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Introduction: The plant alkaloid Maytansine and its derivatives with anti-microtubule activity failed in early trials due to significant toxicity.When linked to trastuzumab as an antibody-drug conjugate (ADC), emtansine can be delivered directly into the target cell with little systemic toxicity since the emtansine is inactive before the linker of the ADC is cleaved inside the tumor cells. Systemic toxicities with trastuzumab-emtansine (T-DM1) include thrombocytopenia and transaminase elevations, unlike trastuzumab alone. We hypothesized that systemic toxicities of this ADC are in part the result of emtansine released from the lysed tumor cells, and if so, that they may predict its tumor response. To evaluate this hypothesis, the correlation between early toxicity and initial tumor response, as well as progression free survival, are examined in a retrospective multi-center study. Methods: Records of women with metastatic or locally advanced/inoperable HER2+ breast cancer who received at least one dose of T-DM1 were retrospectively abstracted from 3 centers with IRB approval. Eighty-two patients were identified. Nine were excluded—one due to a diagnosis of idiopathic thrombocytopenic purpura and eight due to lack of follow-up imaging after starting T-DM1. Platelet count, AST, and ALT results from baseline up to the 8th cycle were graded with the NCI CTCAEv5.0 toxicity scale and grades were summed as a toxicity score for the 73 evaluable patients. Sequential CT or PET/CT response to therapy were defined by RECIST criteria with the addition of a mixed response category. Results: A significant association between improved ordinal imaging response (complete, partial, stable, mixed, progression) and higher toxicity sum score was observed by the Jonckheere-Terpstra two-sided test (Z=-2.194, p=0.028). 66% of the progression free patients (29/44) had toxicity sum scores ≥2 compared to 45% with disease progression (13/29), Z=-1.89, p=0.059 by two-sided Cochran-Armitage Trend Test. Progression free survival (PFS) was significantly longer with toxicity score ≥ 2 compared to score ≤ 1, p = 0.012 by log-rank test. Further, longer PFS was significantly associated with higher toxicity sum score with HR= 0.67 (β= -0.418, SE(β) = 0.169, χ2 = 6.08, d.f.=1, p = 0.014) indicating a 33% decrease in hazard of progression for each one-point increase in toxicity score. Discussion: This small, retrospective study demonstrates a significant association between higher toxicity sum score and more favorable tumor response as well as progression free survival in women with metastatic or locally advanced/inoperable HER2+ breast cancer treated with T-DM1. Further study in large-scale trials is warranted to confirm this association and determine the clinical utility of toxicity score as a predictor of therapeutic response. Our finding does not exclude systemic toxicity from the possible ADC linker cleavage prior to endocytosis. However, when T-DM1 was studied in the metastatic setting, 48% of patients experienced a Grade 3 or higher adverse event leading to dose reductions or discontinuation of the drug in 19% and 10% of patients, respectively. In the adjuvant setting, with only residual tumor that can account for ADC-related tumor lysis, only 25% had a Grade 3 or higher adverse event leading to 18% of patients discontinuing the drug. Should our observation prove predictive in further studies, it may have ramifications for many more antibody-drug conjugates. Citation Format: Shou-Ching Tang, Carter Louis Capra, Germame H Ajebo, Simon Mairs, Judith Meza-Junco, William B. Hillegass, Barbara S. Craft, Xiaofu Zhu. Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-52.

Background Triple negative breast cancer (TNBC) (estrogen receptor (ER) – negative, progesterone receptor (PR) - negative, and human epidermal growth factor receptor 2 (HER2) -negative) is an aggressive subtype of breast cancer that is more common in younger women, carries a poorer prognosis and has a greater metastatic potential than receptor positive subtypes. Radiation therapy’s ability to improve outcomes, especially the overall survival is controversial, more so among African American patients. The objective of this study is to evaluate local control and survival rates of TNBC patients treated with radiotherapy (RT) in our institution with a sizeable cohort of African American women. Methods This is a retrospective analysis of 67 TNBCs (2007–2017) at an academic state institution who underwent a lumpectomy and /or mastectomy (surgery) followed by adjuvant irradiation to a median total dose of 50 Gy (range 40.5–50.40 Gy). Chemotherapy was administered in a neoadjuvant (32) or adjuvant setting (35). For all 67 TNBCs, local control (LC), overall survival (OS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. The significance of survival variables was analyzed using the Cox univariate and multivariate proportional hazards model. A p-value of less than 0.05 was considered statistically significant. The SPSS 24.0 software was used for data analysis. Results The baseline characteristics of all 67 TNBCs were measured with median follow up of 58 months (range 10–142 months). Patients were stratified into two groups (neoadjuvant chemotherapy-RT (32) vs. adjuvant chemotherapy-RT (35)). The five-year rates for LC, DFS and OS were 14.8 % vs. 47.9 % (p = 0.002), 24.2% vs. 53.1 % (p = 0.015), and 65.1% vs. 92.2% (0.002) respectively. On Cox multivariate analysis, patients who received adjuvant chemotherapy were associated with statistically improved significant LC (p = 0.002) and OS (p = 0.002). The variables included were: BMI (p = 0.050), distance travelled (p = 0.027), 8th AJCC TNM staging (p = 0.018) and tumor grade (p = 0.022). Conclusion In this hypothesis-generating report, among TNBC patients undergoing RT, adjuvant chemotherapy appears to be better than neoadjuvant chemotherapy in determining the clinical outcomes.

The mechanism by which trastuzumab‐emtansine (T‐DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T‐DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease‐free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T‐DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression‐free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47‐0.92], P = .014, for each 1‐point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression‐free survival with adjusted HR = 0.67 [95% CI: 0.47‐0.93], P = .020. The analysis suggests that the systemic toxicities of T‐DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T‐DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody‐drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target., What's new? Linkage of trastuzumab to emtansine (T‐DM1), a tumor‐antigen specific antibody, is associated with improved survival in patients with metastatic HER2+ breast cancer. Relative to trastuzumab alone, however, trastuzumab‐emtansine (T‐DM1) has unique side effects, including throbocytopenia and transaminitis. In this investigation of systemic toxicities, tumor response, and patient outcome, higher toxicity sum score for T‐DM1 was significantly associated with improved tumor response and increased progression‐free survival in metastatic HER2+ breast cancer patients. The findings suggest that emtansine freed from lysed HER2+ breast cancer cells potentially influences T‐DM1 toxicity and that systemic toxicities of antibody‐drug conjugates function as predictive biomarkers.

Background The Will Rogers phenomenon [WRP] describes an apparent improvement in outcome for patients’ group due to tumor grade reclassification. Staging of cancers is important to select appropriate treatment and to estimate prognosis. The WRP has been described as one of the most important biases limiting the use of historical cohorts when comparing survival or treatment. The main purpose of this study is to assess whether the WRP exists with the move from the AJCC 7th to AJCC 8th edition in breast cancer [BC] staging, and if racial differences are manifested in the expression of the WRP. Methods This is a retrospective analysis of 300 BC women (2007–2017) at an academic medical center. Overall survival [OS] and disease-free survival [DFS] was estimated by Kaplan-Meier analysis. Bi and multi-variate Cox regression analyses was used to identify racial factors associated with outcomes. Results Our patient cohort included 30.3% Caucasians [Whites] and 69.7% African-Americans [Blacks]. Stages I, II, III, and IV were 46.2, 26.3, 23.1, and 4.4% of Whites; 28.7, 43.1, 24.4, and 3.8% of Blacks respectively, in anatomic staging (p = 0.043). In prognostic staging, 52.8, 18.7, 23, and 5.5% were Whites while 35, 17.2, 43.5, and 4.3% were Blacks, respectively (p = 0.011). A total of Whites (45.05% vs. 47.85%) Blacks, upstaged. Whites (16.49% vs. 14.35%) Blacks, downstaged. The remaining, 38.46 and 37.79% patients had their stages unchanged. With a median follow-up of 54 months, the Black patients showed better stage-by-stage 5-year OS rates using 8th edition compared to the 7th edition (p = 0.000). Among the Whites, those who were stage IIIA in the 7th but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th (p = 0.000). The 8th showed complex results (p = 0.176) compared to DFS estimated using the 7th edition (p = 0.004). Conclusion The WRP exists with significant variability in the move from the AJCC 7th to the 8th edition in BC staging (both White and Black patients). We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data.

Purpose: The objective of this study is to evaluate local control and survival rates of node negative triple negative breast cancer patients (TNBCs) treated with radiotherapy (RT) in our institution. Methods: This is a retrospective analysis of 67 TNBCs (2007 - 2017) at an academic state institution who underwent lumpectomy and /or mastectomy (surgery) followed by adjuvant irradiation to median total dose of 50 Gy (range 40.5-50.40 Gy). Chemotherapy was administered in a neoadjuvant (31) or adjuvant setting (36). For all 67 TNBCs, local control (LC), overall survival (OS) and disease free survival (DFS) were estimated using the Kaplan-Meier method. The significance of survival variables were analyzed using the Cox univariate and multivariate proportional hazards model. A p-value of less than 0.05 was considered statistically significant. The SPSS 24.0 software was used for data analysis. Results: The baseline characteristics of all 67 TNBCs were measured with median follow up of 58 months (range 10-142 months). Patients were stratified into two groups (neoadjuvant chemotherapy-RT (31) vs. adjuvant chemotherapy-RT (36)). The median rates for LC, DFS and OS were 27 % vs. 68 % (p= 0.001), 27.2% vs. 63.2 % (p= 0.034), and 63.4% vs. 92.5% (0.001) respectively. On Cox multivariate analysis, patients who received adjuvant chemotherapy were associated with statistically improved significant LC (p= 0.002) and OS (p=0.005). The variables included were: ethnicity (p=0.251), age (p=0.984), BMI (p=0.032), lump boost (p=0.300), TNM (p=0.162) and tumor grade (p=0.336). Conclusion: Among TNBC patients undergoing RT, adjuvant chemotherapy appears to be better than neoadjuvant chemotherapy in determining the clinical outcomes. Citation Format: Mary R. Nittala, Eswar K. Mundra, Satya Packianathan, Divyang Mehta, Maria L. Smith, William C. Woods, Shawn McKinney, Barbara S. Craft, Srinivasan Vijayakumar. Triple negative breast cancer patients treated with radiation therapy: Improvement in survival and local control with adjuvant chemotherapy compared to neoadjuvant chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6177.

Purpose: To assess whether the Will Roger’s phenomenon [WRP] exists with the move from the AJCC 7th to AJCC 8th edition in Breast Cancer staging and if racial differences are manifested in the expression of the WRP. Methods: A retrospective analysis of 300 women diagnosed with breast cancer between 2007 and 2017 at an academic medical center was performed. Pearson’s square test was used to compare the proportional differences between the anatomic staging system represented by the 7th edition and the prognostic staging of the 8th edition among Caucasian [C] and African-American [AA] women. Kaplan- Meier analysis was used to estimate overall survival [OS] and disease-free survival [DFS] between the races and compared using the log-rank test. Bi and multi-variate Cox hazard regression analyses were used to identify any racial factors associated with outcomes. The SPSS v.24.0 was used for all statistical analyses. Results: Our patient cohort included 30.3% C and 69.7% AA (median age, 62 y; range 34- 92 y). Stages I, II, III, and IV accounted for 46.2%, 26.3%, 23.1%, and 4.4% of C and 28.7%, 43.1%, 24.4%, and 3.8% of AA respectively, in anatomic staging (p= 0.043). In prognostic staging, 52.8%, 18.7%, 23%, and 5.5% were C while 35%, 17.2%, 43.5%, and 4.3 % were AA, respectively (p=0.011). A total number of 41 C (45.05 %) were upstaged compared to 100 AA (47.85 %) patients. Fifteen C patients (16.49 %) and 30 AA patients (14.35 %) were down-staged. Of the remainder, 35 C (38.46 %) and 79 AA (37.79 %) patients had their stages unchanged (P=0.859). The median follow-up duration for this cohort was 58 months (range 4- 235 months). The AA patients showed better stage -by- stage 5- year OS rates using 8th edition compared to the 7th edition, suggesting a manifestation of the WRP. Among the C patients, those who were stage IIIA in the 7th edition but became stage IB in the 8th had a better prognosis than stages IIA and IIB in the 8th edition (p=0.000). For AA patients, stage IIIA, IIIB, IIIC, and IV all demonstrated better prognoses in the 8th edition when compared to the 7th edition (p=0.000). In terms of DFS, the 8th edition’s clinical staging showed complex results (p=0.176) compared to DFS estimated using the 7th’s anatomic staging system (p=0.004). For C patients, stages IA, IB, IIB, and IIIC all recorded better DFS when using the 8th edition while for AA patients, only those with stages IB and IIIC showed better DFS in the 8th edition compared to the 7th. Conclusion: Our analyses suggest that the WRP exists in the move from the AJCC 7thto the 8th edition in breast cancer staging in both C and AA patients. However, there was significant variability between the races in the extent of its manifestation. We suggest that caution needs to be exercised when results are compared across staging systems to account for the WRP in the interpretation of the data. Citation Format: Mary R Nittala, Eswar K Mundra, SatyaSeelan Packianathan, Divyang Mehta, William C Woods, Shawn Mckinney, Barbara S Craft, Srinivasan Vijayakumar. The Will Rogers phenomenon in breast cancer: The AJCC 8th Ed. and the importance of caution in the interpretation of outcomes differences for overall population and race-specific cohorts [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B126.

Phase 1 studies in cancer have changed in recent years. Now, with the advent of new, less toxic, targeted agents, more patients may be candidates for new drug studies earlier in the course of their disease. It is to the advantage of the members of the oncology community to know more regarding the details and requirements for participation in early-phase clinical trials so they can advocate for their patients and help them decide when such trials may be an appropriate choice. To examine the work intensity of early phase cancer clinical trials, the authors of this report compared the study requirements of phase 1 and 2 protocols. Five parameters were studied as a surrogate of study complexity-the number of physical examinations, vital sign determinations, electrocardiograms (ECGs), nonpharmacokinetic laboratory tests, and pharmacokinetic (PK) sampling-in the first 4 weeks of protocol in 90 studies (49 phase 1 studies and 41 phase 2 studies). From July 2004 through March 2007, there were 49 phase 1 trials in the phase 1 Program, 9 phase 2 studies that were conducted by physicians appointed in that program, and 32 phase 2 trials with accessible data in the Department of Thoracic/Head & Neck Medical Oncology. In the phase 1 trials versus the phase 2 trials, there were significantly more (P < .05) physical examinations (mean +/- standard error, 3.16 +/- 0.24 vs 2.22 +/- 0.13), vital sign determinations (5.63 +/- 0.61 vs 2.80 +/- 0.26), ECGs (4.36 +/- 1.16 vs 0.80 +/- 0.17), nonpharmacokinetic laboratory tests (18.08 +/- 1.31 vs 10.12 +/- 0.65), and PK sampling (15.14 +/- 1.79 vs 1.02 +/- 0.53). These values also differed significantly (P < .005 for each) when the median values were compared in nonparametric tests. Although both phase 1 and phase 2 trials had substantial study requirements, those for the phase 1 studies were significantly higher. The successful conduct of early-phase clinical trials requires significant research infrastructure.

Introduction Intrinsic or acquired chemoresistance is a major problem in oncology. Although highly responsive to chemotherapies such as paclitaxel, most triple negative breast cancer (TNBC) patients develop chemoresistance. Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences. Methods We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. We also analyzed a large cohort of breast tumor samples for BRCA1-IRIS, Forkhead box class O3a (FOXO3a) and survivin expression. Finally, we analyzed the effect of BRCA1-IRIS silencing or inactivation on TNBCs formation, maintenance and response to paclitaxel in an orthotopic model. Results We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. This signaling pathway is intact in TNBCs endogenously overexpressing BRCA1-IRIS. These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. Finally, we show BRCA1-IRIS and survivin overexpression is correlated with lack of FOXO3a expression in a large cohort of primary tumor samples, and that BRCA1-IRIS overexpression-induced signature is associated with decreased disease free survival in heavily treated estrogen receptor alpha-negative patients. Conclusions In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. These loops activate AKT, causing FOXO3a degradation and survivin overexpression. Taken together, this underscores the need for BRCA1-IRIS-specific therapy and strongly suggests that BRCA1-IRIS and/or signaling loops activated by it could be rational therapeutic targets for advanced TNBCs.