PathologiCal and moleCular CharaCterization in hereditary and SPoradiC ovarian CanCer PatientS
Maccaroni E.1, Sotte V.2, Bini F.2, Bianchi F.2, Giampieri R.2,
Belvedersi L.2, Brugiati C.2, Pagliaretta S.2, Murrone A.2, Pesci
A.2 and Berardi R.2
1AOU Ospedali Riuniti, Ancona; 2Università Politecnica delle Marche, Ancona
Background: Ovarian cancer (OC) represents the leading cause of cancer deaths among gynaecological malignancies. Germline mutations in the BRCA1 and BRCA2 genes are associated with hereditary predisposition to breast and OC and account for 10-15% of OC cases. Hereditary OC patients (pts) have improved clinical outcomes compared to BRCA-wild type OC, due to greater response to platinum- based treatments and tailored therapeutic options, such as PARP inhibitors. The present study evaluates pathological and molecular features of BRCA-wild type (sporadic) and BRCA-mutant (hereditary) OC pts in Marche Region. Patients and methods: we determined the prevalence of germinal BRCA1 and BRCA2 variants in OC pts undergo- ing genetic counselling and testing between June 1996 and April 2017 at Centro Regionale di Genetica Oncologica, Ancona. Risk assessment was made relying on clinical cri- teria and prediction tools such as BRCApro and Manchester Scoring System. We proposed BRCA test to all pts affected by OC regardless of familiarity according to 2015 AIOM recommendations. BRCA genes were studied by sequenc- ing and Multiplex Ligation Probe Amplification. We referred to Breast Cancer Information Core committee, IARCs databases and ClinVar archive.
Results: 227 OC pts were included in the study; among them 68 (30%) carried a pathogenic variant while 35 (15.4%) had a Variant of Uncertain Significance (VUS). Pathogenic variants were significantly more frequent in the BRCA1 gene (83%) vs BRCA2 gene (51%) (p =
0.00012). High grade serous OC was the most frequent histotype (57%), followed by endometrioid OC (17%).
Median age at diagnosis was 52 years (range 16-83). No significant differences in terms of age at diagnosis were observed between BRCA-mutant and BRCA-wild-type pts, neither between BRCA1- and BRCA2-mutant pts. Positive family history for BRCA-related cancers was reported in 160 (70%) pts, while 67 (29%) had negative family history. In the first group 64 (28%) had a pathogenic BRCA variant, while in the second group only 4 (2%) was carrier of a pathogenic mutation. Detection rate, defined as the probability to detect pathogenic BRCA variants, resulted higher (40%) in OC pts with positive family his- tory vs pts with negative family history (6%) (p = 0.0009). Conclusions: our results highlight the importance of BRCA status analysis in Marche Region OC pts as to perform com- parisons among mutational and clinic-pathological features between our Region and other geographical areas.
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riSk reduCing SalPingo-
ooPhoreCtomy (rrSo) in high-riSk women: beyond brCa
Cassani C.1, Secondino S.1, Zanellini F.1, Roccio M.1, Cesari S.1,
Fiandrino G.1, Nappi R.1, Ferraris E.2, Lasagna A.2, Rizzo G.2,
Sgarella A.2, Ferrari A.2, Grasso M.2, Arbustini E.2, Pedrazzoli
P.2 and Spinillo A.2
1Fondazione IRCCS Policlinico San Matteo, Pavia; 2Fondazione IRCCS Policlinico
San Matteo, Pavia
Background: Previous experiences have demonstrated that RRSO reduced the risk of ovarian cancer in BRCA1-2 carriers1, and the rate of occult neoplasia in RRSO speci-
men ranges from 2.5 to 9%2. Serous tubal intraepithelial
carcinoma (STIC) is an establish precursor of pelvic serous carcinoma, and pre-neoplastic lesions (STIL) has the same aberrant expression of p53 mutations, suggesting a link between these two lesions3. Overexpression of p53 muta-
tions (called p53 signature), is also found in normal areas, and it may represent a role in cancerogenesis.
Patients and Methods: From February 2012 to March 2018, ninety-one high-risk women (median age 49 yrs; range 31-71 yrs) underwent RRSO; fifty-seven women were BRCA1-2 mutation carriers, 9 were VUS and 25 women had family history of ovarian or breast cancer. Sixty-nine (76%) women had a previous history of breast cancer (BC), and 7 of them (10%) had a bilateral BC. Results: No surgical adverse events were recorded, fol- lowing RRSO. Six cases of occult cancer were detected giving an overall incidence of 6.5% (median age was 55 yrs). Concerning non invasive lesions, we identified five STIL (5.4%), and eight p53 signature (8.7%), that repre- sent 14.2% of all pre-neoplastic lesions (median age of
women was 50 yrs). Among BRCA1-2 mutant carriers (n=57), 4 women (7%) had occult carcinoma and 9 (16%) had pre-neoplastic lesions (STIL and p53 signature), while in high risk women non BRCA-carriers (n=34), the pre- neoplastic lesions were identified in 4 of them (11.7%). Conclusions: Our data confirm previous experience in high-risk women undergoing RRSO. Furthermore due to the prevalence of pre-neoplastic lesions, careful ongoing studies about the role of p53 signature, are necessary to make such a conclusion.
References
1 Kauff ND, et al. N Engl J Med 346:1609, 2002 2 Conner JR, et al. Gynecol Oncol 132: 280, 2014 3 Vang R, et al. Int J Gynecol Pathol 31:243, 2012
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role of ParP inhibitorS in ovarian CanCer: SyStematiC review and meta-analySiS
Staropoli N., Ciliberto D., Iuliano E., Del Giudice T., Cucè M., Salvino A., Barbieri V., Tassone P. and Tagliaferri P
Università Magna Graecia di Catanzaro, AOU Mater Domini, Catanzaro
Introduction: Ovarian cancer is the leading cause of death among gynaecological malignancies. The gold standard of treatment still remains the combination Carboplatin and Taxol, while the platinum free interval is considered the major prognostic factor. Moreover, platinum-sensitive patients recognize in 40% of cases a germline or somatic BRCA1/2 mutation. Recently, a new class of drugs, the PARP inhibitors (PARPis), was able to significantly mod- ify the progression free survival (PFS) of these patients when used in a maintenance setting. We performed a sys- tematic review and meta-analysis in order to verify the impact of these agents both in term of efficacy and safety. Patients and Methods: By searching “Pubmed” database and abstracts from cancer meetings clinical trials were identified within a time frame January 2008 - April 2018. PFS was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios (RR) of grade 3-4 toxicity rates were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by fixed and random effect models. An indirect comparison in term of efficacy (PFS) was also performed.
Results: Six randomized trials for a total of 1879 patients were selected and included in the final analysis. In particu- lar, we evaluated a BRCA-mutant cohort (911 patients) with a pooled HR 0.26 (95%CI 0.21-0.31) and the BRCA- wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding the safety pro- file, no significant differences were detected in all grade toxicities, however considering the 3-4 grade toxicities
and severe adverse events (SAEs) we showed that ruca- parib-treated patients, reported major abdominal pain events, while we reported the highest percentage of hae- matological toxicities for niraparib, hypothesizing a “drug effect” for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents.
Conclusions: We confirm the significant benefit in sur- vival outcome of PARPis for EOC patients both in the pair-wise meta-analysis and indirect comparisons (“class- effect”). Particularly, we highlighted that the major effect of this strategy remains in BRCA-mutated patients. Thus, a better selection by genetic testing at diagnosis is needed with the added social value of individualized prevention in BRCA-mutated families.
h04
Platinum-SenSitivity in high-grade SerouS ovarian tumorS with brCa1 and brCa2 mutationS
Tavella K.1, Villanucci A.1, Vannini L.2, Marini A.2, Gatta
Michelet M.R.2, Nobili S.2, Gensini F.2, Papi L.2, Amunni G.2 and
MIni E.2
1Azienda Ospedaliero-Universitaria Careggi Firenze, Firenze; 2Università degli
Studi di Firenze, Firenze
Background: Approximately 10-15% of patients with ovarian cancer (OC) are carriers of genetic mutations in BRCA1 or BRCA2 (BRCA+); these patients show greater sensitivity to platinum-containing chemotherapy (CT). We analyzed the response data to CT and survival of patients in our center by comparing cases of carriers of BRCA genetic mutation with the wild type (WT) population. Material (patients) and methods: We examined 94 patients undergoing genetic investigation for BRCA1/2 genes, aged between 37 and 76 years, with OC undergo- ing CT between 1998 and 2018. 22 patients were BRCA+: 19 with BRCA1 mutation and 3 with BRCA2 mutation; 72 patients were WT. Progression free survival (PFS) and the platinum sensitivity were compared between the 2 groups by Kaplan-Meier curves. Patients were all at the III stage of the disease at the diagnosis time. 70% of all patients had primary radical surgery before CT (carboplatin and paclitaxel), while the remain- ing 30% received neoadjuvant CT with the same drugs, with subsequent interval surgery.
Results: In this study, we evaluated PFS at the first and at the second recurrence in the 2 distinct groups (BRCA+, WT) by median calculation. Platinum-sensitivity (appear- ance of disease recurrence after >6 months from the end of the first platinum-containing CT) was observed in 20/22 (90,9%) BRCA+ patients and 64/72 (88,8%) WT patients for such mutations. In BRCA+ patients the median of PFS
at the first disease recurrence was 23,9 months and at the second disease recurrence was 16,6 months. In WT patients the median of PFS at the first disease recurrence was 21,7 months and at the second disease recurrence was 15,7 months. No statistically significant difference was found in terms of PFS in the 2 groups, but medians PFS were bet- ter in the BRCA+ patients group.
Conclusions: According to literature studies BRCA + patients have a greater response to the first and subsequent lines of platinum-based CT, compared to WT patients. This suggests that patients with BRCA 1/2 mutations have a higher sensitivity to platinum-containing CT. On the other hand it has been observed that also many WT patients are platinum-sensitive (BRCAness). Platinum sensitivity may be due to non-genetic factors, or to the presence of somatic BRCA mutations or of mutations in other genes involved in homologous recombination repair. Finally research into BRCA1/2 genetic mutations may allow to identify more personalized treatments that could improve OC prognosis in this patients setting.
h05
niraParib in reCurrent Platinum SenSitive high-grade ovarian CanCer: a monoCentriC exPerienCe
Tasca G.1, Mantiero M.2, Baldoni A.2, Faggioni G.3, Frezzini S.2,
Menichetti A.2, Nicoletto M.O.3 and Conte P.1
1Department of Surgery, Oncology and Gastroenterology, University of Padova;
Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Padova;
2Department of Surgery, Oncology and Gastroenterology, University of Padova,
Padova; 3Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova,
Padova
Background: NOVA trial has demonstrated that Niraparib as maintenance treatment significantly prolongs progres- sion-free survival in patients (pts) with platinum-sensitive recurrent ovarian cancer (PSROC) regardless of BRCA mutational status.
Methods: This is an observational single-institution expe- rience, which included pts with PSROC (high-grade, endometrial or serous) treated with Niraparib as mainte- nance therapy after complete or partial response to the most recent platinum-based chemotherapy. Drug availabil- ity was made possible thanks to the Compassionate Use Program.
Results: From September 2017 to April 2018, Niraparib was administered to 13 pts: 5 (38%) as 2nd line mainte- nance treatment, 3 (24%) as 3rd line and 5 pts (38%) as >4th line. With regards to BRCA mutational status, 1 pt (8%) was BRCA1 mutated, 11 pts (84%) were wild type, and for 1 pt (8%) the test is ongoing. Treatment started within 12 weeks from the last cycle of platinum therapy for all pts, at the standard dose (300 mg/die) for 8 pts (62%), whereas 5 (38%) received Niraparib starting dose
of 200 mg/die because the weight was <58Kg, as indi- cated in drug data sheet. A total of 44 cycles have been administered, with a median of 3 cycles. Six pts (46%) experienced adverse events (AEs) >G3. Hematological toxicity was the most frequent AE: a >G3 thrombocytope- nia was observed in 3 pts (33%), G3 and G2 anemia in 1 pt (11%) and 2 pts (22%) respectively and G2 neutropenia in 1 pts (11%). The only non-hematological toxicity observed was fatigue G3 (1 pt, 11%). All the AEs >3 resulted in drug dosage reduction. At the time of the present report in 3 pts (23%) a further radiological partial response was observed; among the remaining 10 pts, 1 (8%) had a dis- ease stabilization, 3 (23%) discontinued treatment due to disease progression and for 6 pts re-evaluation of disease status is pending.
Conclusions: In this real life experience, the treatment with Niraparib has shown a good tolerability. The observed >G3 hematological toxicities were as expected and were easily managed with temporary drug interruption. In our PSROC pts, although included patients treated with multi- ple lines of therapy, Niraparib maintenance treatment was effective in maintaining prior platinum response and also in improving tumor shrinkage.
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abstract withdrawn
h07
advanCed uterine CerviCal SquamouS Cell CanCer (auCSCC). high reSPonSe rate uSing a doSe- denSe ChemotheraPy with taxol, ifoSfamide and Platinum (tiP-dd)
Giganti M.O.1, Perrucci B.2, Donini M.2, Panni S.2, Pizzo C.2,
Negri F.2, Tisi M.2 and Passalacqua R.2
1Asst Istituti Ospitalieri Cremona, Cremona; 2Asst Istuti Ospitalieri di Cremona,
Cremona
Background: AUCSCC represents an aggressive tumor with a poor prognosis. To date, no studies have identified the best chemotherapy regimen. Dose-dense chemother- apy is an effective treatment modality for many tumors but the efficacy of this approach in this population is unknown. Aim of this study was to assess the efficacy and tolerability of the TIP-dd regimen given with a dose-dense approach. Patients and Methods: We performed a retrospective review of all cases with a diagnosis of locally advanced or metastatic cervical cancer seen at the Oncology Division of the Istituti Ospitalieri of Cremona from November 2004 to December 2018. Chemotherapy consisted of Ifosfamide 2500 mg/m2 and Mesna 2500 mg/m2, on day 1; Paclitaxel 175 mg/m2 and Cisplatin 70 mg/m2, on day 2; every 2
weeks for a maximum of 6 cycles with prophylactic pegfil- grastim on day 3. Complete staging before chemotherapy was available in all patients. Response rate was evaluated using the RECIST 1.1 criteria; acute and late toxicity of chemotherapy, time to progression (TTP) and overall sur- vival (OS) were recorded.
Results: 17 patients were identified so far. Median age was 52 years (range 25-71), PS 0 (100%),16 (94.1%) squa- mous histology and 1 adenocarcinoma; FIGO Stage was IIB in 2 (11.7%), IIIA in 1 (5.8%); IIIB in 3 (17.6%) and IV in 11 ( 64.7%). Median number of TIP-DD cycles was 6 (range 1 to 7). 16 patients were evaluable. Following chemotherapy, ten patients underwent surgery (62.5%) and five patients received pelvic radiotherapy (31.2%). We observed 7 (43.7%) complete responses and 8 (50%) par- tial responses for a overall response of 93.7%. At this time nine patients have recurred (56.2%) and five patients are still alive (31.2%). Six patients have performed further treatment lines (37.5%). Median TTP was 44.4 months (IC95%: 0.5-NR) and median overall survival was 33 months (95% CI: 23 -236). Treatment was delayed in 10 patients (62%). Toxicities included grade 3-4 neutropenia: 6% (0% febrile neutropenia), grade 3-4 thrombocytopenia: 6%, grade 2 neuropathies 12%; grade 2 asthenia/fatigue 12%, and no treatment-related deaths. 5 patients are still alive (median overall survival = 40,3 months)
Conclusions: These excellent results from a retrospective case series represent a hint for further research with a view to get a possible cure for metastatic cervical cancer. However, due to limitations of the trial design, this approach should be studied in prospective trials prior to drawing any conclusions.
h08
effiCaCy, toxiCity and quality of life of weekly ChemotheraPy regimen in elderly PatientS with gyneCologiCal CanCer
Camera S.1, Persano M.2, Impera V.1, Lai E.1, Liscia N.1,
Mariani S.2, Musio F.2, Pireddu A.G.1, Pretta A.1, Tolu S.1,
Massa E.2, Madeddu C.2, Astara G.2, Ziranu P.2, Cubeddu A.2,
Mais V.3, Peiretti M.3, Proto A.3 and Scartozzi M.2
1Medical Oncology Unit, University of Cagliari - Sapienza University of Rome,
Cagliari, Italy; 2Medical Oncology Unit, University of Cagliari, Cagliari, Italy; 3Divi-
sion of Gynecology and Obstetrics, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
Background: Several studies revealed a strong associa- tion between increasing age and decreased use of chemo- therapy. The aim of this study is to investigate in elderly patients with gynecological cancer the efficacy and toxic- ity (CTCAE version 4.0) of weekly chemotherapy regimen with Carboplatin AUC 2.5 plus Paclitaxel 80 mg/m² on days 1,8 +/− Bevacizumab 15 mg/kg on day 1 (if
indicated for stage and site of cancer) every 21 days. Secondary endpoints are quality of life (QoL) and the cor- relation between safety, efficacy and G8 evaluation at baseline and at the end of treatment.
Patients and methods: We have designed a monocentric phase II non randomized study. Patients eligibility criteria: age⩾70; ovarian, endometrial or cervical cancer; no previ- ous systemic therapy for cancer; adequate baseline func- tional parameters. Patients are stratified on the basis of: age (⩾70-75 vs >75-80); site of cancer (ovarian vs endo- metrial vs cervical); stage (IIA-IIIA vs IIIB-IV for ovarian, III-IV for endometrial, relapsed-IV for cervical cancer); G8 score (>14 vs ⩽14). G8 screening tool is used at base- line. Patients with a score ⩽14 (high risk) are submitted to the CGA (Comprehensive Geriatric Assessment); frail patients are excluded. Safety is recorded in all patients that receive at least 1 cycle. The efficacy endpoints are ORR, PFS, OS. Only patients that complete at least 3 cycles are evaluable for ORR. Tumors are assessed by CT at baseline and every 3 cycles. QoL is measured by SF 36 at baseline and every 3 cycles.
Results: From March 2018 to May 2018 six patients are enrolled: median age 77,5 (range 76-80); 5 ovarian cancer (1 stage IIA, 1 stage IIIA, 3 stage IVB) and 1 cervical cancer (stage IV). Two of six patients with score ⩽14 at G8 screen- ing was evaluated with CGA. No patient resulted frail at CGA. Only G1-G2 hematological toxicity are observed: G1 neutropenia in 33,3% of patients, G1 anemia and thrombo- cytopenia in 16,7%; G2 neutropenia in 16,7%. Between non hematological toxicities, G1 fatigue and neuropathy are observed in 33,3%. No patient has delayed or interrupted chemotherapy due to toxicity. The study is ongoing, the required sample size is 62 patients in 24 months.
Conclusions: The study aims to demonstrate that the weekly regimen in elderly patients to be as effective as standard 3-week scheme but with significantly lower toxicities and better tolerance, adherence to planned treatment and QoL.