Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities.

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 BRCA1 or BRCA2 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.

Molecular characterization as new driver in prognostic signatures and therapeutic strategies for endometrial cancer.

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers.

De Novo Metastatic Prostate Cancer: Are We Moving toward a Personalized Treatment?

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.

Immunotherapy in urothelial cancer: current status and future directions.

INTRODUCTION: Since 2016, the progressive use of immune checkpoint inhibitors (ICIs) starting from second-line treatment has led to an improvement in overall survival in locally advanced and metastatic urothelial cancer (UC). Clinical trials are underway testing the role of ICIs since the first stages of the disease, alone or in combination with standard therapies. AREAS COVERED: This review summarizes the current updated evidence regarding the role of ICIs in the different stages of UC, the ongoing clinical trials exploring the potential benefit of immunotherapy alone or in combination with standard-of-care therapies, as well as the promising association of ICIs with antibody-drug conjugates (ADCs). EXPERT OPINION: In the first-line setting, ICIs alone in platinum-unfit patients have shown unconvincing results; the ongoing EV-302 trial will probably suggest enfortumab vedotin plus pembrolizumab as a new effective option. The optimal duration of maintenance immunotherapy is still to be determined, finding a balance with the risk-benefit profile. The clinical benefit of ICIs as second-line treatment is limited to a subset of patients that cannot be definitively established yet. In the next 5 years, a lot of new ADCs will likely emerge for the treatment of UC.

Management of PALB2-associated breast cancer: A literature review and case report.

Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2-associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple-negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD-L1 positive triple-negative BC, who progressed after an immune checkpoint inhibitor (ICI)-containing regimen and then experienced a pathologic complete response after platinum-based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD-L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2-associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms.

Personalized Systemic Therapies in Hereditary Cancer Syndromes.

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.

Predictive factors for relapse in triple-negative breast cancer patients without pathological complete response after neoadjuvant chemotherapy.

Introduction: 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. Methods: 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. Results: 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. Discussion: 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.

Insights into the Possible Molecular Mechanisms of Resistance to PARP Inhibitors.

PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with impaired homologous recombination. However, the increasingly wide use of PARP inhibitors in clinical practice has highlighted the problem of resistance to therapy. Several different mechanisms of resistance have been proposed, although only the acquisition of secondary mutations in BRCA1/2 has been clinically proved. The aim of this review is to outline the key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors, analysing the complex interactions between PARP1, cell cycle regulation, PI3K/AKT signalling, response to stress replication, homologous recombination, and other DNA damage repair pathways in the setting of BRCA1/2 mutated cancers.

Carboplatin-paclitaxel in triple-negative metastatic breast cancer during pregnancy with neoplastic thrombosis.

The treatment of breast cancer (BC) diagnosed during pregnancy is a challenging situation for the patient, family and healthcare providers. Here we describe the case of a 35-year-old woman diagnosed with a triple-negative breast cancer relapse during pregnancy. She previously underwent neoadjuvant chemotherapy without any response, subsequent left skin sparing mastectomy plus axillary node dissection and radiation therapy to the chest wall and supraclavicular lymph nodes. Two years later, during her first single pregnancy, the patient presented a subclavian vein thrombosis and a BC relapse to locoregional lymph nodes. At 24 weeks of gestation, a first line treatment with weekly paclitaxel and carboplatin was started. Considering the disease progression after two complete cycles of chemotherapy, the patient had an elective caesarean section at 32+6 weeks. A full-body CT-scan and a PET-scan after the delivery showed a massive neoplastic thrombosis involving the left jugular, brachiocephalic and internal mammary vein, as well the superior vena cava and the right atrium. Few data are available on platinum-based chemotherapy during pregnancy in BC patients. Nevertheless, the choice of therapy was conditioned by the previous absence of response to anthracycline and taxane. In case of BC diagnosis during pregnancy, a multidisciplinary management as in the case described is recommended to increase the chance of survival both for the patients and their babies.

Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature.

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.

Germline Mutations in Other Homologous Recombination Repair-Related Genes Than BRCA1/2: Predictive or Prognostic Factors?

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. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 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 PALB2 mutation compared to germline ATM and CHEK2 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 PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers.

The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study.

Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.

The Role of Exosomes in Breast Cancer Diagnosis.

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.

Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA.

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li-Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz-Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.

Lifestyle Intervention on Body Weight and Physical Activity in Patients with Breast Cancer can reduce the Risk of Death in Obese Women: The EMILI Study.

: 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.

The reduction of CA 125 serum levels in BRCA 1/2 mutation carriers after risk-reducing salpingo-oophorectomy is only partially associated with surgery: a prospective cohort, other biomarker controlled, study.

OBJECTIVES: A significant reduction in CA 125 postoperative serum levels was observed after risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers. In contrast to previous studies, where control groups were absent, we conducted a prospective study including also a screening only group (RSSO refusal) and a group having previously undergone RRSO. METHODS: Consecutive BRCA1 and BRCA2 mutation carriers, not hysterectomised, >35 years old and with completed childbearing, were recruited. Some women had previously undergone RRSO (previous RRSO group). The others, who had either chosen RRSO (actual RRSO group) or screening only (screening only group), were enrolled (patient-preference trial). A prospective evaluation (basal and 6-month) of CA 125 and CEA (control biomarker) was performed. RESULTS: The study consisted of 116 women, 44.8% BRCA1 and 55.2% BRCA2 mutation carriers (n = 25 in the previous RRSO group, n = 29 in the actual RRSO group, n = 62 in the screening only group). For all subjects, we observed a 6-month decrease in CA 125 (-7.8%, P = 0.003), which was significantly linked only to endometriosis history (odds ratio 1.4; 95% confidence interval 1.1-1.8; P = 0.002). Between different groups, we recorded a non-significantly different decrease in CA 125. CEA showed a 6 months significant increase (+15.4%, P < 0.0001), which was similar between groups. CONCLUSION: The decrease in CA 125 in BRCA mutation carriers after RRSO was only partially associated with surgery, depending also on a physiological decline: this is extremely important in their longitudinal monitoring for the prevention of ovarian cancer.

BRCA Detection Rate in an Italian Cohort of Luminal Early-Onset and Triple-Negative Breast Cancer Patients without Family History: When Biology Overcomes Genealogy.

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% BRCA2). 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.