The intratumoral immune milieu is crucial for the success of anti-cancer immunotherapy. We show here that stromal modulation by the tubulin-binding anti-cancer drugs combretastatin A4 (CA-4) and eribulin improved tumor perfusion and anti-tumor immunity. This was achieved by reverting highly proliferative, angiogenic pericytes into a quiescent, contractile state which durably normalized the vascular bed and reduced hypoxia in mouse models of pancreatic neuroendocrine cancer, breast cancer and melanoma. The crucial event in pericyte phenotype switching was RhoA kinase activation, which distinguished CA-4 and eribulin effects from other anti-mitotic drugs such as paclitaxel and vinorelbine. Importantly, eribulin pre-treatment sensitized tumors for adoptive T cell therapy or checkpoint inhibition resulting in effector cell infiltration and better survival outcomes in mice. In breast cancer patients, eribulin neoadjuvant treatment induced pericyte maturity and RhoA kinase activity indicating similar vessel remodeling effects as seen in mice. Moreover, a contractile pericyte signature was associated with overall better survival outcome in two independent breast cancer cohorts. This underscores the potential of re-purposing specific anti-cancer drugs to enable synergistic complementation with emerging immunotherapies.

There are few markers to identify those likely to recur or progress after treatment with intravesical BCG. We developed and validated artificial intelligence-based histologic assays that extract interpretable features from transurethral resection of bladder tumor digitized pathology images to predict risk of recurrence, progression, development of BCG unresponsive disease, and cystectomy. Pre-BCG resection-derived whole-slide images and clinical data were obtained for high-risk non-muscle invasive bladder cancer cases treated with BCG from 12 centers and were analyzed through a segmentation and feature extraction pipeline. Features associated with clinical outcomes were defined and tested on independent development and validation cohorts. Cases were classified into high or low risk for recurrence, progression, BCG unresponsive disease, and cystectomy. 944 cases (development:303, validation:641, median follow-up:36 months) representative of the intended use population were included (high-grade Ta:34.1%, high-grade T1:54.8%; carcinoma-in-situ only:11.1%, any carcinoma-in-situ:31.4%). In the validation cohort, "High recurrence risk" cases had inferior high-grade recurrence-free survival versus "Low recurrence risk" cases (HR 2.08, p<0.0001). "High progression risk" patients had poorer progression-free survival (HR 3.87, p<0.001) and higher risk of cystectomy (HR 3.35, p<0.001) than "Low progression risk". Cases harboring the BCG unresponsive disease signature had a shorter time to development of BCG unresponsive disease than cases without the signature (HR 2.31, p<0.0001). AI assays provided predictive information beyond clinicopathologic factors. We developed and validated AI-based histologic assays that identify high-risk non-muscle invasive bladder cancer cases at higher risk of recurrence, progression, BCG unresponsive disease, and cystectomy, potentially aiding clinical decision-making.

Background: Despite access to universal health care, Aboriginal and Torres Strait Islander females (hereafter respectfully referred to as Aboriginal) in Australia have higher breast cancer incidence and mortality rates. We investigated the factors contributing to these survival disparities. Methods: Aboriginal females (n = 395; 0.7%) and non-Aboriginal females (n = 57,618; 99.3%) with breast cancer were identified from Victoria, Australia. Clinical, pathologic, demographic, and socioeconomic variables were analyzed. Endpoints were all-cause and breast cancer–specific mortality. HRs were estimated using Cox regression. Stromal tumor–infiltrating lymphocytes were evaluated from a subset of Aboriginal females and compared with females in The Cancer Genome Atlas. Results: Registry data revealed that Aboriginal females were younger (P < 0.001), had more advanced stage disease (P = 0.007), and were more likely to live in nonmetropolitan areas (P < 0.001) and in areas of greater disadvantage (P < 0.001) compared with other females at diagnosis. Age-adjusted multivariate analysis revealed a higher all-cause mortality risk (HR 1.27; 95% confidence interval, 1–1.61) for Aboriginal females, but this risk diminished for breast cancer–specific mortality and after adjustment for stage and grade. Breast cancers from Aboriginal females had significantly reduced stromal tumor–infiltrating lymphocytes in the luminal and triple-negative subtypes compared with The Cancer Genome Atlas. Conclusions: Mortality for females with breast cancer was influenced by socioeconomic, geographic, and clinical factors. Notably, Aboriginal females with tumor features typically associated with favorable outcomes experienced poorer outcomes. The reduced immune infiltrate warrants further investigation. Impact: These findings highlight the need to address socioeconomic inequities and ensure culturally safe cancer care. Further research should explore biological and environmental factors influencing outcomes for Australian Aboriginal females.

Introduction: An inverse association between high mammographic breast density (MBD) and pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for early breast cancer (EBC) has been reported. However, the relationship of MBD to relapse-free (RFS) and breast cancer-specific survival (BCSS) is unexplored. This study aims to validate the relationship between MBD and NAC pCR in EBC and to assess correlations with RFS and BCSS. Materials & Methods: MBD was measured on contralateral mammograms in 127 women before NAC using Cumulus software. The percent dense area was correlated with patient and tumour characteristics, pCR, RFS and BCSS. Results: Mean MBD was higher in relapsing patients (p = 0.041) but did not vary by pCR or BC-deaths. As a dichotomous variable, no difference was seen between high and low MBD cohorts for pCR (17.5 vs. 25.0%, p = 0.15), BC relapse (38 vs. 30%, p = 0.15) or BC death (32 vs. 25%, p = 0.20). A planned analysis by body mass index (BMI) demonstrated high MBD associated with lower pCR (0% vs. 28.1%, p = 0.036) and trends for higher relapse (56% vs. 28%, p = 0.063) and BC deaths (56 vs. 28%, (p = 0.071)) in obese patients. No relationship was observed in non-obese patients. Conclusions: Obesity and high MBD may interact to cause chemoresistance. Further research in these patients is warranted.

Immune-biology data for Aboriginal females and females from TCGA with breast cancer

Analysis of co-variates for Aboriginal females and females from TCGA