Triple negative (TN) breast cancer (BC) is an uncommon and aggressive subtype of BC associated with early disease recurrence and short survival. In literature, prevalence of BRCA mutations in TNBC patients may vary from 9 to 32%. The prevalence of BRCA germline mutations has been systematically evaluated in this setting of patients at our center.

BACKGROUND: Everolimus, an mTOR inhibitor, in combination with exemestane is approved for hormone receptor (HR) positive advanced breast cancer (ABC), after failure of treatment with non-steroidal aromatase inhibitor (NSAI). We assessed the toxicity of the combination and the correlation between dose intensity and response to therapy, in a real world population of ABC from 11 Italian centers. Moreover, we evaluated OS of the whole population, RR and PFS according to line of treatment (from 1rd to 3th and from 4th on). METHODS: 154 pts were treated with combination of everolimus 10 mg and exemestane 25 mg daily from 05/2011 today. Median age was 62 (47-82). Median time to metastatic disease was 49 months (0-269). Median number of metastatic sites was 2 (55.2% of pts visceral versus 44.8% non visceral disease). N=117 (75.9%) pretreated with HT as adjuvant; N=126 pts (81.8%) treated with HT for advanced disease prior to EVE/EXE, with a median of one line (0-5). N=102 pts (66.2%) treated with chemotherapy for metastatic disease, with a median of one line (0-6) before everolimus treatment. RESULTS: Sixteen pts received EVE/EXE as 1st line (10.4%), 39 as 2nd (25.3%), 37 as 3rd (24%), 62 as 4th or more (40,3%). Response was evaluable in 127 out of 154 pts; CR/PR/SD respectively 5/27/56 pts. RR according to line (from 1st to 3rd vs ≥ 4th) was respectively 22.8% vs 26.4% (p=0,864). The median PFS for all population (150 pts) was 38 weeks (95% CI: 33-42). The PFS according to line (1st- 3rd vs ≥ 4th) was 38 wks in both subgroups, p=0.73. OS (126/154 pts) was 28 mths (95% CI: 31-38). The most frequent adverse events were collected in the table. Median duration of treatment with everolimus 10 mg and 5 mg was respectively 180 (9-854) and 129 days (3-738). Fifty-eight pts (37,6%) never stopped treatment with everolimus 10 mg; 16 pts (10,4%) definitively stopped everolimus for toxicity; 80 pts (52,0%) temporarily interrupted the treatment, resuming at dose level 10 mg (31 pts) or reducing at 5 mg (49 pts). Main reason for discontinuation/interruption was stomatitis G2-G3. RR and PFS evaluated according to dose intensity, 10 mg vs 5 mg, were respectively 25.9% vs 30% p=0.779, 38 wks (27-44) vs 40 wks (31-48) P=0.614 CONCLUSIONS: efficacy in terms of RR and PFS of the combination EVE/EXE is not related to dose intensity (10 mg vs 5 mg), the discontinuation of the treatment is high with the starting dose of 10 mg, the toxicity is consistent with previous phase II-III studies although we collected some different toxicities. Citation Format: Forcignano R, Petrucelli L, Cazzaniga ME, Lupo LI, Chiuri VE, Cairo G, De Matteis E, Febbraro A, Giordano G, Campidoglio S, Fabi A, Giampaglia M, Bilancia D, La Verde N, Maiello E, Morritti M, Giotta F, Lorusso V, Scavelli C, Romito S, Cusmai A, Palmiotti G, Tornesello A, Ciccarese M. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-15.

In families where the hereditary transmission of breast (BC) and/or ovarian cancer (OC) risk is suspected, BRCA1/2 testing is indicated. However, while not all BRCA carriers develop cancer, cases of sporadic BC/OC among non-carriers members of BRCA+ families may occur. No clear data are available so far about the expected frequency of these cases. One 2005 work by Allweis et al. reported a frequency of 0.75% sporadic cancers in a cohort of Ashkenazi BC patients tested for BRCA1/2. Here we report a case series of sporadic BC/OC in families with BRCA-associated HBOC syndrome. Subjects accessing to Hereditary and Familial Tumours Services (HFTS) at Vito Fazzi Hospital in Lecce were considered. Families were classified based on Modena criteria. We identified the HBC/HBOC families in which a 1st-degree non-carrier relative of at least one BC and/or OC affected BRCA carrier also developed cancer. All subjects provided consent to genetic testing and research data collection. Between January 2014-April 2016, 424 subjects from 314 families accessed to HFTS, for a total of 608 counseling visits. Of 424, 271 (63.9%) were considered to be eligible for BRCA1/2 testing, finding 98 BRCA1/2 wild type subjects, and 66 BRCA1/2 mutations carriers (plus 5 subjects with VUS). Of 314 families considered, 87 (27,6%) were classified as HBC/HBOC. Four families (4/87, 4.6%) were identified in which one cancer affected member was non-carrier of the familial BRCA mutation. In particular, these were three BC cases of a paternal aunt, sister and daughter, respectively, of affected BRCA1 mutation carriers; and one case of high-grade serous OC developed at age 57 in a non-carrier younger sister of a BRCA1 carrier patient who had developed high-grade serous OC at age 61. As particularly impressive in the OC case, for the three BC cases we observed similarities in terms of clinical and pathologic characteristics of cancers between carriers and non carriers. Relatives of BRCA carriers who result non-carrier are normally counseled that their BC/OC risk is the same as for the general population, and so are the prevention programs. However, as we report here, sporadic BC/OC may occur in 4.6% cases, most probably due to the same environmental factors shared, or other unconventional triggers (stress/lifestyle-related, or pollution-driven). However, further studies should be conducted to determine prevalence and risk of sporadic cancer, that may help guide counseling.

BACKGROUND: Everolimus, an mTOR inhibitor, in combination with exemestane is approved for hormone receptor (HR) positive advanced breast cancer (ABC), after failure of treatment with non-steroidal aromatase inhibitor (NSAI). We assessed the toxicity of the combination and the correlation between dose intensity and response to therapy, in a real world population of ABC from 11 Italian centers. Moreover, we evaluated OS of the whole population, RR and PFS according to line of treatment (from 1rd to 3th and from 4th on). METHODS: 154 pts were treated with combination of everolimus 10 mg and exemestane 25 mg daily from 05/2011 today. Median age was 62 (47-82). Median time to metastatic disease was 49 months (0-269). Median number of metastatic sites was 2 (55.2% of pts visceral versus 44.8% non visceral disease). N=117 (75.9%) pretreated with HT as adjuvant; N=126 pts (81.8%) treated with HT for advanced disease prior to EVE/EXE, with a median of one line (0-5). N=102 pts (66.2%) treated with chemotherapy for metastatic disease, with a median of one line (0-6) before everolimus treatment. RESULTS: Sixteen pts received EVE/EXE as 1st line (10.4%), 39 as 2nd (25.3%), 37 as 3rd (24%), 62 as 4th or more (40,3%). Response was evaluable in 127 out of 154 pts; CR/PR/SD respectively 5/27/56 pts. RR according to line (from 1st to 3rd vs ≥ 4th) was respectively 22.8% vs 26.4% (p=0,864). The median PFS for all population (150 pts) was 38 weeks (95% CI: 33-42). The PFS according to line (1st- 3rd vs ≥ 4th) was 38 wks in both subgroups, p=0.73. OS (126/154 pts) was 28 mths (95% CI: 31-38). The most frequent adverse events were collected in the table. Median duration of treatment with everolimus 10 mg and 5 mg was respectively 180 (9-854) and 129 days (3-738). Fifty-eight pts (37,6%) never stopped treatment with everolimus 10 mg; 16 pts (10,4%) definitively stopped everolimus for toxicity; 80 pts (52,0%) temporarily interrupted the treatment, resuming at dose level 10 mg (31 pts) or reducing at 5 mg (49 pts). Main reason for discontinuation/interruption was stomatitis G2-G3. RR and PFS evaluated according to dose intensity, 10 mg vs 5 mg, were respectively 25.9% vs 30% p=0.779, 38 wks (27-44) vs 40 wks (31-48) P=0.614 CONCLUSIONS: efficacy in terms of RR and PFS of the combination EVE/EXE is not related to dose intensity (10 mg vs 5 mg), the discontinuation of the treatment is high with the starting dose of 10 mg, the toxicity is consistent with previous phase II-III studies although we collected some different toxicities. Citation Format: Forcignano R, Petrucelli L, Cazzaniga ME, Lupo LI, Chiuri VE, Cairo G, De Matteis E, Febbraro A, Giordano G, Campidoglio S, Fabi A, Giampaglia M, Bilancia D, La Verde N, Maiello E, Morritti M, Giotta F, Lorusso V, Scavelli C, Romito S, Cusmai A, Palmiotti G, Tornesello A, Ciccarese M. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-15.

ABSTRACT Aim: ABC remains an incurable disease although the introduction of targeted agents and newest drugs has significantly improved the overall outcome. Nevertheless, the degree of the benefit provided by CT beyond the 3rd line is controversial. Methods: Data of consecutive ABC patients (pts) were retrospectively gathered, according to pathological subtype (Ki67 Results: The characteristics of 485 pts from 3 different institutions were: median age: 60 years (29-91); median time from primary: 29 months (0-721), median number of sites: 2 (1-6); visceral/bone only disease: 300 (62%)/125 (26%); Luminal A/B/HER2-positive/triple-negative/non-evaluable: 92 (19%)/124 (25%)/117 (24%)/41 (9%)/111 (23%); median number of CT lines: 2 (1-12); overall OS: 45 months (95% CI 34-56). Age (HR 1.01, 95% CI 1.01-1.03, p = 0.04), Conclusions: These data suggest that CT beyond 3rd line may potentially have a significant impact upon survival. The correlation between OS and both PPS and PFS is consistently maintained across all treatment lines. Disclosure: All authors have declared no conflicts of interest.

Abstract Background: MBC remains an incurable disease with a median survival of 2-3 years despite the use of new drugs. The validation of PPS as surrogate endpoint and its correlation to PFS and OS is matter of debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 192 pts treated for MBC outside of clinical trials, 103 with at least 3 lines CT, in order to evaluate post-progression survival (PPS) according to treatment line and its relation to PFS and OS. Moreover we evaluated the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Results: Median age at M+ diagnosis was 59 years (30-89), median site of disease was 2 (1-6), 67% visceral, HER-2 + pts 32%, median number of anti-Her-2 treatment was 2 (0-6); median number of treatment was 3 (1-8). Median OS for all pts was 45.6 (95% CI: 36.5-54.7). Median OS for CT > = 3 vs CT < 3 was respectively 52.5 (95% CI: 43.3-61.7) and 32.3 (95% CI: 23.6-41.2) P = 0.007. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive versus negative p<0.0001) number of lines (>3 vs ≤3) p = 0.001 and number of metastatic sites (>2 vs ≤2) p<0.0001. We evaluated the relation between PFS and OS and between PPS and OS until the 6th line of therapy with a linear regression model. Median PFS (95% c.i.)Median PPS (95% c.i.)Median OS from M+ diagnosisCorrelation OS-PPSCorrelation OS-PFS1st line11.0 (9.5-12.5)29.9 (18.2-41.6)Not reachedP<0.0001 OS-PPS1P<0.0001 OS-PFS12nd line7.0 (5.8-8.2)20.9 (11.7-30.0)29.1 (17.5-40.7)P<0.0001 OS-PPS2P<0.0001 OS-PFS23rd line5.6 (4.5-6.7)19.5 (14.9-24.1)41.9 (15.5-68.2)P<0.0001 OS-PPS3P<0.0001 OS-PFS34th line5.7 (4.0-7.4)15.3 (13.4-17.2)50.4 (27.4-73.4)P<0.0001 OS-PPS4P<0.0001 OS-PFS45th line3.9 (3.1-4.7)11.2 (7.8-14.5)65.9 (20.8-112.2)P = 0.004 OS-PPS5P<0.0001 OS-PFS56th line3.3 (2.6-4.0)8.2 (2.2-14.2)56.8 (48.7-64.9)P = 0.36 OS- PPS6P = 0.002 OS-PFS6 Conclusion: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until the 6th line of treatment. The utility of PPS as surrogate endpoint of OS is a valid hypothesis that could be evaluated in prospective trials of MBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-10-01.

e11123 Background: HER-2 is a 185 kd protein composed of three domains: a cytoplasmatic domain, a transmembrane domain and an extracellular domain (ECD). The ECD of HER-2 can be cleaved from the surface of breast cancer cells by matrix metalloproteases and released into the serum where it is detectable using an enzyme-linked immunosorbent assay (ELISA). The role of high level of ECD as a surrogate of response to trastuzumab treatment in metastatic setting is debated. Its role as predictive factor of response to lapatinib in HER-2 +metastatic breast cancer (MBC) progressing to trastuzumab is unexplored. Moreover it is unknown if high level of ECD in the adjuvant setting of HER-2+ pts with early breast cancer (EBC) could be an early marker of resistance to trastuzumab. Methods: serum was obtained from 40 HER-2 +pts: 19 MBC/21 EBC. Serum ECD was determined using commercial ELISA-kits (Oncogene Science). This ELISA uses a measure of 15 ng/ml as the upper limit of normal. A median of 3 samples was collected (2-5) every three months (+/-1 month). Median age was 55 (34-77), median PS was 1 (0-2) median number of therapy performed for MBC was 2 (2-6), 11 of these pts were treated with lapatinib for metastatic disease. Results: High level of ECD was detectable in 10 of MBC (25%) and in 4 of EBC pts (10%). Median PFS of MBC pts was 51 wks (CI 32-71). No relation was observed with high ECD levels and response to trastuzumab (p= 0.42) or lapatinib (p= 0.11) in MBC. HER-2 ECD level in EBC pts were not significantly associated with high istological grade (G1-G2 vs G3) (p=0.71), lymphonode involvement (N0-N1vsN2) (p= 0.63), degree of endocrine responsiveness respectively estrogen (<50% vs >50%) (p =0.5) and progesterone (<50% vs >50% )(p= 0.3), Ki67 high(≥ 15%) vs low (<15%) (p=0.9). Conclusions: ECD measure in our experience did not predict benefit to trastuzumab or lapatinib. The prognostic value of ECD in EBC needs a larger population to be validated. Our study is ongoing and we have planned to enroll exclusively EBC pts in order to define the role of ECD in this setting, if any.

1041 Background: The combination MC demonstrated to be effective and safe in MBC. Vinorelbine, in combination with anthracyclines, is an active drug as well. This is a multicenter randomized phase III trial to assess the efficacy and tolerability of the regimen MC versus MV. Methods: Patients (pts) must have LABC or MBC, PS (ECOG≤ 2) and measurable disease. Previous anthracyclines, as adjuvant, or endocrine therapy were allowed. Treatment A: M 60 mg/m2 plus C 600 mg/m2 on day1 of a 21 day cycle; treatment B: M 50 mg/m2 plus V 25 mg/m2 i.v. on day 1 and V 60 mg/m2 orally on day 8 on a 21 day cycle. Primary endpoint was PFS, secondary endpoints were ORR, safety and OS. Results: Between July 2006 and December 2010, 253 women were enrolled, 228 are currently evaluable for efficacy and safety. Patient characteristics: arm A 126 pts, median age 59 (range 37−71), ER status +/−/unk 77/18/5%, Her-2 status +/−/unk 7/81/12%, PS 0/1/2 70/25/5%, prior treatment with anthracyclines 34 pts (27%), dominant site of disease visceral 88 pts (71%). Arm B 127 pts, median age 58 (range 25−71), ER status +/−/unk 74/21/5%, Her−2 status +/−/unk 7/84/9%, PS 0/1/2 63/30/7%, prior treatment with anthracyclines 49 pts (39%), dominant site of disease visceral 92 pts (73%). Pts received a median of 6 cycles (range 2−10) of therapy. Median follow-up time was 66 weeks. Overall response rate was 53/116 (45.7% [95% CI, 36.5−54.7%]) for arm A and 51/112 (45.5% [95% CI, 36.3−54.7%]) for arm B respectively. Median PFS was 41 (95% CI, 32−51) and 34 (95% CI, 26−39) weeks respectively for arm A and arm B (p=0.0234). OS data are still not mature. With regard to toxicity, MV showed a slight increase of haematological and non hematological toxicity. No clinical signs of cardiotoxicity evaluated by echocardiogram were observed even in pts pretreated with anthracyclines. One patient in arm B died for sepsis, due to drug-related pancytopenia. Conclusions: Although MC and MV showed similar response rate, a significant difference in PFS was observed in favour of MC. The combination MC remains as an unbeaten “standard” in first line treatment of MBC.