Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT.

PURPOSE: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. METHODS: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. RESULTS: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. CONCLUSION: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

The impact of the Covid-19 pandemic on the stage of endometrial cancer at diagnosis.

Background: Endometrial cancer generally presents at an early stage affording a high rate of surgical cure. Early in the Covid-19 pandemic it was suggested that treatment of tumors with favorable pathologic features might safely be delayed. Objective: We hypothesized that disruption to health care services during the pandemic would impact the stage at presentation for these patients. Here we compare the stage at presentation of Endometrial Cancer in the months immediately preceding the pandemic to the stage at presentation during the pandemic. Study design: Charts of patients presenting with Endometrial Cancer between January 1, 2018 and April 30, 2022 were reviewed. March 1, 2020 separated the "pre-pandemic" era from the "pandemic" era. Data was collected regarding patient age, body mass index (BMI), tumor stage, histology, grade, size, and depth of invasion. Results: 322 of 374 (86.09%) of surgically staged patients presented with FIGO stage I disease "pre-pandemic" compared to 263 of 329 (71.73%) of surgically staged patients in the "pandemic" cohort (p =.029). 2.08% pre-pandemic compared to 5.48% during the pandemic presented with FIGO stage IV (p =.015). Conclusion: We found a significant difference in the stage at presentation in endometrial cancer patients, a statistic which may be attributed to the disruption of healthcare services caused by the Covid-19 pandemic.

Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial.

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3-4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748.

Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial.

PURPOSE: The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS: The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH (P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis (P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION: Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

The microculture-kinetic (MiCK) assay: the role of a drug-induced apoptosis assay in drug development and clinical care.

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development.

Correlation of pretreatment drug induced apoptosis in ovarian cancer cells with patient survival and clinical response.

BACKGROUND: This study was performed to determine if a chemotherapy-induced apoptosis assay (MiCK) could predict the best therapy for patients with ovarian cancer. METHODS: A prospective, multi-institutional and blinded trial of the assay was conducted in 104 evaluable ovarian cancer patients treated with chemotherapy. The MiCK assay was performed prior to therapy, but treating physicians were not told of the results and selected treatment only on clinical criteria. Outcomes (response, time to relapse, and survival) were compared to the drug-induced apoptosis observed in the assay. RESULTS: Overall survival in primary therapy, chemotherapy naïve patients with Stage III or IV disease was longer if patients received a chemotherapy which was best in the MiCK assay, compared to shorter survival in patients who received a chemotherapy that was not the best. (p < 0.01, hazard ratio HR 0.23). Multivariate model risk ratio showed use of the best chemotherapy in the MiCK assay was the strongest predictor of overall survival (p < 0.01) in stage III or IV patients. Standard therapy with carboplatin plus paclitaxel (C + P) was not the best chemotherapy in the MiCK assay in 44% of patients. If patients received C + P and it was the best chemotherapy in the MiCK assay, they had longer survival than those patients receiving C + P when it was not the best chemotherapy in the assay (p = 0.03). Relapse-free interval in primary therapy patients was longer if patients received the best chemotherapy from the MiCK assay (p = 0.03, HR 0.52). Response rates (CR + PR) were higher if physicians used an active chemotherapy based on the MiCK assay (p = 0.03). CONCLUSION: The MiCK assay can predict the chemotherapy associated with better outcomes in ovarian cancer patients. This study quantifies outcome benefits on which a prospective randomized trial can be developed.

Significance of chest computed tomography findings in the evaluation and treatment of persistent gestational trophoblastic neoplasia.

OBJECTIVE: To evaluate whether chest computed tomography (CT) findings in patients with persistent gestational trophoblastic neoplasia (GTN) and a negative chest roentgenogram (CXR) significantly influence clinical outcome and to determine potential clinical predictors of pulmonary micrometastasis STUDY DESIGN: The charts of 201 patients with nonmetastatic GTN (International Federation of Gynecology and Obstetrics [FIGO] stage I) receiving primary treatment with methotrexate (MTX) infusion between December 1985 and December 2000 were reviewed, and data were collected on age, gravidity and parity, FIGO stage, histologic diagnosis, metastatic disease, radiologic findings, surgery, presenting human chorionic gonadotropin (hCG) level, total number of chemotherapy courses and chemotherapeutic agents required to reach remission, and time to remission. The chi2, regression, Kaplan-Meier and log-rank tests were utilized to evaluate the correlation of chest CT with CXR findings, histology of antecedent pregnancy, presenting hCG level, chemotherapeutic requirements and time to remission. RESULTS: Of 30 patients with a negative CXR, 13 (43.3%) had chest CT positive for micrometastasis. Histology of the antecedent pregnancy and mean presenting hCG did not correlate with the chest CT result. There was no significant difference between patients with positive or negative chest CT results in the requirement for > 1 dose of MTX or for additional chemotherapeutic agents. There also was no significant difference in time to remission by chest CT status. Regression analysis using histologic diagnosis, presenting hCG level, age, gravidity and parity as covariates did not reveal any clear risk factors for pulmonary micrometastasis. CONCLUSION: It has been suggested that GTN patients with micrometastases identified on chest CT only are at increased risk of requiring > 1 dose of MTX or of requiring additional chemotherapeutic agents. Our data suggest that chest CT alone is not predictive of clinical outcome. Furthermore, the presence of micrometastases does not correlate with hCG level or histologic diagnosis, and there are no clear risk factors for pulmonary micrometastases.

Paclitaxel and platinum chemotherapy for malignant mixed müllerian tumors of the ovary.

OBJECTIVE: Malignant mixed müllerian tumor (MMMT) of the ovary is a rare tumor with a dismal prognosis. The most effective therapy is unknown. The current study was undertaken to characterize a group of patients treated as if they had aggressive epithelial ovarian tumors, with cytoreductive surgery and combination paclitaxel/platinum chemotherapy. METHODS: Retrospective analysis of data obtained from tumor registry and hospital records of cases of malignant mixed müllerian tumor between January 1, 1992 and January 1, 2000 treated at the Massachusetts General Hospital, Brigham and Women's Hospital, and University of Vermont was performed. Only patients treated with combination paclitaxel and platinum therapy were included in the analysis. Data were collected regarding cytoreduction, response to chemotherapy, disease-free interval, and survival. RESULTS: Fifty-five patients were identified with MMMT. Twenty-eight patients with a clearly ovarian primary had received treatment with combination paclitaxel and platinum. Paclitaxel and carboplatin was given as second-line therapy in 2 patients who had chemoresponsive but incurable disease; the remaining patients were treated with paclitaxel and platinum therapy as first-line therapy. These 28 patients had a median (range) age of 66 (46-84 years) and stage was I in 2 patients, II in 3, III in 18, and IV in 5. Treatment was generally well tolerated. Sixteen patients of 26 treated with paclitaxel and platinum as first-line therapy achieved a complete clinical response (55%) and 6 patients achieved partial response for a total response rate of 72%. Optimal cytoreduction was associated with increased time to recurrence (P = 0.001) but not with survival. Overall median survival for the 28 patients is 27.1 months. CONCLUSION: Although treatment fails many patients, a minority of patients with MMMT in this highly selected population do unexpectedly well. An aggressive approach with surgery and combination paclitaxel-platinum chemotherapy appears to offer very effective therapy.

Methotrexate infusion and folinic acid as primary therapy for nonmetastatic and low-risk metastatic gestational trophoblastic tumors. 15 years of experience.

OBJECTIVE: To investigate the efficacy and toxicity of methotrexate (MTX) given intravenously (i.v.) at a dose of 100 mg/m2 i.v. bolus and 200 mg/m2 infusion over 12 hours followed by folinic acid in the primary treatment of gestational trophoblastic tumors (GTTs). STUDY DESIGN: We reviewed the records of patients at the New England Trophoblastic Disease Center who had received MTX infusion at a dose of 100 mg/m2 i.v. bolus and 200 mg/m2 infusion over 12 hours followed by folinic acid as primary therapy for GTTs that did not resolve with uterine evacuation alone. Data on the patients' age, gravity and parity, disease stage (by FIGO and WHO criteria), antecedent pregnancy, presenting level of hCG, metastatic status, courses of chemotherapy required to achieve remission, toxicity related to chemotherapy treatments and time to normalization of hCG were recorded. RESULTS: One hundred ninety-two patients with persistent GTTs were treated with the MTX infusion protocol between December 1985 and December 2000. One hundred twenty-four patients (64.6%) achieved complete remission with the MTX infusion protocol. Complete remission was induced in 108 (87.1%) with a single course of chemotherapy; 12 others achieved remission with a single additional course of MTX. All patients found to be resistant to MTX therapy later achieved remission with other chemotherapy. Minimal toxicity was experienced during MTX treatment. CONCLUSION: MTX infusion with folinic acid is effective and well tolerated as primary single-agent therapy for nonmetastatic and low-risk metastatic GTT.