Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial.

MedStar author(s):
Citation: Journal of Clinical Oncology. 33(12):1340-7, 2015 Apr 20.PMID: 25559813Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Antibodies, Monoclonal, Humanized/ad [Administration & Dosage] | *Breast Neoplasms/dt [Drug Therapy] | *Breast Neoplasms/ge [Genetics] | *Mutation | *Phosphatidylinositol 3-Kinases/ge [Genetics] | Antineoplastic Agents/ad [Administration & Dosage] | Breast Neoplasms/en [Enzymology] | Breast Neoplasms/pa [Pathology] | Chemotherapy, Adjuvant | Disease-Free Survival | Drug Resistance, Neoplasm | Female | Gene Expression Profiling | Humans | Neoplasm Staging | Predictive Value of Tests | Randomized Controlled Trials as Topic | Receptor, ErbB-2 | Tumor Markers, Biological/ge [Genetics]Year: 2015Local holdings: Available online from MWHC library: 1999 - present, Available in print through MWHC library: 1999 - 2008ISSN:
  • 0732-183X
Name of journal: Journal of clinical oncology : official journal of the American Society of Clinical OncologyAbstract: CONCLUSION: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.Copyright � 2015 by American Society of Clinical Oncology.PATIENTS AND METHODS: Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point.PURPOSE: Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) -positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31.RESULTS: Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64).All authors: Blackmon NL, Costantino JP, Fehrenbacher L, Finnigan M, Gavin PG, Geyer CE Jr, Jeong JH, Kim SR, Mamounas EP, Paik S, Pogue-Geile KL, Rastogi P, Song N, Swain SM, Wickerham DL, Wolmark NFiscal year: FY2015Digital Object Identifier: Date added to catalog: 2016-01-13
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 25559813 Available 25559813

Available online from MWHC library: 1999 - present, Available in print through MWHC library: 1999 - 2008

CONCLUSION: Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.Copyright � 2015 by American Society of Clinical Oncology.

PATIENTS AND METHODS: Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point.

PURPOSE: Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) -positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31.

RESULTS: Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64).

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