Patricia A Ganz’s research while affiliated with Sylvester Comprehensive Cancer Center and other places

PURPOSE Endocrine treatments for patients with hormone-sensitive breast cancer are associated with significant side effects that can negatively affect health-related quality of life and result in treatment discontinuation. The objective of this qualitative study was to obtain feedback from stakeholder clinicians and patients about an online interactive tool that was designed to provide information and visualizations of breast cancer symptoms. METHODS The online Breast Cancer Symptom Explorer tool was developed to allow patients to visualize trajectories for common symptoms associated with tamoxifen and anastrozole using symptom data from the NSABP B35 breast cancer clinical trial. To refine the tool, virtual focus groups were conducted among oncology clinicians and women with a history of breast cancer who had received treatment with an aromatase inhibitor or tamoxifen, seeking feedback on the tool and its potential usefulness. Discussions took place using a secure web-conferencing platform following a semi-structured interview guide. Focus groups were audio-recorded, transcribed, and analyzed using reflexive thematic analysis. RESULTS Nine focus groups were conducted (n = 21 participants: eight clinicians and 13 patients). Key benefits and barriers to tool use emerged from the discussions. Both patients and oncologists valued the ability to engage with the tool and visualize symptoms over time. They indicated that ideal settings for its use would be at home before treatment initiation. Combinations of graphical representations with text were perceived to be most effective in communicating symptoms. Key barriers identified included concerns about accessibility to the tool and digital literacy, with recommendations to simplify the text and provide health literacy support to enhance its clinical utility in the future. CONCLUSION Clinician and patient involvement was critical for refinement of the breast cancer symptom explorer and provided insights into its future use and evaluation of the tool in clinical decision making.

Background The PRO-CTCAE Measurement System was designed to enhance the quality of the standard toxicity evaluation in clinical trials. We developed a sub-study within NRG BR004, a phase III clinical trial in patients with newly documented HER2-positive metastatic breast cancer (MBC), to examine the added value and feasibility of frequent PRO-CTCAE data collection. Methods Patients were asked to complete 23 PRO-CTCAE items assessing 12 symptoms. Electronic PRO (ePRO) reporting was preferred; however, paper administration was allowed. The data on items assessed before treatment initiation, then weekly during Cycles 1-2 (12 weeks) are presented herein. Feasibility of frequent assessment with ePRO reporting was assessed using these data and was pre-defined as ≥ 25% of patients being compliant (submitted ≥75% of scheduled assessments). We also examined PRO-CTCAE and clinician-reported CTCAE data for key symptoms using maximum toxicity grade and the toxicity index (TI). Results Overall, 80% of patients (82 of 103) were compliant with expected weekly assessments (90% CI : 0.72-0.86). For all symptoms, the median maximum grade (TI value) of clinician-reported CTCAE was lower than the median maximum score (TI value) of patient-reported PRO-CTCAE. The differences in the data trend for weekly vs less frequent assessment were more apparent when data were evaluated using the TI vs the maximum score. Conclusions Weekly assessments within the first two chemotherapy cycles were feasible in this trial of MBC patients. As expected, patients reported greater severity of symptoms than clinicians. Demonstrating the feasibility of frequent assessment could have implications for future research and clinical practice. ClinicalTrials.gov NCT03199885 (https://clinicaltrials.gov/study/NCT03199885).

Background Apolipoprotein Ɛ4 genotype (APOE4) has been associated with cancer-related cognitive impairment, but its interaction with treatments remains unclear. This longitudinal study aims to evaluate the association between APOE4 and cognitive impairment in women with breast cancer (BC) undergoing chemotherapy (CT) or endocrine therapy (ET). Findings Patients with stage I–III breast cancer completed cognitive tests at diagnosis (before surgery), then at year-1, year-2, and year-4 post-diagnosis. APOE4 status (APOE4+ [carriers] vs. APOE4− [non-carriers]) was genotyped from blood sample. Cognitive outcomes included episodic memory, working memory, attention, processing speed, and executive functions. Patients were defined as having overall cognitive impairment if ≥ 2 domains were impaired. We fitted logistic and linear mixed models to assess associations of APOE4 status with cognitive impairment over time and interactions of APOE4 with CT and ET. Among 334 patients, 64 (19%) were APOE4+, 117 (35%) patients were treated with CT, 41 (12%) with ET, and 162 (49%) with CT+ET. There were no significant association between overall cognitive impairment and APOE4, nor interactions with CT or ET. At year-4, APOE4+ patients treated with ET had lower attention performance than APOE4− patients not treated with ET, and APOE4+ patients not treated with ET had lower episodic memory performance than APOE4− patients not treated with ET. Conclusions This study suggests APOE4 genotyping is ineffective for detecting cognitive impairment in BC. New genotypes should be identified to predict cognitive decline in BC.

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

Background: Epigenetic changes, particularly DNA methylation, are crucial to breast cancer development. Tumor-adjacent normal (AN) tissue frequently serves as a reference for characterizing genomic alterations but is reported to share some characteristics with tumors. However, it is unclear whether AN's epigenetic profiles reflect a predisposition to cancer or a response to the presence of the tumor. We address this gap by systematically comparing methylation profiles of tumor, AN, and matched-benign tissues from both breasts, as well as to healthy donated breast tissue. Methods: We studied four different sample categories from 69 cancer cases: tumor (TU), AN, ipsilateral opposite quadrant (OQ), and contralateral unaffected breast (CUB); and healthy donated breast (HDB) tissue from 182 cancer-unaffected donors. These constitute a "tumor proximity axis" (TPxA): HDB → CUB → OQ → AN → TU. Methylation profiles were assayed using Illumina's Infinium Methylation EPICv1.0 BeadChip. Differential methylation (DM) analysis was conducted, and the significantly DM CpGs were analyzed for enrichment of transcription factor binding sites (TFBS) and other features. Results: Following data processing and quality control, there were 69 TU, 60 AN, 67 OQ, 68 CUB, and 182 HDB samples for analysis. DM analysis showed distinct methylation profiles of TU relative to benign tissues, whereas case-benign tissues were similar to each other but distinct from HDB. Hypomethylated sites in case-benign versus HDB were enriched for TF binding sites of TP63, GATA3, ESR1, PR, AR, NR3C1, and GREB1. TU hypermethylation events were enriched for Polycomb-repressive complex 2 (PRC2) binding, including EZH2, SUZ12, and JARID2, with hypermethylation enrichment for PRC2-related binding motifs in both ER+ and ER- tumors. TU methylation profiles were otherwise highly distinct by ER status: TFBS enrichment of hypomethylation events for hormone receptor-related pathways in ER+ tumors and for hematopoiesis/immune-related pathways in ER- tumors. We found no differential methylation between benign tissues from patients with ER+ vs. ER- tumors. Conclusions: DNA methylation profiles differ profoundly at two points: tumor to case-benign and case-benign to HDB, with clear distinction between ER+ and ER- tumors. Case-benign tissues are not epigenetically "normal", are similar across both breasts, and do not differ by ER status of paired tumors.

Objective: Cancer-specific psychological interventions like cognitive behavioral stress management (CBSM) demonstrate distress (e.g., anxiety/depression) and quality of life (QoL) benefits. Digital formats can expand access. Method: Patients (80.6% female; 76.5% White; 25–80 years) with Stage I–III cancer and elevated anxiety within 6 months of treatment (surgery/chemotherapy/radiation/immunotherapy) receipt were randomized 1:1 to a 10-module CBSM or health education control digital app and completed questionnaires at Weeks 0, 4, 8, 12. Primary outcomes of greater group-level anxiety (PROMIS-A) and depression symptom (PROMIS-D) reductions for CBSM were met and published; this secondary report evaluates individual-level response results for these outcomes and outcomes beyond anxiety and depression. Chi-square tests compared responder proportions using PROMIS-A/PROMIS-D symptom categories and two levels (≥5/≥7.5) of T-score point reductions. Changes across conditions over time for stress (Perceived Stress Scale), cancer-specific distress (Impact of Event Scale–Intrusions), and QoL (Functional Assessment of Cancer Therapy–General) were analyzed using repeated measures linear mixed-effects modeling (N = 449). Patient Global Impression of Change–Well-being was also examined. Results: At Week 12, a greater proportion of CBSM (vs. control) participants reported normal-to-mild (vs. moderate-to-severe) PROMIS-A and PROMIS-D, and a greater proportion of CBSM participants at Week 8 or 12 had a ≥7.5 T-score reduction in PROMIS-A and a ≥5 T-score reduction in PROMIS-D (ps < .05). CBSM participants (vs. control) showed significantly greater reductions in Perceived Stress Scale and Impact of Event Scale-Intrusions and increases in Patient Global Impression of Change–Well-being and Functional Assessment of Cancer Therapy emotional and physical well-being (ps < .05), but not functional or social/family well-being. Conclusion: Digitized CBSM benefits distress and QoL.

Breast aging encompasses intricate molecular and cellular changes that elevate cancer risk. Our study profiled DNA methylation and gene expression of 181 normal breast samples and systematically evaluated eight epigenetic clocks. We found that clocks trained using breast tissues demonstrate improved age prediction in normal breast tissue, and bias universally exists in epigenetic clocks, necessitating a proper definition of age acceleration. Cell composition analysis revealed significant age-related alterations and highlighted its distinct associations with age acceleration, including increased luminal epithelial and myoepithelial cells and reduced adipocytes and immune cells, connecting age acceleration to carcinogenesis from a cell compositional perspective. Additionally, CpG sites associated with age acceleration were enriched for estrogen receptor binding sites, providing a mechanistic link between estrogen exposure, accelerated aging, and cancer. These findings highlight the importance of cellular heterogeneity in epigenetic age estimates and the potential of age acceleration to guide for risk stratification and prevention strategies.