Maysa Abu-Khalaf

Objective: This prospective study investigated the use of H-scan ultrasound (US) imaging as a novel component of a multiparametric radiomic analysis framework for characterizing human breast cancer response to neoadjuvant chemotherapy (NAC) before and early after treatment initiation. Methods: Thirty breast cancer patients scheduled for NAC were scanned using a clinical US system (Logiq E9, GE HealthCare) equipped with a 9L-D linear array transducer. Radiofrequency (RF) data was obtained at baseline (pre-NAC) and after 10% and 30% of the complete dose of chemotherapy. The RF data was analyzed by a bank of 256 frequency-shifted bandpass filters to form H-scan US frequency images. Grayscale texture features were extracted from both B-scan and H-scan US images. In addition, US attenuation coefficient and speckle statistics based on the Nakagami and Burr distributions were estimated from the RF data. Data classification of tumor and peri-tumoral regions was performed using a novel three-dimensional (3D) score map based on support vector machine (SVM) modeling. Unlike conventional classifiers that report only a single prediction score, a 3D score map provides a visual representation of the classifier decision space, enabling interpretation of class separation and treatment-induced shifts in multiparametric US measurements. Results: The dataset was split into 10 disjoint partitions (90% training, 10% testing) to compute area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy measures. Actual patient response to NAC was assessed at surgery and categorized as either pathologic complete response (pCR) or non-pCR. Multiparametric US and data classification results at pre-NAC found AUC values of 0.78 after using only tumor information (p < 0.01), which increased to 0.81 with inclusion of peri-tumoral information (p < 0.01). Significant differences in multiparametric US measures from both cancer response types was found after integration of patient data collected at 10% completion of the NAC regimen (i.e., first NAC cycle), yielding an improved AUC of 0.86 (p < 0.001). Conclusions: Multiparametric US imaging with radiomic features from both the tumor and peri-tumoral regions is a promising noninvasive approach for monitoring early breast cancer response to NAC.

TEAEs (of any cause, occurring in >20% of patients in the safety analysis set; N = 41).

Survival in patients with no prior systemic therapy for advanced breast cancer in the full analysis population. Kaplan–Meier curve determined in the full analysis population of (A) PFS and (B) OS. PFS was determined by the time from the date of the first dose of study drug to the date of the first radiologic documentation of postbaseline disease progression or death due to any cause. OS was defined as the time from the start of the study drug to death due to any cause.

Response rates to gedatolisib + palbociclib + letrozole in the response evaluable set.

Patient demographic and baseline disease characteristics in the full analysis population with no prior systemic therapy for advanced breast cancer.

Grade 3 or 4 TESAEs, of any cause, occurring in >1 patient, N = 41.

Purpose:Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor–positive (HR+)/HER2− breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2− advanced breast cancer. Simultaneous blockade of the estrogen receptor, CDK4/6, and PAM pathways may optimize antitumor control in the treatment-naïve advanced breast cancer setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2− advanced breast cancer.Patients and Methods:Treatment-naïve patients from a phase Ib study with HR+/HER2− advanced breast cancer treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival.Results:Of 41 patients, all had stage IV disease, 93% had measurable disease, 78% had visceral metastases, and 22% had detectable PIK3CA mutations. The objective response rate was 79% in patients with evaluable disease (N = 33). The median duration of response was 48 months for confirmed responders. The median PFS was 48.4 months, and the median overall survival was 77.3 months. The overall response rate and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).Conclusions:Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for advanced breast cancer. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2− advanced breast cancer.

Best overall response and target lesion improvement. Percentage change from baseline in the sum of the diameters of all target lesions at the time of best response. There were five subjects with 100% target lesion responses, but they were classified as PR due to nontarget lesions. Each bar represents a single patient with no prior systemic therapy for advanced breast cancer in the response evaluable set (N = 33).

Purpose: Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor–positive (HR+)/HER2− breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2− advanced breast cancer. Simultaneous blockade of the estrogen receptor, CDK4/6, and PAM pathways may optimize antitumor control in the treatment-naïve advanced breast cancer setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2− advanced breast cancer. Patients and Methods: Treatment-naïve patients from a phase Ib study with HR+/HER2− advanced breast cancer treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival. Results: Of 41 patients, all had stage IV disease, 93% had measurable disease, 78% had visceral metastases, and 22% had detectable PIK3CA mutations. The objective response rate was 79% in patients with evaluable disease (N = 33). The median duration of response was 48 months for confirmed responders. The median PFS was 48.4 months, and the median overall survival was 77.3 months. The overall response rate and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%). Conclusions: Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for advanced breast cancer. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2− advanced breast cancer.