Fertility and Pregnancy-Related Issues in Young BRCA Carriers With Breast Cancer.

Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 (BRCA1) or BReast CAncer 2 (BRCA2) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA1/2 (gBRCA1/2) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young gBRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young gBRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment.

Unlocking the potential of Molecular Tumor Boards: from cutting-edge data interpretation to innovative clinical pathways.

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.

Patterns of care at the end of life: a retrospective study of Italian patients with advanced breast cancer.

OBJECTIVES: To better understand the type of care offered to Italian patients with advanced breast cancer at the End-of-Life (EoL), we conducted a retrospective observational study. EoL was defined as the period of six months before death. METHODS: One hundred and twenty-one patients with advanced breast cancer (ABC) treated at IRCCS San Martino Policlinic Hospital who died between 2017 and 2021 were included. Data about patient, disease, and treatment characteristics from breast cancer diagnosis to death, along with information about comorbidities, medications, imaging, specialist evaluations, hospitalization, palliative care and home care, hospice admissions, and site of death were collected. RESULTS: 98.3% of the patients received at least one line of active treatment at EoL; 52.8% were hospitalized during the selected period. Palliative (13.9%), psychological (7.4%), and nutritional evaluations (8.2%) were underutilized. Palliative home care was provided to 52% of the patients. Most of the patients died at home (66.1%) and fewer than one out of five (18.2%) died at the hospital. Among the patients who died at home, 27.3% had no palliative support. CONCLUSIONS: Our findings indicate that palliative care in EoL breast cancer patients is still inadequate. Only a minority of patients had psychological and nutritional support While low nutritional support may be explained by the fact that typical symptoms of ABC do not involve the gastrointestinal tract, the lack of psychological support suggests that significant barriers still exist. Data on the site of death are encouraging, indicating that EoL management is increasingly home centered in Italy.

The Advantages of Next-Generation Sequencing Molecular Classification in Endometrial Cancer Diagnosis.

Endometrial cancer (EC) is the most frequent gynecological cancer. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and to improve the diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC) and high- (HGEC) and low-grade (LGEC) endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, tumor DNA was semi-automatically extracted and analyzed using NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k = 0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required, which can be used in clinical practice for more precise diagnostic-therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.

Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?

Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy.

Germline TP53 pathogenic variants and breast cancer: A narrative review.

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention.

Anthracycline, taxane, and trastuzumab-based neoadjuvant chemotherapy in HER2-positive early breast cancer: phase II trial.

OBJECTIVE: Neoadjuvant chemotherapy has become the preferred treatment in HER2-positive early breast cancer. Several trials investigated the neoadjuvant efficacy of dual HER2 blockade with anthracycline-free chemotherapy, whereas few data are available on single-agent trastuzumab and anthracycline-based regimens, which represent the standard of care in the adjuvant setting. This phase II, single-arm trial assessed anthracycline-based chemotherapy and trastuzumab as neoadjuvant treatment for high-risk HER2-positive breast cancer. METHODS: Forty-three patients with stage II-III HER2-positive breast cancer were treated with 4 courses of neoadjuvant 5-fluorouracil 600 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 (FEC ×4) every 21 days, followed by 12 courses of weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/Kg IV (loading dose 4 mg/kg). RESULTS: Pathologic complete response (pCR) was observed in 22 (51%) of 43 patients. After a median follow-up of 6 years, the 5-year disease-free survival and overall survival were 85.8% (95% confidence interval 75.9%-97%) and 89.6% (80.4%-99.8%), respectively. A temporary decrease in left ventricular ejection fraction was observed in two patients. No cardiac death or congestive heart failure occurred. One patient died due to febrile neutropenia. CONCLUSIONS: FEC ×4 followed by paclitaxel and trastuzumab was associated with high pCR rates and favorable long-term outcomes. However, this regimen was associated with relevant hematologic toxicity.

Experience with a nurse-driven genetic counseling pathway of Italian women with uninformative BRCA test result.

Several models of genetic counseling have been proposed to tackle the increasing volume of individuals requiring access to BRCA testing. Few data are available on patient experience and retention of information with nurse-driven genetic counseling. We evaluated the experience and retention of information in women with an uninformative BRCA test result and who were not considered at high risk due to their personal/family history of cancer who underwent geneticist-supervised nurse-driven genetic counseling and who received their test result by phone. Women who received an uninformative BRCA test result between May 2017 and September 2019 were administered a questionnaire exploring experience with genetic counseling and retention of information provided. Of 366 eligible women, 299 (273 breast cancer patients and 26 women without breast cancer) completed the interview. Overall, 280 women (93.6%) positively valued their experience with genetic counseling and 287 (96.0%) considered it helpful with 57.5% of them feeling reassured for themselves and their family. Information on the clinical implications of the test result was correctly retained and women acted accordingly. Overall, 252 women (87.8%) accurately reported their test result as normal/negative. Only 67 (22.4%) recognized that despite a normal BRCA test result, a low probability of a hereditary syndrome remains. Most women showed a poor ability to estimate cancer risk in BRCA mutation carriers and in the general population. Geneticist-supervised nurse-driven genetic counseling process for women with uninformative BRCA test result is associated with a positive patient experience and an adequate retention of information concerning the management of their personal and familial cancer risk. The design and implementation of nurse-driven genetic counseling models may contribute to efficient and timely access to BRCA genetic testing.

Targeting PIK3CA Actionable Mutations in the Circulome: A Proof of Concept in Metastatic Breast Cancer.

The study of circulating cancer-derived components (circulome) is considered the new frontier of liquid biopsy. Despite the recognized role of circulome biomarkers, their comparative molecular profiling is not yet routine. In advanced breast cancer (BC), approximately 40% of hormone-receptor-positive, HER2-negative BC cases harbor druggable PIK3CA mutations suitable for combined alpelisib/fulvestrant treatment. This pilot study investigates PIK3CA mutations in circulating tumor DNA (ctDNA), tumor cells (CTCs), and extracellular vesicles (EVs) with the aim of determining which information on molecular targetable profiling could be recollected in each of them. The in-depth molecular analysis of four BC patients demonstrated, as a proof-of-concept study, that it is possible to retrieve mutational information in the three components. Patient-specific PIK3CA mutations were found in both tissue and ctDNA and in 3/4 cases, as well as in CTCs, in the classical population (large-sized CD45-/EpCAM+/- cells), and/or in the "non-conventional" sub-population (smaller-sized CD44+/EpCAM-/CD45- cells). Consistent mutational profiles of EVs with CTCs suggest that they may have been released by CTCs. This preliminary evidence on the molecular content of the different circulating biomaterials suggests their possible function as a mirror of the intrinsic heterogeneity of BC. Moreover, this study demonstrates, through mutational assessment, the tumor origin of the different CTC sub-populations sustaining the translational value of the circulome for a more comprehensive picture of the disease.

Definition of High-Risk Early Hormone-Positive HER2-Negative Breast Cancer: A Consensus Review.

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2-negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormone-positive/HER2-negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2-negative early breast cancers.

Diversity of Cardiologic Issues in a Contemporary Cohort of Women With Breast Cancer.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

New emerging targets in cancer immunotherapy: the role of GITR.

In the last decade, immunotherapies have revolutionised anticancer treatment. However, there is still a number of patients that do not respond or acquire resistance to these treatments. Despite several efforts to combine immunotherapy with other strategies like chemotherapy, or other immunotherapy, there is an 'urgent' need to better understand the immune landscape of the tumour microenvironment. New promising approaches, in addition to blocking co-inhibitory pathways, such those cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 mediated, consist of activating co-stimulatory pathways to enhance antitumour immune responses. Among several new targets, glucocorticoid-induced TNFR-related gene (GITR) activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Preclinical data on GITR-agonist monoclonal antibodies (mAbs) demonstrated antitumour activity in vitro and in vivo enhancing CD8+ and CD4+ effector T-cell activity and depleting tumour-infiltrating Tregs. Phase I clinical trials reported a manageable safety profile of GITR mAbs. However, monotherapy seems not to be effective, whereas responses have been reported in combination therapy, in particular adding PD-1 blockade. Several clinical studies are ongoing and results are awaited to further develop GITR-stimulating treatments.

Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study.

BACKGROUND: Adjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown. METHODS: In the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS). RESULTS: From 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51-1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51-0.96). CONCLUSIONS: Updated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Potential Mechanisms of Ovarian Protection with Gonadotropin-Releasing Hormone Agonist in Breast Cancer Patients: A Review.

The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation.

CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials.

PURPOSE: Combining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2- breast cancers. Here, we performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2- breast cancer. METHOD: A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, ≥ G3-G4 adverse events (AEs), and G3-G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model. RESULTS: Eight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50-0.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43-0.61) significantly improved the PFS of metastatic HR+/HER2- breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52-0.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24-0.47). The use of these drugs was characterized by a significant increase of G3-G4 AEs (OR 10.88, 95% CI 6.53-18.14). CONCLUSION: Emerging data provide a new standard treatment for advanced HR+/HER2- breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.

Genitourinary tumours in the targeted therapies era: new advances in clinical practice and future perspectives.

Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359 000 newly diagnosed cases and 58 420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management paradigms of these neoplasms. Neoangiogenesis, through the activation of the tyrosine-kinase receptors signalling pathways, represents the key mediator event in promoting tumour proliferation, differentiation, invasiveness and motility. In the last decade, several treatments have been developed with the specific aim of targeting different cell pathways that have been recognized to drive tumour progression. The following review attempts to provide a comprehensive overview of the literature, focusing on new advances in targeted therapies for genitourinary tumours. Furthermore, the promising results of the latest clinical trials and future perspectives will be discussed.

Immunotherapy for genitourinary cancer: state of the art and new perspectives.

In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies.

Safety of antiandrogen therapy for treating prostate cancer.

INTRODUCTION: Antiandrogens are a treatment option in patients with prostate cancer, given either in combination with androgen deprivation or, in selected cases, as monotherapy. New-generation antiandrogens have been recently introduced in clinical practice (enzalutamide) or are under evaluation in clinical trials (ARN-509). AREAS COVERED: This review elucidates the safety profile of antiandrogens, in particular focusing on the tolerability profile of each drug either when employed in combination with castration or as monotherapy, in hormone-naive or in castration-resistant patients. EXPERT OPINION: Non-steroidal antiandrogens are widely used in the management of hormone-sensitive disease in combination with luteinizing hormone-releasing hormone agonists or in patients failing front-line treatment with androgen-deprivative maneuvers. In selected patients, non-steroidal antiandrogen monotherapy appears to yield comparable results as castration. Novel non-steroidal antiandrogens have been investigated with promising results in castration-resistant prostate cancer. Beyond the safety profile specific to any individual compound, increased testosterone and 17ß-estradiol levels are commonly observed during antiandrogen monotherapy, leading to gynecomastia and breast pain. The safety profile of old and novel antiandrogens should be taken into account by clinicians in decision making and in selecting the most suitable patients. Beyond patient selection, full clinical evaluation of patient co-morbidities that might affect the drug tolerability and clinical monitoring are anyway required.

Periostin: a novel prognostic and therapeutic target for genitourinary cancer?

Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.