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Inappropriate prescribing for older people is a global healthcare problem. This study aimed to determine the prevalence of older patients receiving potentially inappropriate medications (PIMs) at admission and discharge at the intermediate care facility of ASP Pio Albergo Trivulzio. We consecutively enrolled 100 patients aged ≥ 65 from December 2017 to May 2018 and evaluated PIMs with the 2015 version of the Beers criteria. We found a significant reduction in the prescription of drugs to avoid and proton pump inhibitors (PPIs), while patients with at least one psychotropic drug to avoid or to use with caution significantly increased. The inappropriate prescription of PPIs was mainly associated with the use of heparin. Optimizing PPI and psychotropic drug prescriptions should be considered for deprescribing inappropriate polypharmacy in intermediate care facilities.

ABSTRACTIntroductionRisk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause.Areas coveredTo evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC.Expert opinionAll BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to ‘progestin-free’ HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these ‘progestin-free’ preparations and BC safety.

IMPORTANCE: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. OBJECTIVE: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. MAIN OUTCOMES AND MEASURES: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. RESULTS: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. CONCLUSIONS AND RELEVANCE: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2and PALB2genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1and CYP1B1polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1rs743572, CYP1B1rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1and CYP1B1polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.

The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologousrecombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCAmutation carriers leads to the persistence of DNA damage usually repaired by the homologousrecombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in “BRCAness” ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice.

ABSTRACTBackground: HER2+ metastatic breast cancer (MBC) is a poor prognosis disease, unusually curable. To date, no predictive factors have been clearly correlated with long-term response to anti-HER2 agents.Methods: 54 HER2+ MBC patients treated with HER2 targeted therapy as first line treatment were analysed: 40 with a time to progression longer than 3 years in Long Responders (LR) group and 14 with a progression disease within one year of anti-HER2 therapy in a control group named Early Progressors (EP). The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on FFPE BC tissues.Results: Considering baseline patients and tumor characteristics, EP women had more CNS spread and more metastatic burden of disease compared to LR (p > 0.05). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down regulated, all in EP group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways. MAPK pathway was differently expressed between LR and EP (p = 0.05). PI3K was the only pathway overexpressed in EP patients.Conclusions: Whole genome expression analysis comparing LR vs. EP identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathway could be a positive predictive factors. Further clinical implications are warranted.Abbreviations: BC: breast cancer; MBC: metastatic breast cancer; LR: long responder; EP: early progressor; FFPE: formalin-fixed paraffin-embedded; CNS: central nervous system; PFS: progression free survival; OS: overall survival.

Aims and background The aim of this retrospective multicenter study was to evaluate the impact of progesterone receptor (PgR) loss on locoregional recurrence in patients with estrogen receptor (ER)-positive primary breast cancer and ER-positive locoregional recurrence.Patients and Methods Eight Italian oncology centers collected data from consecutive patients with ER-positive breast cancer and a subsequent ER-positive locoregional recurrence.Results Data were available for 265 patients diagnosed with breast cancer between 1990 and 2009. Median metastasis-free survival was 111 months in patients with PgR-positive primary tumors and locoregional recurrence (PgRpos), 38 months in patients with PgR-negative primary tumors and locoregional recurrence (PgRneg), and 63 months in patients with PgR-positive primary tumors and PgR-negative locoregional recurrence (PgRloss). In multivariate analysis, PgR status was independently associated with metastasis-free survival, with a hazard ratio of 2.84 (95% CI 1.34-6.00) for PgRnegcompared with PgRpos, and 2.93 (95% CI: 1.51-5.70) for PgRlosscompared with PgRpos.Conclusions PgR absence was found to be a negative prognostic factor in breast cancer patients with ER-positive locoregional recurrence. Thus, PgR status could be a biological marker in ER-positive recurrent breast cancer.

Lurbinectedin is responsible for DNA recognition and binding, producing double-strand DNA (dsDNA) breaks thus resulting in apoptosis. Sensitivity to lurbinectedin is linked to the nucleotide excision repair (NER) system. Furthermore, irinotecan, a topoisomerase I inhibitor, provokes dsDNA breaks that could be reinforced abrogating the NER system using lurbinectedin. BRCA-mutated patients, already treated with platinum-derived drugs, who suffered DNA damage, cannot repair the breaks due to lurbinectedin interaction, whereas irinotecan provokes a dsDNA break that promotes synthetic lethality. This article describes an exceptional response to lurbinectedin alone followed by the association with irinotecan in a BRCA-mutated platinum-resistant ovarian cancer patient. A 44-year-old BRCA1-mutated ovarian cancer patient was treated in sixth line with lurbinectedin and irinotecan with a time to further progression (TTFP) equal to 8 months. In our case, the association with irinotecan overcame the resistance to lurbinectedin alone. In conclusion, lurbinectedin and irinotecan demonstrated a promising response in platinum-resistant patients. However, further studies should be conducted to validate our findings and future trials will be important to further define the clinical utility of lurbinectedin.

Aims and background Based on estrogen receptor (ER), progesterone receptor (PgR) and Her2/neu (HER2) expression, four breast cancer subtypes have been distinguished: luminal A (ER and/or PgR/HER2–, Ki67 <14%), luminal B (ER and/or PgR/HER2–, Ki67 ≥14% or ER and/or PgR/HER2), triple-negative (ER-/PgR-/HER2–), and HER2 (ER-/PgR-/HER2). Our aim was to evaluate the prognosis of these phenotypes in the pre-trastuzumab era in a large cohort of Italian women.Methods and study design We studied 2347 breast cancer patients, in stage I-II, registered by the Modena Cancer Registry from 1999 to 2006 in the Modena province, Italy. Overall survival, disease-free survival and second non-mammary tumors were evaluated.Results A total of 1868 luminal A (79.6%), 195 luminal B (8.3%), 205 triple-negative (8.7%) and 79 HER2 (3.4%) patients were identified. A better prognosis was observed for luminal A than for luminal B, HER2 and triple-negative subtypes (5-year overall survival, 91% vs 89% vs 87% vs 86%, respectively, P <0.001). Disease-free survival for pT1a and pT1b tumors was worse in HER2 (82%) than in triple-negative (90%), luminal B (95%) and luminal A (97%) (P = 0.013). Finally, luminal B patients had a significantly higher rate of second non-mammary tumors than the other groups.Conclusions In the pre-trastuzumab era, luminal A patients showed a better 5-year overall survival than luminal B, HER2 and triple-negative patients, but in terms of disease-free survival, HER2 subtype represented an unfavorable group over time, whereas the triple-negative group had an increased risk of relapse in the first 42 months and then decreased. Among each prognostic factor, ER <10%, Ki67 >14% and HER2 overexpression are considered as risk factors, but only HER2 positivity seems to preserve the role over time.

The prospects for making a vast impact on the morbidity and mortality from breast cancer lie more likely in the area of chemoprevention. Tamoxifen was the first agent considered in a preventive setting. Different studies analyzed the role of tamoxifen in prevention and, although the first results were apparently contradictory, they showed notable reductions in breast cancer. In the same period, in the MORE trial, raloxifene unexpectedly produced a larger reduction of breast cancer than was seen for tamoxifen. This result led to other chemoprevention studies to establish the role of raloxifene. Particularly, the STAR trial showed that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse event. At the same time, the third-generation aromatase inhibitors (AIs) have shown good efficacy in advanced breast cancer and a low toxicity profile. They offer another approach to prevention, which may be superior or complimentary to the use of Selective Estrogen Receptor Modifiers (SERMs). Currently no AIs have yet been fully evaluated. New studies comparing the different agents together are needed and further follow up of the existing chemoprevention trials are necessary to determine which women will truly benefit from this kind of prophylaxis.

Women with BRCA1/2 mutations are at increased risk of developing breast and ovarian cancer. Options to manage this risk are intensive surveillance, chemoprevention, and risk-reducing surgery which includes, risk reduction mastectomy (bilateral or contralateral) and risk reduction salpingo-oophorectomy. Here we reported an overview of the current literature regarding efficacy of risk-reduction surgery, its acceptability and psychological implications. We found that majority of studies reported that: risk-reduction surgery has been proven to be effective in reducing breast and ovarian cancer risk up to 90, women who choose surgery have diminished anxiety about cancer risk, and experience few psychological difficulties, but physical complication and alteration in body image, sexual life are often reported. In conclusion, we could state that decisions about surgery are influenced by several factors, mostly psychological, women need to be counselled about the decision to undergo risk-reduction surgery and multidisciplinary approaches are needed. Potential negative effects should be discussed thoroughly with each woman considering this procedure. Careful psychological follow-up after the surgery should be scheduled.

The aim of this review is to identify the evidence for the surveillance of women at high risk of breast cancer with the different modalities. The definition of high risk refers to the subpopulation of women with a family history of breast cancer, including both those with and without identified genetic mutations. The following topic has been evaluated: clinical breast examination (CBE), mammography, ultrasound and MRI accuracy of detecting breast cancer among women at high risk. The search was limited to full reports published in English and published between 1996 and March, 2010. We found consistent evidence that adding MRI provides a highly sensitive screening strategy (sensitivity range: 93-100) compared to mammography alone (32-86) or mammography plus ultrasound /- CBE (26-93). Three studies that compared MRI plus mammography versus mammography alone showed the sensitivity of MRI plus mammography as 93 (95 CI 86-100) and the incremental sensitivity of MRI as 60. Incremental sensitivity of MRI was lower when added to mammography plus ultrasound (43) or to the combination of mammography, ultrasound plus CBE. Estimates of screening specificity with MRI were less consistent but suggested a 3-5-fold higher risk of patient recall for investigation of false positive results. No studies assessed whether adding MRI reduces patient mortality, interval or advanced breast cancer rates, even if we found strong evidence that MRI leads to the detection of earlier stage disease. This review suggests that a surveillance strategy would be accurate and effective in improving health outcomes for women at high risk of breast cancer, but randomized studies should be considered for a better evaluation of these topics.

Mutations in BRCA1and BRCA2show different expressivity with respect to cancer risk, and allelic heterogeneity may be present in both genes. We collected 179 pedigrees with identified germline mutation (104 BRCA1and 75 BRCA2), ascertained in six collaborating centers of the Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant heterogeneity was detected for several variables, and a logistic regression model including age of diagnosis in the proband, presence of ovarian cancer in the family, presence of prostate or pancreatic cancer in the family, and presence of male breast cancer in the family proved to be effective in predicting the presence of a mutation in a gene rather than the other. Excess of familial aggregation of both breast and ovarian cancer was observed in both genes. Proportion of ovarian cancer was increased in the 5' portion of BRCA1, and presence of prostate or pancreatic cancer in a family was correlated with presence of ovarian cancer in BRCA2.

OBJECTIVE: Assessing changes in breast cancer (BC) incidence and stage distribution in the District of Modena, Italy, during the period 1992–1998, and their relationship to a mammographic screening program launched in 1995. METHODS: Demographic, clinical, and pathological data of all BC cases reported to the population-based Modena Cancer Registry between 1992 and 1998 were collected and linked to the screening database. RESULTS: A total of 3429 women were diagnosed with BC in the District of Modena between 1992 and 1998. In this period the incidence rate increased by 15.7% (from 134.3 in 1992 to 155.4 per 100,000 in 1998). The increase began in 1995 and exclusively included women aged 50–69; the incidence rose by 30.4%. Moreover, the rise was confined to early tumors, with more than half (54%) of all cases reported in 1998 diagnosed as stage 0 or I disease, compared with 42% in 1992. Screen-detected tumors were significantly smaller (13.2 mm) than other tumors diagnosed in women aged 50–69 (18.5 mm), with 46% of screen-detected tumors smaller than 10 mm. Overall, a decline in the average tumor diameter was shown (from 20.2 mm in 1992–1994 to 18 mm in 1996–1998). CONCLUSIONS: Our data confirm that mammographic screening leads to an increase in the incidence of early-stage BC cancers.

Castagnetti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy. Tiribelli:Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau.