Batalini, Felipe

PURPOSE Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy. METHODS A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data. RESULTS In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden. CONCLUSION Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

Abstract Background Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. Results We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P &lt; .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P &lt; .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Conclusion Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

PURPOSE Contrast-enhanced mammography (CEM) and magnetic resonance imaging (MRI) have shown similar diagnostic performance in detection of breast cancer. Limited CEM data are available for high-risk breast cancer screening. The purpose of the study was to prospectively investigate the efficacy of supplemental screening CEM in elevated risk patients. MATERIALS AND METHODS A prospective, single-institution, institutional review board–approved observational study was conducted in asymptomatic elevated risk women age 35 years or older who had a negative conventional two-dimensional digital breast tomosynthesis screening mammography (MG) and no additional supplemental screening within the prior 12 months. RESULTS Four hundred sixty women were enrolled from February 2019 to April 2021. The median age was 56.8 (range, 35.0-79.2) years; 408 of 460 (88.7%) were mammographically dense. Biopsy revealed benign changes in 22 women (22/37, 59%), high-risk lesions in four women (4/37, 11%), and breast cancer in 11 women (11/37, 30%). Fourteen cancers (10 invasive, tumor size range 4-15 mm, median 9 mm) were diagnosed in 11 women. The overall supplemental cancer detection rate was 23.9 per 1,000 patients, 95% CI (12.0 to 42.4). All cancers were grade 1 or 2, ER+ ERBB2–, and node negative. CEM imaging screening offered high specificity (0.875 [95% CI, 0.844 to 0.906]), high NPV (0.998 [95% CI, 0.993 to 1.000), moderate PPV1 (0.164 [95% CI, 0.076 to 0.253), moderate PPV3 (0.275 [95% CI, 0.137 to 0.413]), and high sensitivity (0.917 [95% CI, 0.760 to 1.000]). At least 1 year of imaging follow-up was available on all patients, and one interval cancer was detected on breast MRI 4 months after negative screening CEM. CONCLUSION A pilot trial demonstrates a supplemental cancer detection rate of 23.9 per 1,000 in women at an elevated risk for breast cancer. Larger, multi-institutional, multiyear CEM trials in patients at elevated risk are needed for validation.

Objective Deep learning (DL) has shown promising results for improving mammographic breast cancer diagnosis. However, the impact of artificial intelligence (AI) on the breast cancer screening process has not yet been fully elucidated in terms of potential workload reduction. We aim to assess if AI-based triaging of breast cancer screening mammograms could reduce the radiologist's workload with non-inferior sensitivity. Methods PubMed, EMBASE, Cochrane Central, and Web of Science databases were systematically searched for studies that evaluated AI algorithms on computer-aided triage of breast cancer screening mammograms. We extracted data from homogenous studies and performed a proportion meta-analysis with a random-effects model to examine the radiologist's workload reduction (proportion of low-risk mammograms that could be theoretically ruled out from human's assessment) and the software's sensitivity to breast cancer detection. Results Thirteen studies were selected for full review, and three studies that used the same commercially available DL algorithm were included in the meta-analysis. In the 156,852 examinations included, the threshold of 7 was identified as optimal. With these parameters, radiologist workload decreased by 68.3% (95%CI 0.655–0.711, I² = 98.76%, p < 0.001), while achieving a sensitivity of 93.1% (95%CI 0.882–0.979, I² = 83.86%, p = 0.002) and a specificity of 68.7% (95% CI 0.684–0.723, I² = 97.5%, p < 0.01). Conclusions The deployment of DL computer-aided triage of breast cancer screening mammograms reduces the radiology workload while maintaining high sensitivity. Although the implementation of AI remains complex and heterogeneous, it is a promising tool to optimize healthcare resources.

PURPOSE Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1/ 2 genes (g BRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1/ 2 mutations (s BRCA) or germline PALB2 mutations (g PALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g BRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). METHODS A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record–derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. RESULTS Of 28,920 patients with mBC, g BRCA was detected in 3.4%, whereas the population with any BRCA alteration or g PALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and g PALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g BRCA and s BRCA/ gPALB2 cohorts were similar: g BRCA versus s BRCA/g PALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig– had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). CONCLUSION Patients with s BRCA and g PALB2 derive similar benefit from PARPi as those with g BRCA alterations. In combination, HRDsig+, s BRCA, and g PALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.

Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches.

Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers.

Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% [16 of 134] and 15.7% [21 of 134], respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants.