures for the PLX4720 BRAF inhibitor are associated with an anti-programmed death 1 clinical response, suggesting a common efficacy signature between a targeted therapy and immunotherapy. When searching for genes related to lapatinib resistance, CARE identified PRKD3 as the top candidate. PRKD3 inhibition, by both small interfering RNA and compounds, significantly sensitized breast cancer cells to lapatinib. Thus, CARE should enable large-scale inference of response biomarkers and drug combinations for targeted therapies using compound screen data.

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“…Wang et al [33] found that the PI3K pathway activation resulting from PTEN loss or PIK3CA mutations leads to drug resistance to lapatinib and Tmab in metastatic breast cancer. In the neoadjuvant setting, patients with HER2-positive breast cancer who harbor a PIK3CA mutation are less likely to benefit from the combination of Tmab plus lapatinib [34]. Therefore, PIK3CA mutations may serve as predictive biomarkers to help in selecting appropriate treatment choices.…”

Section: Discussionmentioning

confidence: 99%

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

Nishimura¹,

Toh

Tanaka³

et al. 2017

Oncology

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Objective: The aim of this study was to investigate the correlation between human epidermal growth factor receptor 2 (HER2)-related biomarkers and the treatment outcomes using lapatinib plus capecitabine (LC) and to evaluate the influence of the estrogen receptor (ER) status in trastuzumab-refractory HER2-positive advanced breast cancer. Method: Eighty patients were enrolled in this study. Total HER2, p95HER2, and total HER3 expression were quantified using the VeraTag assays. PTEN (phosphatase and tensin homolog) and p95 expression was evaluated using immunohistochemistry and PIK3CA mutation using direct sequencing. Results: The response rate to LC was 30%, clinical benefit rate was 51.3%, and the median progression-free survival (PFS) was 174.5 days. ER negativity significantly correlated with higher HER2 and p95HER2. The lower HER2 and PIK3CA mutations were often observed in the nonresponders. A high p95HER2 expression correlated with longer PFS especially in the high HER2- and ER-positive cases. Patients without the PIK3CA mutation showed longer PFS in the same subset. Overall survival after LC significantly correlated with the number of recurrence organs. Conclusion: LC therapy is effective in trastuzumab-refractory HER2-positive breast cancer. Moreover, the biomarker expression differed depending on ER status, and a high p95HER2 expression and wild-type PIK3CA gene correlated with longer PFS especially in the ER-positive cases.

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Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer

Cited by 89 publications

References 32 publications

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti‐HER2 targeted therapies

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti‐HER2 targeted therapies

Genome-Scale Signatures of Gene Interaction from Compound Screens Predict Clinical Efficacy of Targeted Cancer Therapies

Role of HER2-Related Biomarkers (HER2, p95HER2, HER3, PTEN, and PIK3CA) in the Efficacy of Lapatinib plus Capecitabine in HER2-Positive Advanced Breast Cancer Refractory to Trastuzumab

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