Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –posit... more Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by theMKI67 gene (Ki67) level was . 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was. 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of . 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox mode...
The role of biomarkers has increased in cancer clinical trials such that novel designs are needed... more The role of biomarkers has increased in cancer clinical trials such that novel designs are needed to efficiently answer questions of both drug effects and biomarker performance. We advocate Bayesian hierarchical models for response-adaptive randomized phase II studies integrating single or multiple biomarkers. Prior selection allows one to control a gradual and seamless transition from randomizedblocks to marker-enrichment during the trial. Adaptive randomization is an efficient design for evaluating treatment efficacy within biomarker subgroups, with less variable final sample sizes when compared to nested staged designs. Inference based on the Bayesian hierarchical model also has improved performance in identifying the sub-population where therapeutics are effective over independent analyses done within each biomarker subgroup. The use of Bayesian hierarchical models for adaptive randomization in biomarker-driven phase II studies Running title: Bayesian hierarchical models for ada...
BACKGROUND HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 20... more BACKGROUND HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM). METHODS All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated. RESULTS Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P<0.0001). Me...
The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drug... more The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drugs. However, immunotherapy combinations have shown promising activity, targeted chemotherapy options via antibody–drug conjugates are in the clinic, and molecular means of identifying targetable subsets are on the horizon. This Clinical Outlook discusses current and future possibilities for treating triple-negative breast cancer.
Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tu... more Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O9Shaughnessy, Javier Cortes, Michaela Tsai, Linda Vahdat, Veronique Dieras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-06.
PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–pos... more PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tuca...
PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 ... more PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34...
American Society of Clinical Oncology Educational Book
Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development... more Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development of multiple highly effective HER2-targeting drugs has transformed treatment and survival. These drugs include the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab; small molecule inhibitors lapatinib, neratinib, and tucatinib; and antibody-drug conjugates trastuzumab emtansine (T-DM1) and now trastuzumab deroxtecan. More complex regimens using these drugs continue to improve outcomes, but the incremental benefits of these advances are often modest. Improved outcomes came from the addition of HER2-targeted therapies to conventional chemotherapy, beginning with trastuzumab, then pertuzumab added to trastuzumab, or with neratinib given for the year after trastuzumab. Neoadjuvant, or preoperative, administration of chemotherapy plus HER2-targeting allows surgical deescalation and tailoring treatment by pathologic complete response (pCR) to therapy. Patients with pCR after conventi...
500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased... more 500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied fo...
501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but ... more 501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) + HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2+ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of succes...
With increasingly effective treatments, breast cancer outcomes have markedly improved, so goals o... more With increasingly effective treatments, breast cancer outcomes have markedly improved, so goals of research in the modern era must be to tailor treatment to risk and response - we must escalate therapy in those who need better, more effective drugs, but we must also de-escalate therapy in those who are overtreated by current approaches. Research priorities in the upcoming years will be to better identify tumor biologic features conferring a high sensitivity to drugs, thereby allowing more tailored and less aggressive regimens, as well as tumor features conferring resistance to drugs, which can be then be omitted. The neoadjuvant approach to therapy, which has become the standard for HER2-positive and triple negative breast cancer, has already given us response-tailored therapy through the advent of residual disease strategies; we will need to learn to leverage this approach even more to further tailor treatment and maximize clinical benefit.
Purpose Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosi... more Purpose Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosis, interpretable as two main etiologic subtypes or groupings of tumors with shared risk factors. While RNA-based methods including PAM50 have identified well-established clinical subtypes, age distribution patterns at diagnosis as a proxy for etiologic subtype are not established for molecular and genomic tumor classifications. Methods We evaluated smoothed age frequency distributions at diagnosis for Carolina Breast Cancer Study cases within immunohistochemistry-based and RNA-based expression categories. Akaike information criterion (AIC) values compared the fit of single density versus two-component mixture models. Two-component mixture models estimated the proportion of early-onset and late-onset categories by immunohistochemistry-based ER (n = 2860), and by RNA-based ESR1 and PAM50 subtype (n = 1965). PAM50 findings were validated using pooled publicly available data (n = 8103). Resu...
Purpose Nurse practitioners, physician assistants, and pharmacists are advanced practice provider... more Purpose Nurse practitioners, physician assistants, and pharmacists are advanced practice providers who are highly trained and qualified healthcare professionals that can help support traditional demands on oncologists' increased time in direct patient care. The purpose of this study was to detail and assess the creation of a privileging process for this group of medical professionals within an academic medical center. Obtaining the designation of limited oncology practice provider (LOPP) gives the right to modify chemotherapy orders and to order supportive care medications. Methods An interdisciplinary team developed a comprehensive training process inclusive of required educational domains, knowledge goals, and educational activities to become an LOPP. In 2018, five years after the implementation of the privileging process, a survey was distributed to assess perceptions of the training process and integration of LOPPs within oncology practice. Results Most oncologists noted tha...
506 Background: Response to chemotherapy and HER2-targeting varies by molecular subtype. In C4060... more 506 Background: Response to chemotherapy and HER2-targeting varies by molecular subtype. In C40601, 305 patients (pts) with stage II-III HER2+ BrCa were randomized to receive 16 weeks of preoperative paclitaxel and trastuzumab (TH), T and lapatinib (TL), or THL, and were followed for pCR. Primary data were reported previously. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 271 pre-Rx and 136 matched post-Rx samples. RNAseq was normalized to HER2+ tumors in The Cancer Genome Atlas Project, and genomic signatures applied including intrinsic subtype and immune cell features. Results: 60% of pre-Rx specimens were hormone receptor+. Overall, 30% were Luminal A, 31% Luminal B, 31% HER2-Enriched, 5% Basal-like, 2% Normal-like, and 1% Claudin-Low. In-breast pCR was 46%, which varied significantly by subtype: Luminal A 35%, Luminal B 36%, Basal-Like 36%, HER2-Enriched 69% (p<0.0001). Within HER2-Enriched, pCR rates by arm were: 50% TL, 71% TH, 80% THL. pCR also varied by risk of relapse scor...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018
Purpose Racial variation in the financial impact of cancer may contribute to observed differences... more Purpose Racial variation in the financial impact of cancer may contribute to observed differences in the use of guideline-recommended treatments. We describe racial differences with regard to the financial impact of breast cancer in a large population-based prospective cohort study. Methods The Carolina Breast Cancer Study oversampled black women and women younger than age 50 years with incident breast cancer in North Carolina from 2008 to 2013. Participants provided medical records and data regarding demographics, socioeconomic status, and financial impact of cancer at 5 and 25 months postdiagnosis. We report unadjusted and adjusted financial impact at 25 months postdiagnosis by race. Results The sample included 2,494 women who completed follow-up surveys (49% black, 51% white). Since diagnosis, 58% of black women reported any adverse financial impact of cancer ( v 39% of white women; P < .001). In models adjusted for age, stage at diagnosis, and treatment received, black women ...
Journal of the National Cancer Institute, Jan 20, 2018
Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome dispar... more Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome disparities, but racial differences in ET behaviors are poorly understood. Women aged 20-74 years with a first primary, stage I-III, hormone receptor-positive (HR+) breast cancer were included. At 2 years postdiagnosis, we assessed nonadherence, defined as not taking ET every day or missing more than two pills in the past 14 days, discontinuation, and a composite measure of underuse, defined as either missing pills or discontinuing completely. Using logistic regression, we evaluated the relationship between race and nonadherence, discontinuation, and overall underuse in unadjusted, clinically adjusted, and socioeconomically adjusted models. A total of 1280 women were included; 43.2% self-identified as black. Compared to white women, black women more often reported nonadherence (13.7% vs 5.2%) but not discontinuation (10.0% vs 10.7%). Black women also more often reported the following: hot flas...
Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer ... more Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer (ER + MBC) holds promise as an early predictor of therapeutic response. Here, we developed dPCR-SEQ, a customized assay that utilizes digital PCR-based target enrichment followed by next-generation sequencing to analyze plasma DNA mutations in ESR1, PIK3CA, and TP53. We validated dPCR-SEQ in a prospective cohort of 58 patients with ER + MBC and demonstrate excellent concordance with hotspot ESR1 mutation abundance measured by conventional digital PCR. The dPCR-SEQ assay revealed ESR1, PIK3CA, and TP53 plasma ctDNA mutations in 55%, 32%, and 32% of the study patients, respectively. We also observed dynamic changes in ESR1, PIK3CA, and TP53 ctDNA mutant allele fraction (MAF) that were frequently discordant between the different genes. Thus, monitoring plasma DNA mutation dynamics using a dPCR-SEQ assay is feasible, accurate, and may be investigated as a biomarker of therapeutic response in ER + MBC.
Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be signif... more Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be significantly prognostic in breast cancer but have not yet been applied for calculation of risk of recurrence in clinical assays. A compact set of 17 immunity genes was derived herein from an Affymetrix-derived gene expression dataset including 1951 patients (AFFY1951). The 17 immunity genes demonstrated significant prognostic stratification of estrogen receptor (ER)-negative breast cancer patients with high proliferation gene expression. Further analysis of blood and breast cancer single-cell RNA-seq datasets revealed that the 17 immunity genes were derived from TIL that were inactive in the blood and became active in tumor tissue. Expression of the 17 immunity genes was significantly ( < 2.2E-16, = 91) correlated with TILs percentage on H&E in triple negative breast cancer. To demonstrate the impact of tumor immunity genes on prognosis, we built a Cox model to incorporate breast cancer s...
Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –posit... more Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by theMKI67 gene (Ki67) level was . 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was. 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of . 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox mode...
The role of biomarkers has increased in cancer clinical trials such that novel designs are needed... more The role of biomarkers has increased in cancer clinical trials such that novel designs are needed to efficiently answer questions of both drug effects and biomarker performance. We advocate Bayesian hierarchical models for response-adaptive randomized phase II studies integrating single or multiple biomarkers. Prior selection allows one to control a gradual and seamless transition from randomizedblocks to marker-enrichment during the trial. Adaptive randomization is an efficient design for evaluating treatment efficacy within biomarker subgroups, with less variable final sample sizes when compared to nested staged designs. Inference based on the Bayesian hierarchical model also has improved performance in identifying the sub-population where therapeutics are effective over independent analyses done within each biomarker subgroup. The use of Bayesian hierarchical models for adaptive randomization in biomarker-driven phase II studies Running title: Bayesian hierarchical models for ada...
BACKGROUND HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 20... more BACKGROUND HER2CLIMB (NCT02614794) primary results have been reported previously (Murthy, NEJM 2019). We report results of exploratory efficacy analyses in pts with brain metastases (BM). METHODS All HER2+ MBC pts enrolled had a baseline brain MRI. Pts with BM were eligible and randomized 2:1 to receive tucatinib (TUC) or placebo, in combination with trastuzumab and capecitabine. Efficacy analyses were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR-IC and DOR-IC were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy until second progression, and time from randomization to second progression or death was evaluated. RESULTS Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; P<0.0001). Me...
The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drug... more The treatment of triple-negative breast cancer remains chemotherapy based and lacks targeted drugs. However, immunotherapy combinations have shown promising activity, targeted chemotherapy options via antibody–drug conjugates are in the clinic, and molecular means of identifying targetable subsets are on the horizon. This Clinical Outlook discusses current and future possibilities for treating triple-negative breast cancer.
Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tu... more Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O9Shaughnessy, Javier Cortes, Michaela Tsai, Linda Vahdat, Veronique Dieras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-06.
PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–pos... more PURPOSE In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS There were 291 patients with BMs: 198 (48%) in the tuca...
PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 ... more PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34...
American Society of Clinical Oncology Educational Book
Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development... more Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development of multiple highly effective HER2-targeting drugs has transformed treatment and survival. These drugs include the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab; small molecule inhibitors lapatinib, neratinib, and tucatinib; and antibody-drug conjugates trastuzumab emtansine (T-DM1) and now trastuzumab deroxtecan. More complex regimens using these drugs continue to improve outcomes, but the incremental benefits of these advances are often modest. Improved outcomes came from the addition of HER2-targeted therapies to conventional chemotherapy, beginning with trastuzumab, then pertuzumab added to trastuzumab, or with neratinib given for the year after trastuzumab. Neoadjuvant, or preoperative, administration of chemotherapy plus HER2-targeting allows surgical deescalation and tailoring treatment by pathologic complete response (pCR) to therapy. Patients with pCR after conventi...
500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased... more 500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied fo...
501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but ... more 501 Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) + HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2+ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of succes...
With increasingly effective treatments, breast cancer outcomes have markedly improved, so goals o... more With increasingly effective treatments, breast cancer outcomes have markedly improved, so goals of research in the modern era must be to tailor treatment to risk and response - we must escalate therapy in those who need better, more effective drugs, but we must also de-escalate therapy in those who are overtreated by current approaches. Research priorities in the upcoming years will be to better identify tumor biologic features conferring a high sensitivity to drugs, thereby allowing more tailored and less aggressive regimens, as well as tumor features conferring resistance to drugs, which can be then be omitted. The neoadjuvant approach to therapy, which has become the standard for HER2-positive and triple negative breast cancer, has already given us response-tailored therapy through the advent of residual disease strategies; we will need to learn to leverage this approach even more to further tailor treatment and maximize clinical benefit.
Purpose Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosi... more Purpose Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosis, interpretable as two main etiologic subtypes or groupings of tumors with shared risk factors. While RNA-based methods including PAM50 have identified well-established clinical subtypes, age distribution patterns at diagnosis as a proxy for etiologic subtype are not established for molecular and genomic tumor classifications. Methods We evaluated smoothed age frequency distributions at diagnosis for Carolina Breast Cancer Study cases within immunohistochemistry-based and RNA-based expression categories. Akaike information criterion (AIC) values compared the fit of single density versus two-component mixture models. Two-component mixture models estimated the proportion of early-onset and late-onset categories by immunohistochemistry-based ER (n = 2860), and by RNA-based ESR1 and PAM50 subtype (n = 1965). PAM50 findings were validated using pooled publicly available data (n = 8103). Resu...
Purpose Nurse practitioners, physician assistants, and pharmacists are advanced practice provider... more Purpose Nurse practitioners, physician assistants, and pharmacists are advanced practice providers who are highly trained and qualified healthcare professionals that can help support traditional demands on oncologists' increased time in direct patient care. The purpose of this study was to detail and assess the creation of a privileging process for this group of medical professionals within an academic medical center. Obtaining the designation of limited oncology practice provider (LOPP) gives the right to modify chemotherapy orders and to order supportive care medications. Methods An interdisciplinary team developed a comprehensive training process inclusive of required educational domains, knowledge goals, and educational activities to become an LOPP. In 2018, five years after the implementation of the privileging process, a survey was distributed to assess perceptions of the training process and integration of LOPPs within oncology practice. Results Most oncologists noted tha...
506 Background: Response to chemotherapy and HER2-targeting varies by molecular subtype. In C4060... more 506 Background: Response to chemotherapy and HER2-targeting varies by molecular subtype. In C40601, 305 patients (pts) with stage II-III HER2+ BrCa were randomized to receive 16 weeks of preoperative paclitaxel and trastuzumab (TH), T and lapatinib (TL), or THL, and were followed for pCR. Primary data were reported previously. Methods: Gene expression by mRNA sequencing (RNAseq) was performed on 271 pre-Rx and 136 matched post-Rx samples. RNAseq was normalized to HER2+ tumors in The Cancer Genome Atlas Project, and genomic signatures applied including intrinsic subtype and immune cell features. Results: 60% of pre-Rx specimens were hormone receptor+. Overall, 30% were Luminal A, 31% Luminal B, 31% HER2-Enriched, 5% Basal-like, 2% Normal-like, and 1% Claudin-Low. In-breast pCR was 46%, which varied significantly by subtype: Luminal A 35%, Luminal B 36%, Basal-Like 36%, HER2-Enriched 69% (p<0.0001). Within HER2-Enriched, pCR rates by arm were: 50% TL, 71% TH, 80% THL. pCR also varied by risk of relapse scor...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2018
Purpose Racial variation in the financial impact of cancer may contribute to observed differences... more Purpose Racial variation in the financial impact of cancer may contribute to observed differences in the use of guideline-recommended treatments. We describe racial differences with regard to the financial impact of breast cancer in a large population-based prospective cohort study. Methods The Carolina Breast Cancer Study oversampled black women and women younger than age 50 years with incident breast cancer in North Carolina from 2008 to 2013. Participants provided medical records and data regarding demographics, socioeconomic status, and financial impact of cancer at 5 and 25 months postdiagnosis. We report unadjusted and adjusted financial impact at 25 months postdiagnosis by race. Results The sample included 2,494 women who completed follow-up surveys (49% black, 51% white). Since diagnosis, 58% of black women reported any adverse financial impact of cancer ( v 39% of white women; P < .001). In models adjusted for age, stage at diagnosis, and treatment received, black women ...
Journal of the National Cancer Institute, Jan 20, 2018
Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome dispar... more Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome disparities, but racial differences in ET behaviors are poorly understood. Women aged 20-74 years with a first primary, stage I-III, hormone receptor-positive (HR+) breast cancer were included. At 2 years postdiagnosis, we assessed nonadherence, defined as not taking ET every day or missing more than two pills in the past 14 days, discontinuation, and a composite measure of underuse, defined as either missing pills or discontinuing completely. Using logistic regression, we evaluated the relationship between race and nonadherence, discontinuation, and overall underuse in unadjusted, clinically adjusted, and socioeconomically adjusted models. A total of 1280 women were included; 43.2% self-identified as black. Compared to white women, black women more often reported nonadherence (13.7% vs 5.2%) but not discontinuation (10.0% vs 10.7%). Black women also more often reported the following: hot flas...
Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer ... more Serial monitoring of plasma DNA mutations in estrogen receptor positive metastatic breast cancer (ER + MBC) holds promise as an early predictor of therapeutic response. Here, we developed dPCR-SEQ, a customized assay that utilizes digital PCR-based target enrichment followed by next-generation sequencing to analyze plasma DNA mutations in ESR1, PIK3CA, and TP53. We validated dPCR-SEQ in a prospective cohort of 58 patients with ER + MBC and demonstrate excellent concordance with hotspot ESR1 mutation abundance measured by conventional digital PCR. The dPCR-SEQ assay revealed ESR1, PIK3CA, and TP53 plasma ctDNA mutations in 55%, 32%, and 32% of the study patients, respectively. We also observed dynamic changes in ESR1, PIK3CA, and TP53 ctDNA mutant allele fraction (MAF) that were frequently discordant between the different genes. Thus, monitoring plasma DNA mutation dynamics using a dPCR-SEQ assay is feasible, accurate, and may be investigated as a biomarker of therapeutic response in ER + MBC.
Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be signif... more Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be significantly prognostic in breast cancer but have not yet been applied for calculation of risk of recurrence in clinical assays. A compact set of 17 immunity genes was derived herein from an Affymetrix-derived gene expression dataset including 1951 patients (AFFY1951). The 17 immunity genes demonstrated significant prognostic stratification of estrogen receptor (ER)-negative breast cancer patients with high proliferation gene expression. Further analysis of blood and breast cancer single-cell RNA-seq datasets revealed that the 17 immunity genes were derived from TIL that were inactive in the blood and became active in tumor tissue. Expression of the 17 immunity genes was significantly ( < 2.2E-16, = 91) correlated with TILs percentage on H&E in triple negative breast cancer. To demonstrate the impact of tumor immunity genes on prognosis, we built a Cox model to incorporate breast cancer s...
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Papers by Lisa Carey