Gene expression alterations predict the pathological complete response in triple-negative breast cancer exploratory analysis of the NACATRINE trial.

This exploratory analysis of the Neoadjuvant Carboplatin in Triple Negative Breast Cancer (NACATRINE) study aimed to identify the biomarkers of pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC) within the context of a clinical trial. The NACATRINE trial is a phase II, single-center, randomized, open-label clinical trial that investigated the addition of carboplatin to sequential anthracycline- and taxane-based NAC for TNBC. We evaluated the gene expression in untreated samples to investigate its association with pCR, overall survival (OS), and disease-free survival (DFS). RNA was extracted from the tissue biopsy, and the nCounter Breast Cancer panel was used to analyze gene expression. Of the 66 patients included in the gene expression profiling analysis, 24 (36.4%) achieved pCR and 42 (63.6%) had residual disease. In unsupervised hierarchical clustering analyses, differentially expressed genes between patients with and without pCR were identified irrespective of the treatment (24 genes), carboplatin (37 genes), and non-carboplatin (27 genes) arms. In receiver operating characteristic (ROC) curve analysis, 10 genes in the carboplatin arm (area under the ROC curve [AUC], 0.936) and three genes in the non-carboplatin arm (AUC, 0.939) were considered to be potential pCR-associated biomarkers. We identified genes that were associated with improvements in OS and DFS in addition to being related to pCR. We successfully identified gene expression signatures associated with pCR in pretreatment samples of patients with TNBC treated with NAC. Further investigation of these biomarkers is warranted.

Neoadjuvant carboplatin in triple-negative breast cancer: results from NACATRINE, a randomized phase II clinical trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is the mainstay of treatment of stages II and III triple-negative breast cancer (TNBC). This study aims to evaluate if the addition of carboplatin to NACT is associated with an increase in the pathological complete response (pCR) rates in TNBC. METHODS: We conducted an open-label phase II randomized clinical trial in a single center in Brazil. Patients with stage II and III TNBC were randomized to receive standard NACT with or without carboplatin. All the patients received doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) both intravenously (i.v.) q21 days for four cycles. Patients were then randomized for additional treatment with weekly (wk) paclitaxel (80 mg/m2 i.v., for 12 cycles) plus wk carboplatin AUC 1.5 (experimental arm) or without wk carboplatin (control arm). Randomization was stratified according to gBRCA status, age, and AJCC 8th edition clinical stage (II vs. III). The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints included recurrence-free survival and overall survival. RESULTS: Between 2017 and 2021, 146 patients were randomized, 73 on each arm. The median age was 45 years. Most patients (66.4%) had locally advanced stage III disease, 67.1% had T3/T4 tumors, and 56.2% had clinically positive axillary lymph nodes. Germline BRCA status was available for all patients, and 19.9% had pathogenic BRCA1/2 variants. The pCR rate (ypT0ypN0) was numerically increased by 13.7%, being 43.8% (31 of 73 patients) in the experimental and 30.1% (22 of 73 patients) in the control arm, not meeting the prespecified goal of increasing the pCR in 15% (p-value = 0.08). Survival outcomes are immature. CONCLUSION: The addition of carboplatin to standard NACT in stages II and III TNBC was associated with a non-statistically significant numerical increase in the pCR rate. Follow-up for survival outcomes and translational research initiatives are ongoing.

Molecular Biology of Pediatric and Adult Ovarian Germ Cell Tumors: A Review.

Ovarian germ cell tumors (OGCTs) are rare in adults; indeed, they occur predominantly in children, adolescents, and young adults, and they account for approximately 11% of cancer diagnoses in these groups. Because OGCTs are rare tumors, our current understanding of them is sparse; this is because few studies have investigated the molecular basis of pediatric and adult cancers. Here, we review the etiopathogenesis of OGCTs in children and adults, and we address the molecular landscape of these tumors, including integrated genomic analysis, microRNAs, DNA methylation, the molecular implications of treatment resistance, and the development of in vitro and in vivo models. An elucidation of potential molecular alterations may provide a novel field for understanding the pathogenesis, tumorigenesis, diagnostic markers, and genetic peculiarity of the rarity and complexity of OGCTs.

Evaluation of upper limb lymphoedema and diagnostic accuracy of bioimpedance spectroscopy. A comprehensive validation in a Brazilian population.

Lymphoedema is a complication of breast cancer treatment. Its early diagnosis is related to a good prognosis for lymphoedema treatment. The bioimpedance spectroscopy (BIS) evaluates changes in extracellular fluid. The objective of our study was to evaluate the validity, agreement and accuracy of BIS in the diagnosis of breast cancer-related lymphoedema in a Brazilian population. Methods: This is a prospective, cross-sectional study of a convenience sample of 462 women who underwent surgical treatment for breast cancer (mastectomy or breast-conserving treatment). The validity, agreement and accuracy were performed comparing BIS (lymphoedema index (L-DEX) ≥ 6.5 or 10) with volumetry by water displacement, which is the gold standard for evaluating lymphoedema. Receiver operating characteristic curve was performed. Additionally, other methods like perimetry and indirect volumetry of the upper limbs were compared with water displacement volumetry (direct volumetry), and the BIS were compared with subjective evaluation. Results: Considering L-DEX ≥ 10 the sensitivity of the BIS was 44.1%, specificity 95.4%, positive predictive value (PPV) was 70.7%, negative predictive value (NPV) was 87% and kappa was 0.459. The BIS with L-DEX ≥ 6.5, the sensitivity, specificity, PPV, NPV and kappa were 57%, 88.5%, 55.8%, 89% and 0.452, respectively. Area under curve was 0.724 and a possible cut-off point of L-DEX ≥ 7.35 with sensitivity of 57%, specificity of 90.7% and kappa value = 0.489. Conclusion: Although BIS was significantly associated with the subjective evaluation of lymphoedema, it showed low sensitivity and agreement and moderate correlation when used as a method for diagnosing the condition. Thus, it is not the most valid method for evaluating lymphoedema. In addition, it was not the most accurate method when compared with other objective evaluation tools. Public health resources are scarce and must be used consciously. The knowledge that BIS is not a more accurate method than other, lower-cost instruments allows for better targeting of these resources.

Does neoadjuvant therapy for pancreatic head adenocarcinoma increase postoperative morbidity? A systematic review of the literature with meta-analysis.

Neoadjuvant treatment (NT) for pancreatic head cancer may allow some patients to undergo curative resection, but its impact on postoperative complications remains unclear. A systematic review and meta-analysis were performed to compare overall postoperative morbidity, pancreatic fistula, and mortality between patients who underwent upfront surgery and those who underwent neoadjuvant therapy first. Forty-five studies with 3359 patients were included. No significant differences in morbidity and mortality rates associated with NT for pancreatic head cancer were detected in this study.

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.

The Functionality Assessment Flowchart (FAF): a new simple and reliable method to measure performance status with a high percentage of agreement between observers.

BACKGROUND: Performance status (PS) assessment is an integral part of the decision-making process in cancer care. Karnofsky Performance Status (KPS) and Eastern Cooperative Oncology Group (ECOG) PS are the most widely used tools. In some studies, the absolute agreement rate of these tools between observers has been moderate to low. The present study aimed to evaluate the inter-observer reliability and construct validity of the new Functionality Assessment Flowchart (FAF) and compare it with ECOG PS and KPS in a sample of cancer patients. METHODS: The patients were recruited by convenience from the waiting rooms of the Breast and Gynecology Ambulatory in a cross-sectional study. Two trained medical students (observer A) and five medical oncologists (observers B) independently rated women according to the ECOG PS, KPS and FAF. After the determining the PS scores, observer A administered the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaire to the participants. The agreements between observers A and B were investigated using the absolute agreement rate (%), weighted and unweighted kappa and Spearman's correlation test. For construct validity, the PS scores were correlated with functional and fatigue scores by performing correlation analysis. RESULTS: Eighty women with a median age of 57 years were included in the study (86% accrual rate). Among these women, 39 (48.8%) had advanced cancer. The overall absolute agreement rate between observers was 49.4% for KPS, 67% for ECOG PS, and 78.2% for FAF. When using unweighted kappa values, the inter-observer reliability was "fair", "moderate" and "substantial" for KPS, ECOG PS and FAF, respectively. However, when using weighted kappa statistics, "substantial" agreement was observed for KPS and ECOG PS and "nearly perfect" agreement was observed for FAF. All of the PS scales correlated very well with the functional and fatigue scores. CONCLUSIONS: We present a new instrument with moderate to high inter-observer agreement and adequate construct validity to measure PS in cancer patients.

A critical analysis of test-retest reliability in instrument validation studies of cancer patients under palliative care: a systematic review.

BACKGROUND: Patient-reported outcome validation needs to achieve validity and reliability standards. Among reliability analysis parameters, test-retest reliability is an important psychometric property. Retested patients must be in a clinically stable condition. This is particularly problematic in palliative care (PC) settings because advanced cancer patients are prone to a faster rate of clinical deterioration. The aim of this study was to evaluate the methods by which multi-symptom and health-related qualities of life (HRQoL) based on patient-reported outcomes (PROs) have been validated in oncological PC settings with regards to test-retest reliability. METHODS: A systematic search of PubMed (1966 to June 2013), EMBASE (1980 to June 2013), PsychInfo (1806 to June 2013), CINAHL (1980 to June 2013), and SCIELO (1998 to June 2013), and specific PRO databases was performed. Studies were included if they described a set of validation studies. Studies were included if they described a set of validation studies for an instrument developed to measure multi-symptom or multidimensional HRQoL in advanced cancer patients under PC. The COSMIN checklist was used to rate the methodological quality of the study designs. RESULTS: We identified 89 validation studies from 746 potentially relevant articles. From those 89 articles, 31 measured test-retest reliability and were included in this review. Upon critical analysis of the overall quality of the criteria used to determine the test-retest reliability, 6 (19.4%), 17 (54.8%), and 8 (25.8%) of these articles were rated as good, fair, or poor, respectively, and no article was classified as excellent. Multi-symptom instruments were retested over a shortened interval when compared to the HRQoL instruments (median values 24 hours and 168 hours, respectively; p = 0.001). Validation studies that included objective confirmation of clinical stability in their design yielded better results for the test-retest analysis with regard to both pain and global HRQoL scores (p < 0.05). The quality of the statistical analysis and its description were of great concern. CONCLUSION: Test-retest reliability has been infrequently and poorly evaluated. The confirmation of clinical stability was an important factor in our analysis, and we suggest that special attention be focused on clinical stability when designing a PRO validation study that includes advanced cancer patients under PC.