Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice.

BACKGROUND: The treatment landscape for HR(+)HER2(-) metastatic breast cancer (MBC) is evolving for patients with ESR1 mutations (mut) and PI3K/AKT pathway genomic alterations (GA). We sought to inform clinical utility for comprehensive genomic profiling (CGP) using tissue (TBx) and liquid biopsies (LBx) in HR(+)HER2(-) MBC. METHODS: Records from a de-identified breast cancer clinicogenomic database for patients who underwent TBx/LBx testing at Foundation Medicine during routine clinical care at ~ 280 US cancer clinics between 01/2011 and 09/2023 were assessed. GA prevalence [ESR1mut, PIK3CAmut, AKT1mut, PTENmut, and PTEN homozygous copy loss (PTENloss)] were calculated in TBx and LBx [stratified by ctDNA tumor fraction (TF)] during the first three lines of therapy. Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared between groups by Cox models adjusted for prognostic factors. RESULTS: ~ 60% of cases harbored 1 + GA in 1st-line TBx (1266/2154) or LBx TF ≥ 1% (80/126) and 26.5% (43/162) in LBx TF < 1%. ESR1mut was found in 8.1% TBx, 17.5% LBx TF ≥ 1%, and 4.9% LBx TF < 1% in 1st line, increasing to 59% in 3rd line (LBx TF ≥ 1%). PTENloss was detected at higher rates in TBx (4.3%) than LBx (1% in TF ≥ 1%). Patients receiving 1st-line aromatase inhibitor + CDK4/6 inhibitor (n = 573) with ESR1mut had less favorable rwPFS and rwOS versus ESR1 wild-type; no differences were observed for fulvestrant + CDK4/6 inhibitor (n = 348). CONCLUSION: Our study suggests obtaining TBx for CGP at time of de novo/recurrent diagnosis, followed by LBx for detecting acquired GA in 2nd + lines. Reflex TBx should be considered when ctDNA TF < 1%.

Is Routine Recurrence Score Testing in Patients Older than 70 Years of Age Warranted? An Evaluation of the National Cancer Database After TAILORx.

BACKGROUND: Recurrence score (RS) testing in early-stage, ER-positive breast cancer is used to predict the benefit of adjuvant chemotherapy for disease recurrence and overall survival. TAILORx results decreased the ambiguity of "intermediate risk" RS by creating a binary classification system. We aimed to determine how women ≥ 70 years with intermediate RS were redistributed post-TAILORx and to identify predictors of low RS. METHODS: Patients ≥ 70 years with early-stage, node-negative, ER-positive breast cancers in the National Cancer Database(2006-2014) were included. "Pre-TAILORx" RS were classified as low (0-17), intermediate (18-30), and high (> 30). "Post-TAILORx" RS were classified as low (0-25) and high (> 25). RESULTS: In total, 14,925 women were included. Average age was 74 years. 60% (n = 9009) had low pre-TAILORx RS, 31% (n = 4635) intermediate, and 9% (n = 1281) high. Of 4635 patients with intermediate RS, 72% (n = 3660) were reclassified to low RS. Only 12% (n = 1783) of patients received chemotherapy. Of patients with pre-TAILORx intermediate RS who received chemotherapy, 55% (n = 417) would have been spared chemotherapy by being reclassified with low RS post-TAILORx. The strongest predictor of post-TAILORx low RS was tumor grade; 95% of well-differentiated had low RS, compared with 56% of poorly/undifferentiated tumors (p < 0.001). Smaller tumor size also was associated with low RS. Age was not associated with RS. CONCLUSIONS: With post-TAILORx RS criteria, the vast majority of patients ≥ 70 years can be classified as low-risk and unlikely to benefit from chemotherapy. Given that the elderly have greater rates of chemotherapy-associated complications, reconsideration of routine RS testing in patients ≥ 70 years is warranted. Tumor grade and size also may inform the decision to omit RS testing.

Extended Endocrine Therapy: Is 5 Years Enough?

PURPOSE OF REVIEW: Women with hormone receptor (HR)-positive breast cancer remain at risk for cancer recurrence for decades. In this review, we address recent data regarding the benefits and risks of extended endocrine therapy. RECENT FINDINGS: Ten years of treatment with either tamoxifen or an aromatase inhibitor resulted in superior disease-free survival compared to 5 years of treatment. However, there are risks associated with extended therapy with either class of medication. Multiparameter genetic tests are in development to individualize the risk of late breast cancer recurrence and predict benefit from extended endocrine treatment. Extended endocrine therapy is a promising strategy to reduce breast cancer recurrence in women with HR-positive breast cancer. This approach should be considered based on individual risk of cancer recurrence compared to potential benefit, comorbidities, and tolerance of therapy.

Racial Disparities in Clinical Outcomes on Investigator-Initiated Breast Cancer Clinical Trials at an Urban Medical Center.

BACKGROUND: Black women are 40% more likely to die of breast cancer compared to White women. Inadequate representation of Black patients in clinical trials may contribute to health care inequity. We aimed to assess breast cancer clinical outcomes in Non-Hispanic Black (Black) versus Non-Hispanic White (White) women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials at Winship Cancer Institute at Emory University, given the significant number of patients from underrepresented minority groups seen at Winship. MATERIALS AND METHODS: Black and White women with MBC on investigator-initiated trials at Emory between 2009 and 2019 were retrospectively evaluated. Univariate analyses and multiple logistic regression models were used to assess clinical response and treatment toxicities. Differences in overall survival between groups was assessed using quantile analysis. RESULTS: Sixty-two women with MBC were included (66% White vs. 34% Black). Black patients had less clinical benefit from the trial therapy as only 57% had partial response or stable disease as best response compared to 78% of White women (P = .09). Quantile analysis showed significant difference in mean survival between Whites and Blacks by the end of follow up (64 vs. 38 months). There were no significant differences in toxicities between groups. CONCLUSION: Participation rates of Black women with MBC on investigator-initiated clinical trials at an urban cancer center were higher compared to key national trials. Black women had worse treatment response and survival. These results reinforce the need for assessment of tumor differences by ancestry and continued improvement in minority representation on clinical trials.

A Discordant Pattern of Uptake on 68 Ga-PSMA PET/CT Versus 18 F-Fluciclovine PET/CT in Radiation-Induced Hepatitis : Implications for Early Postradiotherapy Imaging-Based Response Assessment.

ABSTRACT: A 62-year-old woman with right-sided invasive lobular breast carcinoma completed external beam radiotherapy 6 weeks before undergoing a 68 Ga-PSMA PET/CT and 18 F-fluciclovine PET/CT scan as part of an ongoing clinical trial (NCT04750473) assessing the performance of these molecular imaging modalities in invasive lobular breast carcinoma. The 68 Ga-PSMA PET/CT demonstrated a band-like area of increased radiotracer uptake in the dome of the right lobe of the liver anteriorly, whereas 18 F-fluciclovine PET/CT done a day later revealed photopenia in the corresponding area of the liver. The external beam radiotherapy plan confirmed that the radiotherapy field overlaid the region of the hepatic discordant radiotracer uptake on the PET/CT scans.

Effect of Aromatase Inhibitor Therapy on Sleep and Activity Patterns in Early-stage Breast Cancer.

INTRODUCTION: Adherence to aromatase inhibitor (AI) therapy is poor, often because of treatment-emergent side effects, including musculoskeletal symptoms, fatigue, and insomnia. In the present analysis, we examined the sleep patterns and daytime function both objectively using actigraphy and subjectively using validated questionnaires in women initiating AI therapy. PATIENTS AND METHODS: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were initiating AI therapy were eligible. The patients wore actigraphy devices for 10 consecutive days and completed questionnaires at baseline before the initiation of AI and after 3 months of AI therapy. Associations between the baseline demographics and symptoms, changes in patient-reported outcomes and actigraphy measures from baseline to 3 months of AI therapy and discontinuation of AI therapy were examined using sign tests, logistic regression models, Spearman's correlation, and linear mixed models. RESULTS: Forty-two patients (86%) completed the baseline assessments and 23 patients (47%) completed both the baseline and the 3-month assessments. Objectively measured daytime function as measured by total daytime activity decreased during the 3 months after starting AI (232,566 activity count vs. 204,205 activity count; P = .023), and the decrease was more evident in women with higher baseline physical function. Reduced daytime activity correlated with increased fatigue (ρ = -0.49; P = .017). CONCLUSION: Daytime function decreased after initiation of AI therapy and correlated moderately with increased fatigue, although no association was identified with changes in pain or sleep quality. Additional studies are required to understand why function is reduced, which could have implications for interventions to improve patient tolerance of, and persistence with, AI therapy.

Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. MATERIALS AND METHODS: A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments. RESULTS: Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively. CONCLUSIONS: ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.