Predictive Biomarker Profiling of &gt; 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications

Millis, Sherri Z.; Gatalica, Zoran; Winkler, Josiah; Vranić, Semir; Kimbrough, J. C.; Reddy, Sandeep K.; O’Shaughnessy, Joyce

doi:10.1016/j.clbc.2015.04.008

Cited by 92 publications

(82 citation statements)

References 39 publications

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“…Interestingly, NGS analyses identified a targetable alteration in 71% of patients. A majority of these alterations are related to the PIK3CA pathway supporting previous findings of high rate of PIK3CA pathway mutation among ARpositive TNBC (11,35,36). Preclinical data of antiandrogen plus PI3K inhibitor combination have also been published (11) on the basis of those findings and clinical trials are ongoing.…”

Section: Discussionsupporting

confidence: 78%

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target

Grellety

Callens

Richard

et al. 2019

Clinical Cancer Research

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Purpose: Our aim was to identify predictive factors of abiraterone acetate efficacy and putative new druggable targets in androgen receptor (AR)-positive triple-negative breast cancer (TNBC) treated in the UCBG 2012-1 trial.Experimental Design: We defined abiraterone acetate response as either complete or partial response, or stable disease at 6 months. We sequenced 91 general and breast cancer-associated genes from the tumor DNA samples. We analyzed transcriptomes from the extracted RNA samples on a NanoString platform and performed IHC using tissue microarrays. We assessed abiraterone acetate and Chk1 inhibitors (GDC-0575 and AZD7762) efficacies, either alone or in combination, on cell lines grown in vitro and in vivo.Results: Classic IHC apocrine markers including AR, FOXA1, GGT1, and GCDFP15, from patients' tumors allowed identifying abiraterone acetate-responders and nonrespon-ders. All responders had clear apocrine features. Transcriptome analysis revealed that 31 genes were differentially expressed in the two subgroups, 9 of them being linked to proliferation and DNA damage repair. One of the most significant differences was the overexpression, in nonresponders, of CHEK1, a gene encoding Chk1, a protein kinase that can be blocked by specific inhibitors. On the basis of cell line experiments, abiraterone acetate and Chk1 inhibitor combination showed at least additive effect on cell viability, cell cycle, apoptosis, and accumulation of DNA damages. In vivo, orthotopic xenograft experiments confirmed the efficacy of this combination therapy.Conclusions: This study suggests that apocrine features can be helpful in the identification of abiraterone acetateresponders. We identified Chk1 as a putative drug target in AR-positive TNBCs.

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Section: Discussionsupporting

confidence: 78%

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target

Grellety

Callens

Richard

et al. 2019

Clinical Cancer Research

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“…7–9 Additionally, approximately half of triple-negative breast cancers have deficient expression of the tumour suppressor PTEN, which is associated with a higher degree of AKT pathway activation. 2,10 …”

Section: Introductionmentioning

confidence: 99%

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Kim¹,

Dent²,

Im³

et al. 2017

The Lancet Oncology

404

327

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Summary Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche.

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“…Enrichment in PIK3CA mutations has been described in triple-negative tumors that are AR-positive (36%-40%) by IHC compared with AR-negative (4%-9%; refs. 30,31), the majority of which are located in the kinase domain…”

Section: Androgen Receptor-positive Tnbcmentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specifi c molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profi ling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratifi cation of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.Signifi cance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identifi cation of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population. TNBC AND INTRINSIC BREAST CANCER SUBTYPESEarly transcriptomic profi ling of breast cancer using microarrays classifi ed tumors into fi ve intrinsic subtypes: luminal-A, luminal-B, HER2-enriched, basal-like, and a normal breast-like group ( 5,6 ). Although all intrinsic subtypes can be found within immunohistochemically defi ned triplenegative disease, basal-like tumors exhibit the greatest overlap with TNBC. Between 50% and 75% of TNBC have basal phenotype, and approximately 80% of basal-like tumors are ER-negative/HER2-negative ( Fig. 2 ; refs. 7, 8 ). Characterization Research.on August 1, 2020.

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Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications

Cited by 92 publications

References 39 publications

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target

Enhancing Abiraterone Acetate Efficacy in Androgen Receptor–positive Triple-negative Breast Cancer: Chk1 as a Potential Target

Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

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