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Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers After Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets

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Molecular Profiling of the Residual Disease of Triple-Negative Breast Cancers After Neoadjuvant Chemotherapy Identifies Actionable Therapeutic Targets Published OnlineFirst December 19, 2013; DOI: 10.1158/2159-8290.CD-13-0286 RESEARCH ARTICLE Molecular Profi ling of the Residual Disease of Triple-Negative Breast Cancers after Neoadjuvant Chemotherapy Identifi es Actionable Therapeutic Targets Justin M. Balko1 , 5 , Jennifer M. Giltnane2 , 5 , Kai Wang 8 , Luis J. Schwarz1 , 9 , 10 , Christian D. Young1 , Rebecca S. Cook3 , 5 , Phillip Owens 3 , Melinda E. Sanders 2 , 5 , Maria G. Kuba 2 , Violeta Sánchez 1 , Richard Kurupi 1 , Preston D. Moore 1 , Joseph A. Pinto 9 , Franco D. Doimi 9 , Henry Gómez 10 , Dai Horiuchi 6 , 7 , Andrei Goga 6 , 7 , Brian D. Lehmann 4 , Joshua A. Bauer 4 , Jennifer A. Pietenpol 4 , 5 , Jeffrey S. Ross 8 , Gary A. Palmer 8 , Roman Yelensky 8 , Maureen Cronin8 , Vincent A. Miller 8 , Phillip J. Stephens 8 , and Carlos L. Arteaga 1 , 3 , 5 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst December 19, 2013; DOI: 10.1158/2159-8290.CD-13-0286 ABSTRACT Neoadjuvant chemotherapy (NAC) induces a pathologic complete response (pCR) in approximately 30% of patients with triple-negative breast cancers (TNBC). In patients lacking a pCR, NAC selects a subpopulation of chemotherapy-resistant tumor cells. To under- stand the molecular underpinnings driving treatment-resistant TNBCs, we performed comprehensive molecular analyses on the residual disease of 74 clinically defi ned TNBCs after NAC, including next- generation sequencing (NGS) on 20 matched pretreatment biopsies. Combined NGS and digital RNA expression analysis identifi ed diverse molecular lesions and pathway activation in drug-resistant tumor cells. Ninety percent of the tumors contained a genetic alteration potentially treatable with a currently available targeted therapy. Thus, profi ling residual TNBCs after NAC identifi es targetable molecular lesions in the chemotherapy-resistant component of the tumor, which may mirror micro- metastases destined to recur clinically. These data can guide biomarker-driven adjuvant studies targeting these micrometastases to improve the outcome of patients with TNBC who do not respond completely to NAC. SIGNIFICANCE: This study demonstrates the spectrum of genomic alterations present in residual TNBC after NAC. Because TNBCs that do not achieve a CR after NAC are likely to recur as metastatic disease at variable times after surgery, these alterations may guide the selection of targeted thera- pies immediately after mastectomy before these metastases become evident. Cancer Discov; 4(2); 232–45. ©2013 AACR. INTRODUCTION have recently shown that these subtypes differ vastly in their post-NAC Ki67 scores, confounding the prognostic utility Neoadjuvant chemotherapy (NAC) is used increasingly in of Ki67 in this setting ( 10 ), and this has been confi rmed by patients with triple-negative breast cancer (TNBC), a subtype other investigators ( 9 ). Furthermore, Ki67 scoring is diffi cult lacking expression of estrogen receptor (ER), progesterone to standardize among clinical laboratories and many stud- receptor (PR), or HER2 amplifi cation. The goals of NAC are ies have defi ned different “cutoffs” for patient stratifi cation, to increase the likelihood of breast-conserving surgery and ranging from 14% to 50% ( 4–6 ). Finally, the Ki67 scoring of to eliminate clinically silent micrometastases. Approximately the post-NAC residual tumor is not actionable as it does not 30% of TNBC patients who receive NAC achieve a pathologic identify a pathogenic driver of the tumor and, as such, a drug complete response (pCR). These patients have a favorable target and rational treatment decision. recurrence-free survival (RFS) and overall survival (OS; refs. Intuition suggests that tumor cells remaining after NAC 1–3 ). The remaining patients with residual viable cancer in contain the cancer cell population intrinsically resistant to the breast or lymph nodes exhibit high rates of metastatic chemotherapy. These tumor cells likely mirror the micrometa- recurrence and an overall poor long-term outcome ( 1–3 ). static component of the disease that is ultimately responsible Immunohistochemistry (IHC) of the proliferation marker for distant metastases, and is unlikely to be highly sensitive Ki67 in post-NAC residual disease has been shown to corre- to further chemotherapy once clinical metastases become evi- late with patient outcome ( 4–6 ). Previous studies showing the dent. The standard of care for patients with TNBC who have prognostic ability of Ki67 after NAC included all subtypes of residual disease after NAC is observation, as therapies that breast cancer (i.e., HER2-enriched, luminal A, luminal B, and would be effective in reducing recurrences are unknown. Thus, basal-like), which also offer prognostic information ( 7–9 ). We we molecularly profi led the residual disease remaining after NAC in a cohort of 111 TNBCs [including gene expression analysis of 89 tumors and next-generation sequencing (NGS) Authors’ Affi liations: Departments of 1 Medicine, 2 Pathology, Microbi- ology & Immunology, 3 Cancer Biology, and 4 Biochemistry; 5 Breast Can- of 80 tumors, 74 of which were TNBC] to identify lesions that cer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt could be therapeutically targeted in adjuvant trials. University, Nashville, Tennessee; Departments of 6 Cell & Tissue Biology and 7 Medicine, University of California, San Francisco, San Francisco, California; 8 Foundation Medicine, Cambridge, Massachusetts ; 9 Oncosalud; RESULTS and 10 Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú Ki67 Does Not Predict Clinical Outcome in TNBCs Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Because TNBC is a heterogeneous subtype of breast can- Corresponding Author: Carlos L. Arteaga, Vanderbilt University Medical cer ( 11 ), we determined whether Ki67 could predict patient Center, 2200 Pierce Ave, 777 PRB, Nashville, TN 37232-6307. Phone: 615- outcome within this clinical subtype by scoring Ki67 in the 936-3524; Fax: 615-936-1790; E-mail: [email protected] residual disease of a cohort of 111 TNBCs after NAC. Patient doi: 10.1158/2159-8290.CD-13-0286 demographics are listed in Supplementary Table S1. Molecu- © 2013 American Association for Cancer Research. lar subtyping based on gene expression using the PAM50 FEBRUARY 2014CANCER DISCOVERY | 233 Downloaded from cancerdiscovery.aacrjournals.org on September 29, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst December 19, 2013; DOI: 10.1158/2159-8290.CD-13-0286 RESEARCH ARTICLE Balko et al. centroids ( 7 ) revealed a predominance of tumors with basal- (trend, P = 0.0697), and JAK2 amplifi cations (trend, P = 0.08) like gene expression (Supplementary Fig. S1A). After adjust- in the residual disease. Amplifi cations in CDK6 and CCND1, ing for seven tumors that exhibited HER2 amplifi cation (see CCND2 , and CCND3 were collectively enriched as well (24% below), 70% of TNBCs were basal-like, which is similar to in post-NAC TNBC vs. 10% in TCGA basal-like tumors). This previously published rates in larger datasets ( 12 ). Basal-like difference suggests that these alterations are present at higher status was associated with a trend toward worse RFS and frequency in chemotherapy-treated TNBCs, and may play a OS (log-rank test, P = 0.12 and 0.058, respectively; Supple- role in de novo or acquired therapeutic resistance. However, it mentary Fig. S1B). As we have previously demonstrated ( 10 ), is important to note that these comparisons of CNAs with the the Ki67 score in the residual disease varied signifi cantly TCGA data are made between platforms [NGS vs. Affymetrix among molecular subtypes within this TNBC cohort, but single-nucleotide polymorphism (SNP) arrays], and thus some was not prognostic (Supplementary Fig. S1C and S1D). Ki67 variation in calling rates and detection of alterations may be staining decreased signifi cantly in response to chemotherapy platform-specifi c. ( P < 0.0001, paired t test; Supplementary Fig. S1E), but this Identifi ed alterations were categorized into several key path- change was not different among the molecular subtypes way or functional groups: cell-cycle alterations (amplifi cations (Supplementary Fig. S1F). Tumor cellularity was signifi cantly in CDK4 , CDK6 , CCND1, CCND2, CCND3 , CCNE1 , or AURKA decreased between the pre- and post-NAC samples (paired and loss of CDKN2A CDKN2B , , or RB1 ); phosphoinositide t test, P < 0.0001; Supplementary Fig. S1G). Node status at 3-kinase (PI3K)/mTOR alterations (amplifi cations of AKT1, surgery (an established prognostic marker), but not a change AKT2, AKT3 , PIK3CA , RAPTOR , or RICTOR ; loss or mutation in Ki67, was predictive of both RFS and OS, although this of PTEN ; truncations or nonsense mutations in TSC1 ; ampli- effect seemed to be confi ned only to postmenopausal women fi cations or mutations in PIK3CA or PIK3R1 ); growth factor (Supplementary Fig. S2). These data suggest that the underly- receptor (GFR) amplifi cations ( EGFR , MET , KIT , FGFR1, 2 , and ing molecular subtype may confound the prognostic ability 4 , or IGF1R); RAS/mitogen-activated protein kinase (MAPK) of Ki67 score in the residual disease after NAC. alterations (amplifi cations/gains of KRAS , BRAF , or RAF1 , or truncations of NF1 ); or DNA repair alterations (truncations, Genomic Alterations in Drug-Resistant loss or mutations of BRCA1 or BRCA2 , or mutations in ATM ; Residual
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