Early Assessment Window for Predicting Breast Cancer Neoadjuvant Therapy using Biomarkers, Ultrasound, and Diffuse Optical Tomography.

PURPOSE: The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to neoadjuvant therapy (NAT). METHODS: This prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the first three treatment cycles, and prior to definitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical significance was tested using two-sided two-sample student t-test with P < 0.05 considered statistically significant. Logistic regression was used for ROC analysis. RESULTS: Thirty-eight patients (mean age = 47, range 24-71 years) successfully completed the study, including 15 HER2 + of which 11 were ER + ; 12 ER + or PR + /HER2-, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI 0.869-1.0). Similarly an AUC of 0.910 (95% CI 0.810-1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI 0.933-1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status. CONCLUSION: The combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the first treatment cycle. CLINICAL TRIAL REGISTRATION NUMBER: NCT02891681. https://clinicaltrials.gov/ct2/show/NCT02891681 , Registration time: September 7, 2016.

Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

PURPOSE: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. RESULTS: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1-11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300-750 mg/m2). CONCLUSIONS: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS.See related commentary by Benjamin and Minotti, p. 3809.

Novel pathways and molecular targets for the treatment of sarcoma.

Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed.