Background: Higher cytotoxic T lymphocyte (CTL) numbers in the tumor microenvironment (TME) predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and positive long-term outcomes in triple-negative breast cancer (TNBC). pCR to NAC is achieved only in 30–40% of patients. The combination of NAC with pembrolizumab increases the pCR rate but at the cost of immune-related adverse events (irAEs). Based on these considerations, we tested if systemic infusion of the chemokine modulatory regimen (CKM; selective toll-like receptor 3 (TLR3) agonist rintatolimod, interferon (IFN)-α2b, and cyclooxygenase-2 (COX-2) inhibitor celecoxib) regimen can be safely combined with NAC to enhance intratumoral CTL numbers and NAC effectiveness. Methods: Phase I study NCT04081389 evaluated nine patients with early-stage TNBC who received 3 weeks of paclitaxel with CKM (dose-escalation of IFN-α2b), followed by 9 weeks of paclitaxel alone, dose-dense doxorubicin and cyclophosphamide, and surgery. Primary and secondary endpoints were safety and clinical efficacy, respectively. Results: The combination treatment was well-tolerated with no dose-limiting toxicities or irAEs. 5/9 patients achieved pCR and one patient had microinvasive disease (ypTmic). We observed elevated IFN signature and uniform decreases in CTL numbers (average 8.3-fold) in the blood of all treated patients. This was accompanied by reciprocal uniform increases in CD8β (overall 5.9-fold), CD8α/FoxP3 (2.11-fold), and CCL5 (4.73-fold) transcripts in TME, particularly pronounced in patients with pCR. Multiplex immunohistochemistry revealed selectively increased numbers of CTL (but not regulatory T cells) in both the epithelial and stromal tumor compartments and early decreases in the numbers of αSMA⁺ vascular/stromal cells in the tumors of all pCR patients. Conclusions: Combined paclitaxel/CKM regimen was safe, with desirable TME changes and preliminary indications of promising pCR+ypTmic of 66%, comparable to the combination of NAC with pembrolizumab.

The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration.

Background: Recent evidence suggests that vitamin D might lower breast cancer mortality. There is also growing interest in vitamin D's potential association with health-related quality-of-life (HRQoL). Associations between circulating 25-hydroxyvitamin D (25OHD) concentrations and HRQoL were examined prospectively among breast cancer survivors at the time of diagnosis and 1 year later. Methods: 504 women with incident early-stage breast cancer at Roswell Park Comprehensive Cancer Center were included, and 372 patients provided assessments 1 year later. At each timepoint, participants provided blood samples and completed the SF-36 Health Survey, and surveys on perceived stress, depression, and fatigue. Season-adjusted serum 25OHD concentrations were analyzed in relation to HRQoL measures using multivariable logistic regression models. Results: Approximately 32% of participants had deficient vitamin D levels at diagnosis, which decreased to 25% at 1 year. Concurrently, although SF-36 physical health summary scores were lower at 1 year, mental health summary scores improved, and levels of depression and perceived stress were lower. In comparison with women with sufficient 25OHD levels (>30 ng/mL) at diagnosis, those who were deficient (<20 ng/mL) had significantly worse HRQoL at diagnosis and 1 year later. Vitamin D deficiency 1 year post-diagnosis was also associated with worse HRQoL, particularly among breast cancer survivors who took vitamin D supplements. Conclusions: Breast cancer survivors with vitamin D deficiency were more likely to report lower HRQoL than those with sufficient levels at the time of diagnosis and 1 year post-diagnosis. Impact: Our results indicate a potential benefit of vitamin D supplementation for improving breast cancer survivorship.

Background: Physical activity helps cancer survivors ameliorate physiological and psychosocial effects of disease and treatments. However, few cancer survivors meet physical activity recommendations, with many facing barriers such as limited interest, enjoyment, and social support. It is critical to develop enjoyable and supportive physical activity programs to improve well-being among the growing population of cancer survivors. Pickleball is increasingly popular due to its unique combination of physical activity, friendly competition, and social interaction, making it a promising strategy to increase and sustain physical activity in cancer survivorship. Objective: We examined feasibility, acceptability, and preliminary outcomes in a single-arm pilot study of Project Rally, a YMCA-based pickleball program for adult cancer survivors. Results: Twenty-one cancer survivors and seven family or friend partners enrolled in Project Rally with a targeted program duration of 3–7 months. All programming and study assessments occurred at a single YMCA with coaching and supervision from a YMCA exercise trainer and certified pickleball coach. Feasibility and acceptability were strong and met a priori targets for recruitment, retention, intervention adherence, and ratings of program aspects. Participants demonstrated significant increases in physical activity and improvements in aspects of fitness, physical functioning, and social support. Conclusion: These results will inform further development of the Project Rally program to increase physical activity and improve cancer survivorship outcomes, including efforts to expand the program’s scale and reach more survivors via community-based delivery.