Deciphering the Molecular Mechanisms behind Drug Resistance in Ovarian Cancer to Unlock Efficient Treatment Options.

Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer.

BACKGROUND: In monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. METHODS: Patients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. RESULTS: At baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69-78 %) reported being bothered "a little bit" or "not at all" by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. CONCLUSION: PRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

Real-life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial).

BACKGROUND: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). METHODS: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months. RESULTS: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). CONCLUSIONS: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. LAY SUMMARY: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.

Impressive and durable clinical responses obtained with dabrafenib and trametinib in low-grade serous ovarian cancer harbouring a BRAF V600E mutation.

Low-grade serous ovarian cancer (LGSOC) is now considered a different entity from high-grade serous ovarian cancer. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. Here we present a case report of two patients with a BRAF V600E mutation that achieved sustained clinical responses with combination treatment with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor).

Tumor Testing for Somatic and Germline BRCA1/BRCA2 Variants in Ovarian Cancer Patients in the Context of Strong Founder Effects.

Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency (HRD) status are considered strong predictors of response to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). The introduction of PARPi in clinical practice for the treatment of patients with advanced ovarian cancer imposed changes in the molecular diagnosis of BRCA1/BRCA2 variants. BRCA1/BRCA2 tumor testing by next-generation sequencing (NGS) can detect simultaneously both somatic and germline variants, allowing the identification of more patients with higher likelihood of benefiting from PARPi. Our main goal was to determine the frequency of somatic and germline BRCA1/BRCA2 variants in a series of non-mucinous OC, and to define the best strategy to be implemented in a routine diagnostic setting for the screening of germline/somatic variants in these genes, including the BRCA2 c.156_157insAlu Portuguese founder variant. We observed a frequency of 19.3% of deleterious variants, 13.3% germline, and 5.9% somatic. A higher prevalence of pathogenic variants was observed in patients diagnosed with high-grade serous ovarian cancer (23.2%). Considering the frequencies of the c.3331_3334del and the c.2037delinsCC BRCA1 variants observed in this study (73% of all BRCA1 pathogenic germline variants identified) and the limitations of NGS to detect the BRCA2 c.156_157insAlu variant, it might be cost-effective to test for these founder variants with a specific test prior to tumor screening of the entire coding regions of BRCA1 and BRCA2 by NGS in patients of Portuguese ancestry.

Male breast cancer: Looking for better prognostic subgroups.

PURPOSE: Male Breast Cancer (MBC) remains a poor understood disease. Prognostic factors are not well established and specific prognostic subgroups are warranted. PATIENTS/METHODS: Retrospectively revision of 111 cases treated in the same Cancer Center. Blinded-central pathological revision with immunohistochemical (IHQ) analysis for estrogen (ER), progesterone (PR) and androgen (AR) receptors, HER2, ki67 and p53 was done. Cox regression model was used for uni/multivariate survival analysis. Two classifications of Female Breast Cancer (FBC) subgroups (based in ER, PR, HER2, 2000 classification, and in ER, PR, HER2, ki67, 2013 classification) were used to achieve their prognostic value in MBC patients. Hierarchical clustering was performed to define subgroups based on the six-IHQ panel. RESULTS: According to FBC classifications, the majority of tumors were luminal: A (89.2%; 60.0%) and B (7.2%; 35.8%). Triple negative phenotype was infrequent (2.7%; 3.2%) and HER2 enriched, non-luminal, was rare (≤1% in both). In multivariate analysis the poor prognostic factors were: size >2 cm (HR:1.8; 95%CI:1.0-3.4 years, p = 0.049), absence of ER (HR:4.9; 95%CI:1.7-14.3 years, p = 0.004) and presence of distant metastasis (HR:5.3; 95%CI:2.2-3.1 years, p < 0.001). FBC subtypes were independent prognostic factors (p = 0.009, p = 0.046), but when analyzed only luminal groups, prognosis did not differ regardless the classification used (p > 0.20). Clustering defined different subgroups, that have prognostic value in multivariate analysis (p = 0.005), with better survival in ER/PR+, AR-, HER2-and ki67/p53 low group (median: 11.5 years; 95%CI: 6.2-16.8 years) and worst in PR-group (median:4.5 years; 95%CI: 1.6-7.8 years). CONCLUSION: FBC subtypes do not give the same prognostic information in MBC even in luminal groups. Two subgroups with distinct prognosis were identified in a common six-IHQ panel. Future studies must achieve their real prognostic value in these patients.

Missing data imputation on the 5-year survival prediction of breast cancer patients with unknown discrete values.

Breast cancer is the most frequently diagnosed cancer in women. Using historical patient information stored in clinical datasets, data mining and machine learning approaches can be applied to predict the survival of breast cancer patients. A common drawback is the absence of information, i.e., missing data, in certain clinical trials. However, most standard prediction methods are not able to handle incomplete samples and, then, missing data imputation is a widely applied approach for solving this inconvenience. Therefore, and taking into account the characteristics of each breast cancer dataset, it is required to perform a detailed analysis to determine the most appropriate imputation and prediction methods in each clinical environment. This research work analyzes a real breast cancer dataset from Institute Portuguese of Oncology of Porto with a high percentage of unknown categorical information (most clinical data of the patients are incomplete), which is a challenge in terms of complexity. Four scenarios are evaluated: (I) 5-year survival prediction without imputation and 5-year survival prediction from cleaned dataset with (II) Mode imputation, (III) Expectation-Maximization imputation and (IV) K-Nearest Neighbors imputation. Prediction models for breast cancer survivability are constructed using four different methods: K-Nearest Neighbors, Classification Trees, Logistic Regression and Support Vector Machines. Experiments are performed in a nested ten-fold cross-validation procedure and, according to the obtained results, the best results are provided by the K-Nearest Neighbors algorithm: more than 81% of accuracy and more than 0.78 of area under the Receiver Operator Characteristic curve, which constitutes very good results in this complex scenario.

Staging and survival of rectal cancer in Vila Nova de Gaia, Portugal.

INTRODUCTION: In the county of Vila Nova de Gaia (northern Portugal) in the period of 2004-2006, there were an average of 35 new cases of colorectal cancer per 100,000 population, which constitutes one of the highest rates in the world. The latest research has shown that there are many differences between colon and rectal cancers, thereby justifying an independent approach. PATIENTS AND METHODS: The study pertained to the period 1995-2004, by using the census of 1991 and 2001 for calculating specific rates. The 399 diagnosed cases of rectal cancer were drawn from a specialized and active cancer registry, oncological registry of Gaia. Overall survival was calculated using the Kaplan-Meier method and the curves were compared using a Log Rank test. The effect of topography and histological type on survival was obtained by controlling the stage disease, using a Cox proportional hazards regression model. RESULTS: There was a slight predominance of males, with a ratio between sexes of 1 : 3. The 50% overall survival rate after 5 years increased over time. The localization of the tumour and the histological type, after adjusting by stage, were not significant factors in the prognosis. CONCLUSION: Our study shows an increase in the number of cases over time, particularly in elderly women. The cumulative risk of having rectal cancer remains unchanged from 1981 to 2004. Unlike other studies, an increase in early lesions was not observed.