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Abstract Background Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression‐free survival (PFS) in patients with hormone receptor (HR)‐positive, HER2‐negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real‐world benefit of first‐line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. Methods This study included HR‐positive, HER2‐negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression‐free survival (PFS) was determined using Kaplan–Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil‐to‐lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time‐dependent variable. Results In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93–NR). Median PFS for patients with bone‐only metastases (n = 54) was not reached (95% CI 18.21–NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33–33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71–0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97–1.18, p = 0.203). Conclusion The effectiveness of palbociclib and endocrine therapy in the treatment of HR‐positive, HER2‐negative mBC in the real‐world setting is similar to the efficacy reported in the PALOMA‐2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Abstract Background Cyclin‐dependent kinase 4 and 6 (CDK4/6) inhibitor targeted therapies dramatically improve survival outcomes for metastatic breast cancer (MBC), but they are associated with significant symptom burden that can impact patients’ health‐related quality of life (HRQOL) and treatment outcomes. This study is the first to describe CDK4/6 inhibitor symptoms from the lived perspectives of MBC patients taking CDK4/6 inhibitors and healthcare providers involved in MBC care. This study also explored patients’ symptom management and HRQOL concerns, and gathered feedback about developing supportive interventions for MBC. Methods MBC patients taking CDK4/6 inhibitors (N = 20) and MBC healthcare providers (N = 12) participated in semi‐structured interviews that were analyzed for qualitative themes. MBC patients completed surveys about HRQOL, symptoms, and unmet needs. Results Patient and provider perceptions of CDK4/6 inhibitor symptoms did not align with patients perceiving symptoms as more burdensome. Patients reported that supportive resources (e.g., support groups, blogs) that are not specific to MBC do not adequately meet their needs. Patients and providers were enthusiastic about developing supportive interventions specifically for MBC and offered considerations for designing such interventions. Conclusions Findings highlight differences in perceptions of CDK4/6 inhibitor symptom burden between MBC patients and providers. Results will inform the development of supportive interventions to assist MBC patients in managing CDK4/6 inhibitor symptom burden and maintaining HRQOL. Such interventions could also improve treatment outcomes.

Abstract Disseminated cancer cells (DCCs) are detected in the circulation and bone marrow of up to 40% of breast cancer (BC) patients with clinically localized disease. The formation of metastases is governed by eco-evolutionary interactions of DCCs with the tissue during the transition from microscopic populations to macroscopic disease. Here, we view BC adjuvant and neoadjuvant treatments in the context of small population extinction dynamics observed in the Anthropocene era. Specifically, the unique eco-evolutionary dynamics of small asexually reproducing cancer populations render them highly vulnerable to: (1) environmental and demographic fluctuations, (2) Allee effects, (3) genetic drift and (4) population fragmentation. Furthermore, these typically interact, producing self-reinforcing, destructive dynamics—termed the Extinction Vortex—eradicating the population even when none of the perturbations is individually capable of causing extinction. We propose that developing BC adjuvant and neoadjuvant protocols may exploit these dynamics to prevent recovery and proliferation of small cancer populations during and after treatment—termed “Eco-evolutionary rescue” in natural extinctions. We hypothesize more strategic application of currently available agents based on the extinction vulnerabilities of small populations could improve clinical outcomes.

We conducted a prospective study to evaluate immune responses to SARS-CoV-2 in oncology workers in which we collected blood and clinical data every 6 months. Spike-specific CD4+ T-cells and immunoglobulin G responses were measured using interferon-gamma enzyme-linked immunosorbent spot and enzyme-linked immunosorbent assay, respectively. Sixty (81%) vaccinated and 14 (19%) unvaccinated individuals were enrolled. CD4+ T-cell responses of those individuals currently naturally infected were comparable to those who were 6 months from receiving their last dose of the vaccine; both responses were significantly higher than among those who were unvaccinated. Unvaccinated participants who became vaccinated while in the study showed a significant increase in both types of spike-specific immune responses. Previously vaccinated individuals who received a third dose (booster) showed a similar response to the spike protein. However, this response decreases as soon as 3 months but does not dip below the established response following two doses. Response to variants of concern B.1.617.2 (Delta) and B.1.1.529 (Omicron) also increased, with the Omicron variant having a significantly lower response when compared to Delta and the wild type. We conclude that antibody and T-cell responses increase in oncology workers after serial vaccination but can wane over time

Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2+ breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC.

Pancreatic cancer is the fourth most common cancer death in the United States despite comprising a small percentage of the total number of cancer cases. The estimated 5-year overall survival (OS) for patients with distant metastatic disease is approximately 3%. New treatment options are an unmet need and remain an area of active investigation. A 53-year-old male with metastatic pancreatic cancer presented to the hospital with acute-on-chronic respiratory failure approximately 24 hours after receiving a novel therapeutic combination. Chest imaging showed marked changes as concerning for pneumonitis. Infectious workup was negative. The patient had initial clinical improvement after receiving initial intravenous steroids and oxygen support but eventually deteriorated later opting for supportive measures only. With infection ruled out, drug-induced pneumonitis was felt to be the likely cause of the radiologic and clinical changes. The rapidity of onset of symptoms is the aspect being highlighted in this case.

Abstract Background Lymphopenia has been associated with inferior cancer outcomes, but there is limited data in breast cancer. We describe the effects of neoadjuvant chemotherapy on circulating immune cells and its association with pathological complete response (pCR) rates in triple negative breast cancer (TNBC). Methods We constructed a database of patients with early stage TNBC treated with neoadjuvant chemotherapy. Circulating lymphocytes and monocytes were assessed before and after neoadjuvant chemotherapy. These were correlated with pCR rates and disease‐free survival (DFS) using Fisher's exact test, logistic regression, and the log‐rank test. Results From 2000 to 2015, we identified 95 eligible patients. Median age was 50; 29 (31%) were treated with platinum‐containing chemotherapy; and 66 (69%) with nonplatinum‐containing chemotherapy (anthracycline‐taxane, or either alone). About 32 (34%) patients achieved a pCR; and 33 (35%) had recurrence events. Median follow‐up time was 47 months. No significant associations were found between changes in lymphocytes and pCR or DFS. There was a correlation between lower monocyte levels after neoadjuvant chemotherapy and pCR (mean monocyte 0.56 in those with no‐pCR vs 0.46 in those with pCR, P = .049, multivariate P = .078) and DFS (median DFS in highest monocyte quartile was 30 vs 107 months in lowest quartile, P = .022, multivariate P = .023). In patients who received nonplatinum regimens, DFS was better among those who had larger decreases in monocytes. Conclusions Development of lymphopenia from neoadjuvant chemotherapy was not associated with pCR in patients with TNBC. However, lower absolute circulating monocytes after neoadjuvant chemotherapy was associated with improved outcomes.