In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER+ Patients (RSF ER+). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

Breast Cancer Diagnostics, Therapy, and Outcomes in Sub-Saharan Africa: A Population-Based Registry Study

Background: Breast cancer (BC) is the most common cancer in sub-Saharan Africa (SSA). However, little is known about the actual therapy received by women with BC and their survival outcome at the population level in SSA. This study aims to describe the cancer-directed therapy received by patients with BC at the population level in SSA, compare these results with the NCCN Harmonized Guidelines for SSA (NCCN Harmonized Guidelines), and evaluate the impact on survival. Methods: Random samples of patients with BC (≥40 patients per registry), diagnosed from 2009 through 2015, were drawn from 11 urban population–based cancer registries from 10 countries (Benin, Congo, Cote d’Ivoire, Ethiopia, Kenya, Mali, Mozambique, Namibia, Uganda, and Zimbabwe). Active methods were used to update the therapy and outcome data of diagnosed patients (“traced patients”). Excess hazards of death by therapy use were modeled in a relative survival context. Results: A total of 809 patients were included. Additional information was traced for 517 patients (63.8%), and this proportion varied by registry. One in 5 traced patients met the minimum diagnostic criteria (cancer stage and hormone receptor status known) for use of the NCCN Harmonized Guidelines. The hormone receptor status was unknown for 72.5% of patients. Of the traced patients with stage I–III BC (n=320), 50.9% received inadequate or no cancer-directed therapy. Access to therapy differed by registry area. Initiation of adequate therapy and early-stage diagnosis were the most important determinants of survival. Conclusions: Downstaging BC and improving access to diagnostics and care are necessary steps to increase guideline adherence and improve survival for women in SSA. It will also be important to strengthen health systems and facilities for data management in SSA to facilitate patient follow-up and disease surveillance.

Multiple Primary Cancer and Survival after Lumpectomy with or without Radiotherapy for Ductal Carcinoma in Situ: A Propensity- Score-Matching Study

Background: Radiotherapy combined with breast-conserving surgery is widely performed in patients with ductal carcinoma in situ (DCIS). This research was conducted to evaluate the use of radiotherapy to reduce the risk of multiple primary cancer (MPC) and mortality in DCIS patients.Methods: 108,416 patients first diagnosed with DCIS between 1998 and 2015 who received lumpectomy in the Surveillance, Epidemiology, and End Results (SEER) 18 database were included. Age, race, year of diagnosis, laterality, pathologic grade, surgery, radiation, estrogen receptor status, progesterone receptor status, tumor size and vital status were extracted. A comparison of lumpectomy vs. lumpectomy plus radiotherapy was performed using 1:1 propensity score-based matching.Results: Of the 108,416 patients, 39,039 patients were treated with lumpectomy alone, and 69,377 were treated with lumpectomy and radiotherapy. The adjusted hazard ratio (HR) for death was 0.801 and 0.7444 for occurrence of MPC in the lumpectomy and radiotherapy vs. lumpectomy alone groups, respectively. Conclusion: Lumpectomy plus radiotherapy is associated with a significant reduction in mortality and risk of MPC, mainly second primary BC. Younger patients, Black women with high-grade tumors were likely to benefit most. Radiotherapy reduced the risk of occurrence rather than the mortality of MPC patients to reduce the overall mortality.

Integrative multiomics-histopathology analysis for breast cancer classification

Histopathologic evaluation of biopsy slides is a critical step in diagnosing and subtyping breast cancers. However, the connections between histology and multi-omics status have never been systematically explored or interpreted. We developed weakly supervised deep learning models over hematoxylin-and-eosin-stained slides to examine the relations between visual morphological signal, clinical subtyping, gene expression, and mutation status in breast cancer. We first designed fully automated models for tumor detection and pathology subtype classification, with the results validated in independent cohorts (area under the receiver operating characteristic curve ≥ 0.950). Using only visual information, our models achieved strong predictive performance in estrogen/progesterone/HER2 receptor status, PAM50 status, and TP53 mutation status. We demonstrated that these models learned lymphocyte-specific morphological signals to identify estrogen receptor status. Examination of the PAM50 cohort revealed a subset of PAM50 genes whose expression reflects cancer morphology. This work demonstrates the utility of deep learning-based image models in both clinical and research regimes, through its ability to uncover connections between visual morphology and genetic statuses.

Does Routine Follow-Up after Patients Have Completed Adjuvant Therapy for Early-Stage Breast Cancer at a Cancer Center Improve Prognosis?

<b><i>Introduction:</i></b> This study aimed to assess whether follow-up of patients with operative breast cancer at cancer centres (CCs) improved prognosis compared with follow-up by family physicians (FPs). <b><i>Methods:</i></b> The study included 254 patients who relapsed within 7 years from the first postoperative period. The patients were divided into two groups according to the follow-up facility: the CC and FP groups (the follow-up of patients was structured in the same way between FPs and CCs). There are 146 and 108 cases of recurrence in the CC and FP groups, respectively. The analysis targets of the two groups were determined using the propensity matching method based on the following 7 factors: oestrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status, St. Gallen category, menopausal status, surgical procedure, and receipt of postoperative chemotherapy at the time of surgery. Overall survival (OS) in both groups was analysed using the Kaplan-Meier method and compared using the log-rank test. <b><i>Results:</i></b> Overall, 97 patients each in the CC and FP groups who relapsed were analysed using the propensity matching method. The median recurrence-free survival periods were 1,676 and 994 days in the FP and CC groups, respectively, and were significantly longer in the FP group. However, the median OS starting from the day of surgery was 3,424 and 2,794 days in the FP and CC groups, respectively, with no significant difference. <b><i>Conclusion:</i></b> This study revealed that regular follow-up at CCs did not improve survival compared with regular follow-up by FPs.