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Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published.A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®).A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found.MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics.This study is registered under NCT02408536 on ClinicalTrials.gov .

Background: Molecular diagnostics for non-small cell lung cancer (NSCLC) has become the standard of care for personalized treatment. Epidermal growth factor receptor ( EGFR ) mutation and EML4-ALK translocation represent the two most important alterations in first-line treatment decision-making. However, other potentially targetable alterations are also present. Methods: One thousand consecutive NSCLC patients with EGFR wild type (wt) tumors diagnosed by routine molecular analysis were considered. KRAS, BRAF, ERBB2, PIK3CA, NRAS, ALK, MAP2K1, RET and DDR2 gene mutations were analyzed using the multiparametric Sequenom MassARRAY ® platform. EML4-ALK and ROS1 rearrangements were also assessed by fluorescent in situ hybridization. HER4 status was determined by direct sequencing. Results: Three hundred and forty-eight (34.8%), 31 (3.1%), 39 (4.4%), 14 (1.8%), 6 (0.7%), 16 (1.8%), 5 (0.6%) and 9 (0.9%) patients showed an alteration in KRAS, BRAF, ALK, ROS1, NRAS, PIK3CA, MAPK1/2 and HER2 genes, respectively. Of the 657 patients for whom all markers were determined, 318 (48%) patients had at least one alteration. Eight patients showed overlapping mutations, 4 KRAS mutation/ EML4-ALK translocation, one KRAS mutation/ ROS1 rearrangement, 2 KRAS/PIK3CA mutations, and one BRAF/PIK3CA mutations. Conclusions: About 50% of our patients had a potentially targetable alteration, confirming the usefulness of a multiparametric approach for routine molecular diagnostics aimed at identifying potential therapeutic targets.

The variability in progression-free survival (PFS) and overall survival (OS) among patients with epithelial ovarian cancer (EOC) makes it difficult to reliably predict outcomes. A predictive biomarker of bevacizumab efficacy as first-line therapy in EOC is still lacking. The MITO group conducted a multicenter, retrospective study (MITO 24) to investigate the role of inflammatory indexes as prognostic factors and predictors of treatment efficacy in FIGO stage III–IV EOC patients treated with first-line chemotherapy alone or in combination with bevacizumab. Of the 375 patients recruited, 301 received chemotherapy alone and 74 received chemotherapy with bevacizumab. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) were evaluated to identify a potential correlation with PFS and OS in both the overall population and the two treatment arms. In the overall population, the PFS and OS were significantly longer in patients with low inflammatory indexes (p

Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21–8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71–36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34–20.87, P < 0.001) and HR 4.75 (95% CI, 1.38–16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195–202. ©2016 AACR.

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

Small-cell lung cancer has a high chemotherapeutic sensitivity but with disappointing outcome results. Patients with “sensitive disease” are those who respond to treatment with a long relapse-free interval (RFI): in these cases rechallenge with first-line chemotherapy might represent a therapeutic opportunity. Our largest retrospective experience confirmed that rechallenge is feasible with interesting outcome results; there are no statistical differences between RFI and outcome.Patients with small-cell lung cancer (SCLC) that progresses after first-line (FL) chemotherapy have a poor prognosis and second-line (SL) chemotherapy has limited efficacy. Patients whose disease relapses/progresses90 days after FL platinum-based treatment are considered platinum-sensitive and could be rechallenged with a similar regimen. We conducted a multicenter retrospective analysis to evaluate outcomes of SCLC patients rechallenged with platinum/etoposide.Records of all SCLC patients treated in 7 institutions between January 2007 and December 2011 were reviewed. The primary end point was overall survival from the time of rechallenge (OS-R); secondary end points were progression-free survival (PFS) and overall survival from the time of diagnosis (OS-D). Survival curves were calculated using the Kaplan-Meier method.Of the 2000 SCLC patients identified, 112 (5.6%) had sensitive disease treated with rechallenge platinum/etoposide; 65% were men with a median age of 64 years. At the time of diagnosis, 44% of patients had limited disease, 82% had an Eastern Cooperative Oncology Group performance status of 0 to 1. A median of 4 cycles of rechallenge was administered. Tumor response was 3% for complete response and 42% for partial response, 19% of patients maintained stable disease, 27% progressive disease, and 9% were not evaluable. Median PFS from the time of rechallenge was 5.5 months (95% confidence interval [CI], 4.4-6.3). Median OS-R and OS-D were 7.9 months (95% CI, 6.9-9.7) and 21.4 months (95% CI, 19.8-24.1), respectively. Subgroup analysis according to relapse-free interval (90-119 vs. 120-149 vs.150 days) did not show any statistically significant difference in PFS or OS-R.The outcome for SL chemotherapy for SCLC is poor. Rechallenge platinum/etoposide is a reasonable option with potentially better outcomes than standard chemotherapy.

Germ cell tumors of the testes represent a unique paradigm of diseases which can be cured even in extremely advanced phase. Unfortunately, this makes them unique among adult solid tumors. Seminoma and non seminoma are relatively rare with approximatively 25,000 patients in Europe per year, but numbers are increasing world wide. Different strategies are needed depending on stage and prognostic scores. Seminoma is extremely sensitive to radiation therapy and chemotherapy, while all germ cell tumors show a very good response to chemotherapy. Clinical stage I seminoma is currently treated with radiation, single course carboplatin or surveillance policy. Clinical stage I non seminoma can also be approached with different strategies such as retroperitoneal lymph node dissection, observation or one-two courses of standard chemotherapy. Stage II seminoma may be treated with either radiation or chemotherapy, while for all advanced stages chemotherapy is mandatory. Since the mid-eighties PEB (Cisplatin, Etoposide and Bleomycin) is the regimen of choice and no other schedule has proved superior in terms of efficacy. Surgery on the residual disease is crucial to the whole strategy and should be performed or attempted in all cases. Consequently, the correct treatment strategy for these tumors does not depend only on the ability of a single physician, but on a skilled team specialized in this particular tumor. Second line therapies (VeIP, PEI, TIP) can cure 25%–40% of patients, but improved strategies for resistant tumors are desperately needed. High-dose chemotherapy has shown very good results in some studies while being less impressive in others. In any case, it should remain an option for relapsing patients and could be used in some cases of upfront chemotherapy in patients with slow marker decline, but this should only be considered in referring centers.

We report the case of a HER2+ breast cancer patient, with early relapse, refractory to HER2-targeted therapy and treated with eribulin mesylate. The patient progressed during two different HER2 target therapies: trastuzumab as adjuvant/first-line treatment and lapatinib as second-line treatment. The patient underwent nine cycles of eribulin (1.23 mg/m2 days 1–8 every 3 weeks). The therapy was well tolerated. Restaging with computed tomography after the second cycle of treatment demonstrated stable disease. After nine cycles of eribulin therapy the patient experienced disease progression and she died 6 months later. This case report provides further insights regarding the use of eribulin mesylate as third-line treatment in a HER2+ breast cancer patient.

e20676 Background: Elderly and patients with ECOG PS ≥ 2 often present with medical and physiological characteristics that make the selection of their treatment more challenging. Single-agent vinorelbine improves survival and quality of life compared with best supportive care. At constant effectiveness between two treatments formulations patient preference must be taken into account. Methods: Stage IIIB or IV NSCLC patients candidates to receive a first line chemotherapy with Vinorelbine alone due to age ≥ 70 and Eastern Cooperative Oncology Group (ECOG) Performance status ≤2 or age ≤ 70 but ECOG PS ≥ 2, could enter the study. Patients were randomized to receive: • Arm A: first cycle of IV vinorelbine (30 mg/m2) and second cycle of oral vinorelbine (60mg/m2) • Arm B: first cycle of oral vinorelbine followed by a second cycle of IV vinorelbine. In both arms vinorelbine was administered at day 1 and day 8 every 3 weeks. From the third cycle onwards patients had to choose to continue with oral or intravenous vinorelbine. The dosage of oral vinorelbine could be subsequently increased to 80 mg/m2 at physician’s choice. Treatment continued until disease progression, intolerable toxicity or patient refusal. The primary objective of the study was the patient preference for oral or intravenous vinorelbine. Results: Ninety-three patients entered the study and were randomized. Sixty-two were able to complete the first two cycles and to express a preference (32 in Arm A and 30 in Arm B). Forty-five out of 62 were males and 17 females. Median age was 80 (72-89). Nineteen patients had an ECOG PS of 0, 39 a PS of 1 and 4 a PS of 2 (30.7%, 62.9% and 6.4% respectively). Eighteen patients (29%) decided to continue with IV vinorelbine while 44 patients (71%) expressed a preference for oral vinorelbine p = 0.001 (Gart's test). Regarding secondary enpoints, median OS was 5.7 (4.7-7.7) and 5.5 (3.8-9.1) months and median PFS was 3.5 (2.4-4.4) and 3.5 (3.5-5.0) for arm A and arm B respectively. Conclusions: The study has clearly demonstrated that elderly or frail patients with NSCLC prefer to receive an oral rather than an intravenous chemotherapy. The reasons for the choice were expressed in a questionnaire still in evaluation. Clinical trial information: nct01848613.

9052Background: Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations are usually responsive to tyrosine kinase inhibitors (TKIs). However, ab...

Background Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy. Patients and Methods Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m 2 days 1 and 8 immediately followed by gemcitabine at 1000 mg/m 2 every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses. Results Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively. Conclusions The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic.

6003 Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1+ 130 Arm B1) and 160 received CET/RT (80 Arm A2+ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. [Table: see text]

5513 Background: The standard treatment options for LASCCHN are cCHT+RT or CET+RT. Strategies to improve the efficacy with the integration of induction chemotherapy are being investigated. Primary endpoints of this study were to compare: 1) the overall survival (OS) of induction vs. no induction arms; 2) the Grade(G)3-4 in-field toxicity of cCHT+RT vs. CET+RT. Methods: Patients (pts) with unresectable LASCCHN, stage III-IV, ECOG PS 0–1 were randomized to a 2x2 factorial design: Arm A1: cCHT+RT (2 cycles of ciplatin/5fluorouracil); Arm A2: CET+RTX; Arm B1: 3 cycles of TPF followed by the same cCHT+RT; Arm B2: 3 cycles of TPF followed by CET+RT. A total of 204 deaths over 420 pts ( including the 101 randomized in the phase II part of the study comparing cCHT+RT with or w/o induction TPF) were required to detect a HR of death of 0.675 (A1+A2 vs. B1+B2; 2-sided a=0.05; b=0.20) and a 10% difference in G3-4 in-field mucosal toxicity (A1+B1 vs. A2+B2). Results: By February 2012, 387 pts over 413 pts were evaluable for toxicity. 82% of pts were male; median age was 60y; PS: 0=77.8% and 1=22.2%. Disease stage was III (31%) or IV (69%). Sites of disease were oral cavity (21.7%), oropharynx (54.8%), hypopharynx (23.5%). At a median follow-up of 21 months, 126 deaths occurred. Data on G3-4 in-field toxicity (primary endpoint) and compliance to cCHT+RT vs CET+RT are shown in the table. Conclusions: No advantage for CET+RT over cCHT+RT was observed regarding G3-4 in-field toxicities and feasibility. Pts are still being followed-up to assess OS. [Table: see text]

e18561 Background: Response and duration to initial chemotherapy are important factors used to classify SCLC patients into two groups. The first group comprises sensitive disease that responds to initial chemotherapy and relapses after more than 3 months and for which disease control could be obtained by re-challenging with first-line chemotherapy. The second group comprises refractory disease that progresses at the end or within 3 months of finishing first-line chemotherapy and for whom second-line chemotherapy represents the gold-standard. Methods: We reviewed clinical data from 4 Oncology Departments on sensitive SCLC treated with a first-line chemotherapy re-challenge in order to evaluate its activity and efficacy. Results: Of 211 SCLC patients diagnosed from January 2007 to December 2011, 25 (12%; 20 males, 5 females) had sensitive disease of whom 13 (52%) limited disease (LD) and 12 (48%) extended disease (ED). Median interval between the last day of chemotherapy and the onset of disease progression was 205 days (95% CI 169 – 279; range: 90 – 665). Chemotherapy consisted of etoposide + carboplatin in 15 (60%) patients or cisplatin in 10 (40%). On average 3-4 (range: 1-6) chemotherapy courses were administered, producing 8 (32%) partial responses, 3 (12%) stable disease, 10 (40%) progressive disease and 4 (16%) non evaluable disease. Further-line chemotherapy, mainly topotecan, was administered in 13 (52%) patients. Median overall survival produced by all treatments was 19.6 months (95% CI 16.5 – 27.6). Conclusions: In our experience, sensitive SCLC treated with first-line platinum/etoposide re-challenge produced interesting results in terms of activity and efficacy. Prospective randomized trials are warranted to investigate whether this strategy produces better results than standard second-line chemotherapy.

7600 Background: Rechallenge might be used as rescue therapy in progressing platinum-sensitiveSmall Cell Lung Cancer (SCLC). This international multicenter retrospective analysis evaluates the clin...