The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved.
germline ...mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than
have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline
mutation compared to germline
and
mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that
is a high-penetrant gene with a key role in the HRR system,
mutations are predictive factors for response to treatment. Moreover, germline mutations in the
gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type
. In conclusion, sequencing of HRR-related genes other than
should be routinely offered as part of a biological characterization of pancreatic and breast cancers.
The importance of molecular re-characterization of metastatic disease with the purpose of monitoring tumor evolution has been acknowledged in numerous clinical guidelines for the management of ...advanced malignancies. In this context, an attractive alternative to overcome the limitations of repeated tissue sampling is represented by the analysis of peripheral blood samples as a 'liquid biopsy'. In recent years, liquid biopsies have been studied for the early diagnosis of cancer, the monitoring of tumor burden, tumor heterogeneity and the emergence of molecular resistance, along with the detection of minimal residual disease. Interestingly, liquid biopsy consents the analysis of circulating tumor cells, circulating tumor DNA and extracellular vesicles (EVs). In particular, EVs play a crucial role in cell communication, carrying transmembrane and nonmembrane proteins, as well as metabolites, lipids and nucleic acids. Of all EVs, exosomes mirror the biological fingerprints of the parental cells from which they originate, and therefore, are considered one of the most promising predictors of early cancer diagnosis and treatment response. The present review discusses current knowledge on the possible applications of exosomes in breast cancer (BC) diagnosis, with a focus on patients at higher risk.
More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has ...paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of
or
pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.
Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age ...than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.
De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5–10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC ...has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities for de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have modified the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road toward personalized treatment for de novo mHSPC is still long, considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that did not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as a predictive biomarker requires further validation, and it remains to be ascertained how the genomic variants detected in mHSPC, which are regarded as predictive in the castration-resistant disease, can be exploited in the mHSPC setting.
Background obesity and sedentary lifestyle have been shown to negatively affect survival in breast cancer (BC). The purpose of this study was to test the efficacy of a lifestyle intervention on body ...mass index (BMI) and physical activity (PA) levels among BC survivors in Modena, Italy, in order to show an outcome improvement in obese and overweight patients. Methods: This study is a single-arm experimental design, conducted between November 2009 and May 2016 on 430 women affected by BC. Weight, BMI, and PA were assessed at baseline, at 12 months, and at the end of the study. Survival curves were estimated among normal, overweight, and obese patients. Results: Mean BMI decreased from baseline to the end of the study was equal to 2.9% (p = 0.065) in overweight patients and 3.3% in obese patients (p = 0.048). Mean PA increase from baseline to the end of the study was equal to 125% (p < 0.001) in normal patients, 200% (p < 0.001) in overweight patients and 100% (p < 0.001) in obese patients. After 70 months of follow-up, the 5-year overall survival (OS) rate was 96%, 96%, and 93%, respectively in normal, obese, and overweight patients. Overweight patients had significantly worse OS than normal ones (HR = 3.69, 95%CI = 1.82–4.53 p = 0.027) whereas no statistically significant differences were seen between obese and normal patients (HR 2.45, 95%CI = 0.68–8.78, p = 0.169). Conclusions: A lifestyle intervention can lead to clinically meaningful weight loss and increase PA in patients with BC. These results could contribute to improving the OS in obese patients compared to overweight ones.
Triple-negative breast cancer (TNBC) patients who do not obtain pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. ...Risk factors for relapse in this subset of patients are poorly characterized. This study aimed to identify the predictive factors for relapse in TNBC patients without pCR after NACT.
Women with TNBC treated with NACT from January 2008 to May 2020 at the Modena Cancer Center were included in the analysis. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of relapse.
We identified 142 patients with a median follow-up of 55 months. After NACT, 62 patients obtained pCR (43.9%). Young age at diagnosis (<50 years) and high Ki-67 (20%) were signi!cantly associated with pCR. Lack of pCR after NACT resulted in worse 5-year event-free survival (EFS) and overall survival (OS). Factors independently predicting EFS in patients without pCR were the presence of multifocal disease hazard ratio (HR), 3.77; 95% CI, 1.45-9.61; p=0.005 and residual cancer burden (RCB) III (HR, 3.04; 95% CI, 1.09-9.9; p=0.04). Neither germline BRCA status nor HER2-low expression were associated with relapse.
These data can be used to stratify patients and potentially guide treatment decision-making, identifying appropriate candidates for treatment intensi!cation especially in neo-/adjuvant setting.
NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is ...still debated, especially when BRCA testing is offered by the national health service. Our analysis evaluated the rate of BRCA pathogenic or likely-pathogenic variants in 159 triple-negative breast cancer (TNBC) patients diagnosed ≤60 years, and 109 luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family histories. In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31-40, 16.1% for those aged 41-50 and 7.9% in 51-60s. A total of 40% of patients with estrogen receptors (ER) 1-9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (4.6%
). Mutation prevalence was 0% between 0-25 years, 9% between 26-30 years and 6% between 31-35 years. In conclusion, BRCA testing is recommended in TNBC patients diagnosed ≤60 years, regardless of family cancer history or histotype, and by using immunohistochemical staining <10% for both ER and/PR. In luminal-like early-onset BC, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes along with BRCA genetic testing.
MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). ...Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value.
The most common breast cancer (BC) susceptibility genes beyond
are
and
. For the purpose of exploring the clinicopathologic characteristics of BC developed by
or
mutation carriers, we reviewed the ...archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen
and 17
mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in
(26.3%) and
mutation carriers (41.2%). While 64.3% of
tumors were luminal A-like, 56.2% of
tumors were luminal B-like/HER2-negative. Moreover, 21.4% of
-related invasive tumors showed a lobular histotype. About a quarter of all
-related BCs and a third of
BCs were in situ carcinomas and more than half of
and
-related BCs were diagnosed at stage I-II. Finally, 63.2% of
mutation carriers and 64.7% of
mutation carriers presented a positive BC family history. The biological and clinical characteristics of
and
-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with
and
mutation carriers at the first diagnosis of BC.
PDF
