Taxanes trigger cancer cell killing in vivo by inducing non-canonical T cell cytotoxicity.

Although treatment with taxanes does not always lead to clinical benefit, all patients are at risk of their detrimental side effects such as peripheral neuropathy. Understanding the in vivo mode of action of taxanes can help design improved treatment regimens. Here, we demonstrate that in vivo, taxanes directly trigger T cells to selectively kill cancer cells in a non-canonical, T cell receptor-independent manner. Mechanistically, taxanes induce T cells to release cytotoxic extracellular vesicles, which lead to apoptosis specifically in tumor cells while leaving healthy epithelial cells intact. We exploit these findings to develop an effective therapeutic approach, based on transfer of T cells pre-treated with taxanes ex vivo, thereby avoiding toxicity of systemic treatment. Our study reveals a different in vivo mode of action of one of the most commonly used chemotherapies, and opens avenues to harness T cell-dependent anti-tumor effects of taxanes while avoiding systemic toxicity.

Artificial intelligence-based morphometric signature to identify ductal carcinoma in situ with low risk of progression to invasive breast cancer.

Ductal carcinoma in situ (DCIS) may progress to ipsilateral invasive breast cancer (iIBC), but often never will. Because DCIS is treated as early breast cancer, many women with harmless DCIS face overtreatment. To identify these women that may forego treatment, we hypothesized that DCIS morphometric features relate to the risk of subsequent iIBC. We developed an artificial intelligence-based DCIS morphometric analysis pipeline (AIDmap) to detect DCIS as a pathologist and measure morphological structures in hematoxylin-eosin-stained (H&E) tissue sections. These were from a case-control study of patients diagnosed with primary DCIS, treated by breast-conserving surgery without radiotherapy. We analyzed 689 WSIs of DCIS of which 226 were diagnosed with subsequent iIBC (cases) and 463 were not (controls). The distribution of 15 duct morphological measurements in each H&E was summarized in 55 morphometric variables. A ridge regression classifier with cross validation predicted 5-years-free of iIBC with an area-under the curve of 0.65 (95% CI 0.55-0.76). A morphometric signature based on the 30 variables most associated with outcome, identified lesions containing small-sized ducts, low number of cells and low DCIS/stroma area ratio. This signature was associated with lower iIBC risk in a multivariate regression model including grade, ER, HER2 and COX-2 expression (HR = 0.56; 95% CI 0.28-0.78). AIDmap has potential to identify harmless DCIS that may not need treatment.

Estimation of covariate effects on net survivals in the relative survival progressive illness-death model.

Recently, there has been a lot of development in relative survival field. In the absence of data on the cause of death, the research has tended to focus on the estimation of survival probability of a cancer (as a disease of interest). In many cancers, one nonfatal event that decreases the survival probability can occur. There are a few methods that assess the role of prognostic factors for multiple types of clinical events while dealing with uncertainty about the cause of death. However, these methods require proportional hazard or Markov assumptions. In practice, one or both of these assumptions might be violated. Violation of the proportional hazard assumption can lead to estimates that are biased, and difficult to interpret and violation of Markov assumption results in inconsistent estimators. In this work, we propose a semi-parametric approach to estimate the possibly time-varying regression coefficients in the likely non-Markov relative survival progressive illness-death model. The performance of the proposed estimator is investigated through simulations. We illustrate our approach using data from a study on rectal cancer resected for cure conducted in two French population-based digestive cancer registries.

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.