Browsing by Author "Goetz, Matthew P."
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Item A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer(American Association for Cancer Research, 2023) Veeraraghavan, Jamunarani; Gutierrez, Carolina; De Angelis, Carmine; Davis, Robert; Wang, Tao; Pascual, Tomas; Selenica, Pier; Sanchez, Katherine; Nitta, Hiroaki; Kapadia, Monesh; Pavlick, Anne C.; Galvan, Patricia; Rexer, Brent; Forero-Torres, Andres; Nanda, Rita; Storniolo, Anna M.; Krop, Ian E.; Goetz, Matthew P.; Nangia, Julie R.; Wolff, Antonio C.; Weigelt, Britta; Reis-Filho, Jorge S.; Hilsenbeck, Susan G.; Prat, Aleix; Osborne, C. Kent; Schiff, Rachel; Rimawi, Mothaffar F.; Medicine, School of MedicinePurpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. Experimental design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.Item Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer(Massachusetts Medical Society, 2018-07) Sparano, Joseph A.; Gray, Robert J.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Ravdin, Peter M.; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffery L.; Abrams, Jeffrey; Sledge, George W., Jr.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger.Item Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor α(American Association of Cancer Research, 2020-06-15) Ingle, James N.; Cairns, Junmei; Suman, Vera J.; Shepherd, Lois E.; Fasching, Peter A.; Hoskin, Tanya L.; Singh, Ravinder J.; Desta, Zeruesenay; Kalari, Krishna R.; Ellis, Matthew J.; Goss, Paul E.; Chen, Bingshu E.; Volz, Bernhard; Barman, Poulami; Carlson, Erin E.; Haddad, Tufia; Goetz, Matthew P.; Goodnature, Barbara; Cuellar, Matthew E.; Walters, Michael A.; Correia, Cristina; Kaufmann, Scott H.; Weinshilboum, Richard M.; Wang, Liewei; Medicine, School of MedicinePurpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental design: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. Conclusions: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.Item Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer(Massachusetts Medical Society, 2019-06-20) Sparano, Joseph A.; Gray, Robert J.; Ravdin, Peter M.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffrey L.; Abrams, Jeffrey; Sledge, George W.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.Item Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole(Elsevier, 2015-07) Ingle, James N.; Kalari, K. R.; Buzdar, Aman U.; Robson, Mark E.; Goetz, Matthew P.; Desta, Zeruesenay; Barman, Poulami; Dudenkov, Tanda T.; Northfelt, Donald W.; Perez, Edith A.; Flockhart, David A.; Williard, Clark V.; Wang, Liewei; Weinshilboum, Richard M.; Department of Medicine, IU School of MedicinePURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.Item Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes(Springer, 2023) Lenz, Lauren; Neff, Chris; Solimeno, Cara; Cogan, Elizabeth S.; Abramson, Vandana G.; Boughey, Judy C.; Falkson, Carla; Goetz, Matthew P.; Ford, James M.; Gradishar, William J.; Jankowitz, Rachel C.; Kaklamani, Virginia G.; Marcom, P. Kelly; Richardson, Andrea L.; Storniolo, Anna Maria; Tung, Nadine M.; Vinayak, Shaveta; Hodgson, Darren R.; Lai, Zhongwu; Dearden, Simon; Hennessy, Bryan T.; Mayer, Erica L.; Mills, Gordon B.; Slavin, Thomas P.; Gutin, Alexander; Connolly, Roisin M.; Telli, Melinda L.; Stearns, Vered; Lanchbury, Jerry S.; Timms, Kirsten M.; Medicine, School of MedicinePurpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. Results: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. Conclusions: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.Item Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial(Oxford University Press, 2021-04-06) Albain, Kathy S.; Gray, Robert J.; Makower, Della F.; Faghih, Amir; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Wood, William C.; Keane, Maccon M.; Gomez, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffrey L.; Abrams, Jeffrey; Sledge, George W., Jr.; Sparano, Joseph A.; Pathology and Laboratory Medicine, School of MedicineBackground: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.Item TBCRC023: A Randomized Phase II Neoadjuvant Trial of Lapatinib Plus Trastuzumab Without Chemotherapy for 12 versus 24 Weeks in Patients with HER2-Positive Breast Cancer(AACR, 2020-02) Rimawi, Mothaffar F.; Niravath, Polly A.; Wang, Tao; Rexer, Brent; Forero, Andres; Wolff, Antonio C.; Nanda, Rita; Storniolo, Anna M.; Krop, Ian E.; Goetz, Matthew P.; Nangia, Julie R.; Jiralerspong, Sao; Pavlick, Anne C.; Veeraraghavan, Jamunarani; De Angelis, Carmine; Gutierrez, Carolina; Schiff, Rachel; Hilsenbeck, Susan G.; Osborne, C. Kent; Medicine, School of MedicinePurpose: Prior neoadjuvant trials with 12 weeks of dual anti-HER2 therapy without chemotherapy demonstrated a meaningful pathologic complete response (pCR) in patients with HER2-positive breast cancer. In this trial, we sought to determine whether longer treatment would increase the rate of pCR. Patients and Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon phase II design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2-positive breast tumors measuring ≥2 cm (median = 5 cm) were randomized in a 1:2 ratio to 12 versus 24 weeks of lapatinib and trastuzumab. Letrozole (along with ovarian suppression if premenopausal) was administered in patients whose tumors were also estrogen receptor (ER) positive. All evaluable patients were assessed for in-breast pCR. Results: Ninety-seven patients were enrolled (33 in 12-week arm and 64 in 24-week arm), of whom 94 were evaluable. Median age was 51 years, and 55% were postmenopausal. Median tumor size was 5 cm, and 65% were ER-positive. The rate of pCR in the 24-week arm was 28% and numerically superior to the 12-week arm (12%). This was driven by increased pCR in the ER-positive subgroup (33% vs. 9%). Study treatment was well tolerated, with grade 1–2 diarrhea and acneiform rash being the most common toxicities. Conclusions: Treatment with dual anti-HER2 therapy for 24 weeks led to a numeric increase in pCR rate in women with HER2-positive breast cancer, without using chemotherapy. If validated, this approach may help identify patients who may benefit from deescalation of therapy.Item Tumor and serum DNA methylation in women receiving preoperative chemotherapy with or without vorinostat in TBCRC008(Springer Nature, 2018-01) Connolly, Roisin M.; Fackler, Mary Jo; Zhang, Zhe; Zhou, Xian C.; Goetz, Matthew P.; Boughey, Judy C.; Walsh, Bridget; Carpenter, John T.; Storniolo, Anna Maria; Watkins, Stanley P.; Gabrielson, Edward W.; Stearns, Vered; Sukumar, Saraswati; Medicine, School of MedicineBACKGROUND: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy. METHODS: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses. RESULTS: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients. CONCLUSION: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).