Clinical Outcomes of HER2-Negative Metastatic Breast Cancer Patients in Italy in the Last Decade: Results of the GIM 13-AMBRA Study.

GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes-based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79-19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months-95% CI 5.7-9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7-15.1) and Luminal B patients (11.8 months, 95% CI 10.3-12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3-6.5 vs. Luminal A-9.4, 95% CI 8.1-10.7, and Luminal B-7.7 95% CI 6.8-8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8-37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2-31.2) and TNBC (18.5 months, 95% CI 16-20.1, F-ratio 7.44, p = 0.0006). The GIM 13-AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients.

Results of the observational prospective RealFLOT study.

BACKGROUND: Perioperative FLOT (5-fluorouracil, oxaliplatin and docetaxel) has recently become the gold standard treatment for fit patients with operable gastric (GC) or gastroesophageal (GEJ) adenocarcinoma, getting a 5-year overall survival (OS) of 45%, over 23% with surgery alone. METHODS: RealFLOT is an Italian, multicentric, observational trial, collecting data from patients with resectable GC or GEJ adenocarcinoma treated with perioperative FLOT. Aim of the study was to describe feasibility and safety of FLOT, pathological complete response rate (pCR), surgical outcomes and overall response rate (ORR) in an unselected real-world population. Additional analyses evaluated the correlation between pCR and survival and the prognostic role of microsatellite instability (MSI) status. RESULTS: Of 206 patients enrolled that received perioperative FLOT at 15 Italian centers, 124 (60.2%) received at least 4 full-dose cycles, 190 (92.2%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received de-intensified regimens, depending on clinical condition or previous toxicities. pCR was achieved in 7.3% of cases. Safety profile was consistent with literature. Neutropenia was the most common G 3-4 adverse event (AE): 19.9% in the preoperative phase and 16.9% in the postoperative phase. No toxic death was observed and 30-day postoperative mortality rate was 1.0%. ORR was 45.6% and disease control rate (DCR) was 94.2%. Disease-free survival (DFS) and OS were significantly longer in case of pCR (p = 0.009 and p = 0.023, respectively). A trend towards better DFS was observed among MSI-H patients. CONCLUSIONS: These real-world data confirm the feasibility of FLOT in an unselected population, representative of the clinical practice. pCR rate was lower than expected, nevertheless we confirm pCR as a predictive parameter of survival. In addition, MSI-H status seems to be a positive prognostic marker also in patients treated with taxane-containing triplets.

Identifying ethical values for guiding triage decisions during the COVID-19 pandemic: an Italian ethical committee perspective using Delphi methodology.

OBJECTIVES: This study aimed to identify the guiding ethical principles that should be considered for critical resource allocation during pandemic emergency situations, and especially for the COVID-19 outbreak. The secondary objective was to define the priority to be assigned to each principle. SETTING: The study was conducted from March to June 2020 within the context of an ethical committee (EC) in Northern Italy. PARTICIPANTS: Eleven EC members and five additional external healthcare and bioethical professionals, forming a multidisciplinary panel, took part in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The compilation of a list of ethical principles (maximum of 10 items) and their priority ranking and application within an emergency pandemic context was established as the expected outcome of this work. RESULTS: A consensus on 10 guiding ethical principles was reached by the multidisciplinary panel. Transparency ranked first on the priority list as the most frequently voted principle, followed by the number of lives saved, life-years saved, respect for individuals' autonomy and equity. Other principles including life cycle, 'sickest first', reciprocity, instrumental value and lottery were also considered appropriate as potential tiebreakers. These principles were discussed and made consistent with the current Italian pandemic context by producing an explanatory document. CONCLUSIONS: The identified principles could be used in preparedness plans to guide resource allocation during pandemic events. By combining their rank and relevance in relation to disease, health system organisations, social and economic settings, and critical resources at risk of scarcity, these principles could help to maximise the benefit of resource use for the community, thus reducing inequalities for individuals.

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.

Axillary nodal metastases in Italian early breast cancer patients with positive sentinel lymph node: can axillary node dissection be avoided by using predictive nomograms?

AIMS AND BACKGROUND: Clinical guidelines recommend axillary lymph node dissection (ALND) in cases of metastatic sentinel lymph node (SNL) in patients with clinically node-negative early breast cancer. However, a relevant number of ALND could be avoided in a subset of patients in whom the risk of non-SNL metastases is low. In order to define this population, several authors have proposed mathematical models, which have been validated in many studies. These studies reached different conclusions regarding which model demonstrated the best statistical discrimination power, mainly due to differences in clinical and pathologic variables used, and particularly differences in the number of dissected SLNs. METHODS: We retrospectively reviewed clinically node-negative patients who underwent ALND in our surgical ward after the diagnosis of breast cancer metastases on SLN biopsy from January 2000 to December 2012. The predictive accuracy of the widely used nomograms to predict the risk of additional nodal disease in our patients with SLN breast cancer metastases was measured by receiver operating characteristic curve. We then attempted to develop a new nomogram by analyzing the dataset. RESULTS: A total of 105 patients were included in this study, with ratio of metastatic lymph node/removed lymph node of about 0.89; we found axillary nodal metastases on ALND in only 31 patients (29.5%). Applied to our dataset, Mayo nomogram showed the best area under the receiving operator characteristic curve (0.74) followed by our model (0.71). Instead, the Memorial Sloan-Kettering model showed poor discrimination, as did Tenon (0.56). CONCLUSIONS: Based on our data, we cannot recommend the clinical use of validated predictive nomograms in order to avoid ALND. We suggest setting up a multicenter Italian study to build a model specific to our setting and based on larger series.

Increased mean corpuscular volume of red blood cells in patients treated with capecitabine for advanced breast and colon cancer.

PURPOSE: Capecitabine has demonstrated significant activity in metastatic breast and colorectal cancer. During the course of treatment with capecitabine, we observed that a relevant number of patients developed elevated levels of the mean corpuscular volume (MCV) of red blood cells. METHODS: This retrospective analysis reviewed treatment with capecitabine in 35 patients with histologically proven advanced breast and colon cancer. After 9 weeks of treatment, restaging was performed using the criteria proposed by the Committee of the Response Evaluation Criteria in Solid Tumours. RESULTS: Prior to the first cycle of capecitabine treatment, there were no abnormalities in red blood cells, white blood cells, haemoglobin or platelets. The median haemoglobin level prior to the first cycle was 13 g/dl and the MCV (normal range 80-98 fl) was 86.5 fl in colon cancer patients and 12.8 g/dl and 88.7 fl in breast cancer patients, respectively. During the course of treatment, 12 weeks after the baseline evaluation, an increase in MCV was documented, while haemoglobin levels remained stable. An MCV increase was documented between baseline and the end of treatment. We noticed an increase in MCV at the end of treatment both in patients with stable disease or a partial response (n = 17) compared to patients with tumour progression (n = 11) at the first evaluation (12-14 weeks). DISCUSSION: Preliminary results showed that there is a significant MCV increase in patients receiving capecitabine for metastatic colon and breast cancer after 12 weeks of treatment. However, when we compared the MCV rise after 12 weeks that occurred with stable disease or a partial response compared to that in patients with disease progression at the first evaluation, the analysis was not statistically significant.

Italian Survey on adjuvant treatment of non-small cell lung cancer (ISA).

BACKGROUND: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours. PATIENTS AND METHODS: To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail. RESULTS: Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians. CONCLUSIONS: A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen.

Tailored preoperative treatment of locally advanced triple negative (hormone receptor negative and HER2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel.

BACKGROUND: No specific treatment guidelines are available for triple-negative breast cancers, defined by a lack of expression of estrogen (ER), progesterone (PgR), and HER2 receptors. PATIENTS AND METHODS: We investigated in patients with T2-T3 N0-3 ER, PgR <10% and HER2 negative breast cancers the activity both in terms of pathological (pCR) and objective responses of four courses of cisplatin containing chemotherapy (ECF, epirubicin, cisplatin, and fluorouracil as continuous infusion) followed by three courses of weekly paclitaxel. Adjuvant metronomic chemotherapy including cyclophosphamide and methotrexate for 4-6 months was administered. RESULTS: Thirty patients are evaluable. Median age was 41 years (28-64 years). Twenty-three of 25 evaluable tumors stained positively for epidermal growth factor receptor. An objective response, either complete and partial, was observed in 26 patients (86, 95% CI 69.3-96.2%). and a pCR was obtained in 12 patients (40, 95% CI 22.7-59.4%). Two patients progressed during paclitaxel. Negative axillary nodes were found in 80% (95% CI 61.4-92.3%) of patients at surgery. Twenty-six patients (86, 95% CI 61.4-92.3%) underwent breast conserving surgery. Grade >2 non-hematological toxicity was observed in three and two patients during ECF and paclitaxel, respectively. The 2-year disease free survival (DFS) was 87.5% (95% CI 74.7-100%). No significant correlation was observed between EGFR staining and either pCR or DFS. CONCLUSIONS: Preoperative cisplatin containing chemotherapy followed by paclitaxel induced an high pCR rate in a population of triple-negative breast cancer. The impact of this schedule on long-term outcome should be investigated in larger series.

A randomized phase II trial comparing preoperative plus perioperative chemotherapy with preoperative chemotherapy in patients with locally advanced breast cancer.

The aim of this study was to investigate in a randomized trial the activity of perioperative chemotherapy in patients treated with preoperative chemotherapy for locally advanced breast cancer and to compare it with the preoperative chemotherapy alone. Patients with cT2-3 N0-2 M0 histologically proven breast cancer, with estrogen receptors and progesterone receptors in less than 20% of cells, or with absence of progesterone receptors, received epirubicin 25 mg/m days 1 and 2, cisplatin 60 mg/m day 1, and fluorouracil 200 mg/m daily as continuous infusion. Responding patients were randomized to continue fluorouracil until 2 weeks after surgery (perioperative chemotherapy) or to stop fluorouracil 1 week before surgery. Fifty-eight patients completed six courses of epirubicin, cisplatin and fluorouracil, and were randomized to perioperative chemotherapy (29 patients) or to control (29 patients). The median Ki-67 index remained stable (32-27.5%) in the perioperative chemotherapy arm (P=0.3) and decreased from 55 to 22.5% in the control arm (P=0.01). The rate of pathological complete remission was 41% in both arms (P=1.0). No significant difference in terms of disease-free survival and overall survival was observed between the two arms. Perioperative chemotherapy failed to show an increase in the pathological complete remission rate. A biological effect on Ki-67 expression was demonstrated.

Pleural malignant solitary fibrous tumor with sarcomatous overgrowth showing PDGFRbeta mutation.

Pleural malignant solitary fibrous tumors (SFTs) are uncommon, and little is known about their histogenesis and molecular features. We report a case of pleural SFT with sarcomatous overgrowth that showed expression for PDGFRbeta and a missense mutation on exon 18 of the PDGFRbeta gene. The involvement of the PDGFRbeta gene in SFT is compatible with a pericytic derivation, also supporting a possible role of this tyrosine kinase in malignant transformation and in the adoption of novel molecular therapies.