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Background: Extending adjuvant endocrine treatment (ET) with aromatase inhibitors (AI) to 7-10 years decreases the risk of relapse in hormone receptor-positive (HR+) breast cancer (BC). However, such benefit comes at the price of higher incidence of skeletal and cardiovascular (CV) events. Biomarkers predicting such toxicities might help clinicians in tailoring adjuvant ET to patient’s needs. We conducted a prospective study to assess whether SNPs in the gene encoding for the aromatase enzyme (CYP19A1) affect the risk of skeletal and CV events in HR+ early BC patients enrolled in the GIM4 trial. Methods: The GIM4 trial randomized HR+ BC postmenopausal patients who had been already treated with 2-3 years of adjuvant tamoxifen to either 3-2 years or 5 years of adjuvant letrozole. Four SNPs of CYP19A1 were evaluated: rs10046, rs4646, rs479292 and rs727479. SNPs were genotyped through PCR on DNA obtained from patients’ peripheral blood samples. Skeletal and CV events were assessed from randomization in the GIM4 trial to last follow-up, disease recurrence or death. Skeletal events were defined as the onset of osteoporosis or bone fractures. CV events were defined as the onset of thrombosis, embolism, stroke, myocardial infarction, hearth failure, or arrythmia. Univariate and multivariate logistic regressions were performed to evaluate the association between SNPs and skeletal and CV events. Bonferroni correction for multiplicity was used for univariate SNPs association tests, with a corrected alpha of 0.012. Only associations with an alpha level Citation Format: Benedetta Conte, Chiara Molinelli, Giancarlo Bisagni, Antonio Durando, Giovanni Sanna, Stefania Gori, Ornella Garrone, Stefano Tamberi, Sabino De Placido, Francesco Schettini, Antonio Pazzola, Riccardo Ponzone, Filippo Montemurro, Gianluigi Lunardi, Rosario Notaro, Anna Turletti, Claudia Bighin, Francesca Poggio, Giulia Buzzatti, Matteo Lambertini, Luca Boni, Lucia Del Mastro. Single nucletotide polymorphisms of aromatase gene (CYP19A1) and toxicity of adjuvant aromatase inhibitors: A translational, prospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-03.

Background: TNBC shows a very bad prognosis: median time to relapse is 18 months and median overall survival (OS) is less than 24 months. Methods: AMBRA is a longitudinal cohort study, describing the choice of 1st- and subsequent treatments in HER2-ve MBC pts in the years 2012-2015. The present analysis is focused on TNBC pts (127 out of 879 evaluable; 14.4%) and CHT strategies, overall and according to adj treatment. Kaplan Meyer probability of survival from primary (DFS), 1st(PFS1) and 2nd(PFS2) progression and Time from last CHT and death were calculated for the whole population and according the main adj regimens. Results: Median age at primary diagnosis was 53 years. The most used regimens in the adj setting were anthra/taxane(tax) 50.7%, anthra 22.1% or others (CMF included) 20.6%. Median time to events was: DFS 23.2, PFS1 6.5 and PFS2 4.3 months, respectively. CHT choices in the metastatic setting according to adj treatment were: Adj Anthra-basedAdj Taxane-basedAdj other1st-lineTax* 57.6% - VRL/CAPE 18.2% - Plat 15.2% Other 3% - None 6.1%Tax* 46.2% - VRL/CAPE 24.6% Plat 24.6% - Other 4.6%Tax*52% - VRL/CAPE 16% - Anthra 16% - Anthra/Tax 8%2nd-lineTax**18.2% - Anthra 13.6% - VRL/CAPE 22.7% - Plat 27.3% - Erib 9.1% - Other 9.1%Tax**22% - VRL/CAPE 22% Plat 22% - Erib 14.6% - Other 17.1%VRL/CAPE 38.5% - Anthra 23.1% - Tax**23.1% - Plat 15.4%3rd lineVRL/CAPE 37.5% - Erib 25% - Anthra 18.8% - Tax***12.5% - Plat 6.3%Erib 26.9% - VRL/CAPE 23.1% - Plat 15.4% - Anthra 11.5% - Tax***11.5% - Other 11.5%VRL/CAPE 42.9% - Erib 28.6% - Plat 14.3% - Other 14.3%*docetaxel 8.4%, nab-paclitaxel 7%, paclitaxel 59%**docetaxel 7%, nab-paclitaxel 71.4%, paclitaxel 21%***docetaxel 20%, nab-paclitaxel 80%At a median follow up of 3.3 years 50% of pts are still alive. OS rates at 5 and 8 years from primary are 50% and 40%. OS rates from 1st progression are 50% and 20% at 22 and 40 months. Median OS (months) according to 1st line regimen was similar (ns) across the regimens (paclitaxel+bevacizumab: 17.8; Platinum-based: 14.1; CAPE/VRL: 16.3). Median time from last CHT and death was 1.5 months (29.6%< 1 month; 14% < 2 weeks) Conclusion: Our results show that taxanes play a crucial role in MBC even if used in 50% of Adj. CAPE/VRL, Platinum regimens and Eribuline are also widely used. Time from last CHT administration and Death is very short in 30% of cases Citation Format: Giorgio Mustacchi, Alessandra Beano, Alessandra Fabi, Lorenzo Livi, Antonio Bernardo, Ferdinando Riccardi, Paolo Marchetti, Ornella Garrone, Lucrezia Diodati, Laura Biganzoli, Monica Giordano, Anna Turletti, Livio Blasi, Andrea Milani, Clara Natoli, Marta Riemma, Alessia D'Alonzo, Grazia Arpino, Paolo Pronzato, Marina E Cazzaniga, on behalf of GIM-13 AMBRA Study Group. Triple negative (TNBC) metastatic breast cancer (MBC) patients (pts): Is chemotherapy (CHT) choice influenced by adjuvant (adj) treatments? Results from the GIM-13 AMBRA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-14.

BACKGROUND Pts with ABC have a diverse clinical course and OS rates vary significantly among pts. New strategies had potentially changed the natural history of these pts, however data from clinical studies are still lacking and Real-World Studies (RWS) are crucial in clinical outcome evaluation. PATIENTS AND METHODS AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve ABC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. The present analysis is focused on the description of Progression-Free Survival (PFS) and OS according to the biologic subtype in the deceased population. So far, 791/1500 pts have been registered into the study and 255 (32.2%) are evaluable. Time to event analysis between subtypes was evaluated by Cox-Mantel Hazard Ratio and Logrank Test. DFS by Wilcoxon Rank-Sum Test RESULTS Pts distribution according to molecular subtype was: Luminal A (86, 33.7%), Luminal B (107 (42.1%), TNBC (62, 24.3%). Median ages at diagnosis were 55.8, 52.9 and 55.1 years for the 3 subgroups, respectively. Mean DFS was significantly different according to the molecular subtypes: 87.28, 61.37 and 23.9 months. The difference between Luminal B and TNBC is statistically significant as well. Mean PFS of 1st-line therapy was 17.9 11.7 and 7.8 months respectively. Mean OS from 1stprogression was 32.9 24.2 and 15.8 months respectively. CONCLUSIONS Our data confirm in a RWS the different biological behaviour between Lum A and B. Metastatic life span is quite good for Luminals and disappointing for TNBC. Median time from last CHT and Death is quite short and similar. Luminal ALuminal BTNBCMean DFS (months)87.28 [95%CI: 72.9-101.7]61.37 [95%CI: 52.3-70.4] p=0003623.9 months [95%CI: 18.5-29.3] p=0.000000Mean PFS (months)17.9 [95%CI: 12.5-23.5]11.7 [95%CI:9.8-13.7]7.8 months [95%CI: 5.9-9.6]Mean OS from 1st progression (months)32.9 [95%CI:25.4-40.4]24.2 [95%CI: 21.3-26.9]15.8 [95%CI: 13.0-18.6]Median time from last CHT and Death (months)2.231.951.53Lum A/Lum B HR (p value)Lum A/TNBC HR (p value)Lum B/TNBC HR (p value)PFS 1st-Line0.73 (0.02)0.49 (0.0000)0.63 (0.003)OS from diagnosis (years)0.59 (0.0003)0.25 (0.0000)0.34 (0.0000)OS from 1st-PD0.72 (0.02)0.47 (0.0000)0.50 (0.0002) Citation Format: Marina Elena Cazzaniga, Sabino De Placido, Alessia D'Alonzo, Michela Piezzo, Clara Natoli, Andrea Milani, Alessandra Bologna, Massimiliano Alu, Anna Turletti, Palma Pugliese, Laura Biganzoli, Claudia De Angelis, Ornella Garrone, Paolo Marchetti, Ferdinando Riccardi, Antonio Bernardo, Lorenzo Livi, Alessandra Fabi, Cristiana Taverniti, Emanuela Romagnoli, Paolo Pronzato, Giorgio Mustacchi, on behalf of GIM-13 AMBRA Study Group. Progression-free survival (PFS) and overall survival (OS) in HER2-ve advanced breast cancer (ABC) patients (pts) according to the molecular subtype in the era of modern agents. Results from the GIM-13 AMBRA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-10.

This abstract was not presented at the conference. Citation Format: Cazzaniga ME, Blasi L, Pronzato P, Giordano M, Garrone O, Donadio M, Del Mastro L, Livi L, Natoli C, Michelotti A, Turletti A, Riccardi F, De Laurentiis M, Marchetti P, Montemurro F, Romagnoli E, De Placido S, Biganzoli L, Bologna A, Bria E, Mustacchi G. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-04.

Frequency of CHT regimens according to biological subtypes and Setting of treatmentLuminal TumoursSettingRegimenAdj (%)1st-line (%)2nd-line (%)3rd-line (%)anthra-based (w/o Taxanes)44.27.15.19.9Anthra-Taxanes30.52.60.50CMF-like17.50.61.02.1Taxane mono/combo*6.319.314.521.5Pacliataxel + Bevacizumab020.24.33.7Platinum-based03.61.70.8Capecitabine +/- Vinorelbine019.122.217.4Eribuline002.312.4 TNBCSettingRegimenAdj (%)1st-line (%)2nd-line (%)3rd-line (%)Anthra-based (w/o Taxanes)25.73.15.116.2Anthra-Taxanes36.11.100CMF-like8.22.15.10Taxane mono/combo*6.318.417.810.8Paclitaxel + Bevacizumab024.71.70Platinum-based020.622.42.7Capecitabine +/- Vinorelbine025.720.610.8Eribuline003.429.7**Irrespectively of biological subtype, nab-paclitaxel was used in 3.6%, 15.3% and 16.4% of cases in 1st, 2nd and 3rd line, respectively BACKGROUND Breast Cancer prognosis improved in the last years due both to early diagnosis and Adj treatments. The choice of CHT regimens should consider previous Adj treatments, pattern of relapse and biological subtype. There are few information on the treatment of MBC in the clinical practice outside controlled trials, last study has been published 15 yrs ago in Italy. PATIENTS AND METHODS The GIM13-AMBRA Study is a multicenter longitudinal cohort study, describing the choice of first and subsequent lines of treatment for MBC in HER2-ve pts. We are collecting data of 30 consecutive pts from 42 Italian Centres who developed the first relapse in the years 2012-2015 and were treated with CHT, (+/- previous endocrine treatments (HT)) for MBC. One of the secondary aims is to evaluate the Time to Treatment Change (TTC) (time between treatment start and its change for any reason) as surrogate endpoint for Time To Progression outside clinical trials. The present report is focused on the choice of treatments in any line and TTC, according to biological subtypes. . RESULTS For the present analysis, 683 pts are evaluable. Pts with Luminal A and B tumours received CHT and HT in 65.3% (Adjuvant), 21.7% (1st line), 7.1% (2nd line) and 7% (3rd line) of the cases. The most used regimens according to tumour subtype and line of treatment are shown in Table 1. Median TTC from 1st to 2nd line was 8.1 and 17.9 months in TNBC and Luminal tumours, respectively, whereas TTC from 2nd to 3rd line was 3.1 and 12.9 months, respectively. CONCLUSION Preliminary results of the AMBRA-GIM13 Italian observational study confirm that in most cases treatment for MBC is strongly related to the type of the Adj regimen, being the use of anthracyclines marginal in MBC, whereas taxanes are widely used in any line. In 1st line the most used regimens are Taxane and Bevacizumab or Capecitabine/Vinorelbine combinations. The last one remains the most used CHT in 2nd and 3rd lines. No difference have been observed according to biological subtype, except for Platinum-based regimens in TNBC. HT alone remains the preferred choice in 1st and 2nd line in Luminal cases. TTC seems to be a reliable surrogate for PFS in the “real world” practice . CHT still plays a crucial role in the treatment of MBC HER2-ve pts. Citation Format: Mustacchi G, Cazzaniga ME, Biganzoli L, De Laurentiis M, Del Mastro L, De Placido S, Donadio M, Garrone O, Giordano M, Latini L, Livi L, Marchetti P, Michelotti A, Montemurro F, Natoli C, Pronzato P, Riccardi F, Turletti A. First and further line choices of treatment for HER2-VE metastatic breast cancer (MBC) according to adjuvant treatment and biological subtype. Preliminary results of the observational “GIM-13 – AMBRA” Italian study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-07.

Background. Using a 2 × 2 factorial design, we compared the efficacy of two different schedules of chemotherapy (CT), dose-dense (DD) every 2 weeks versus standard duration every 3 weeks and the role of Fluorouracil (F) in addition to EC, in the adjuvant treatment of node positive BC pts. Patients and Methods. Node positive early BC pts younger than 70 years were eligible and randomly assigned to one of the following treatment arms: ARM A (4 courses of EC [90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM B (4 courses of FEC [600/90/600 mg/m2, on day 1, q 21] followed by 4 courses of T [175 mg/m2 on day 1, q 21]); ARM C (4 courses of EC [90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]); ARM D (4 courses of FEC [600/90/600 mg/m2, on day 1, q 14] followed by 4 courses of T [175 mg/m2 on day 1, q 14]). Pts enrolled in the DD arms (ARM C and D) received subcutaneous pegfilgrastim (6 mg) 24 hours after CT. HER2-positive pts enrolled after April 2006 received trastuzumab for 1 year at the end of CT. The primary study endpoint was disease free survival (DFS). Secondary endpoints included overall survival (OS) and toxicity. All analyses were conducted according to the intention-to-treat principle. Results. From April 2003 to July 2006, 2091 pts were enrolled (545 in ARM A, 544 in ARM B, 502 in ARM C, 500 in ARM D). The planned number of CT cycles was completed in 89% of pts in the DD group and in 88.1% of pts in the standard duration group. Pts treated with DD CT (ARM C + ARM D) experienced more frequently anemia (all grades: 67.2% vs 49.5%, p < .0001; G3-G4: 0.2% vs 1.4%, p = .004) and bone pain (53.5% vs 39.2%, p < .0001). Neutropenia occurred more frequently in standard duration arms (ARM A + ARM B): 66.7% vs 28.0%, p = < .0001. At a median follow up of 7.0 years, multivariate analysis, showed that DD treatments (ARM C + ARM D vs ARM A + ARM B) improved the primary endpoint, DFS (hazard ratio [HR] = 0.78; 95% CI 0.66-0.94; p = .007), and OS (HR = 0.68; 95% CI 0.52-0.87; p = .002). Conversely, the addition of F to EC did not improve clinical outcomes: the HR for DFS and OS (ARM A + ARM C vs ARM B + ARM D) were respectively 0.98 (95% CI 0.83-1.17; p = .85) and 0.93 (95% CI 0.73-1.19; p = .578). Subgroup analyses revealed that the benefits associated with DD CT were independent of hormone receptor status: in hormone receptor positive the HRs for DFS and OS were 0.80 (0.65-0.98) and 0.69 (0.51-0.93) respectively; in hormone receptor negative the HRs for DFS and OS were 0.67 (0.47-0.95) and 0.57 (0.36-0.92) respectively (p for interaction for DFS: 0.339; p for interaction for OS: 0.495). Pathological tumor size, nodal status (1-3 vs ≥ 4 positive nodes), histological grade and hormone receptor status were independently associate with DFS and OS. Conclusions. DD CT as adjuvant treatment in node positive BC pts, improves DFS and OS significantly. Conversely, the addition of F to EC does not improve clinical outcomes. (ClinicalTrials.gov number, NCT00433420). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-06.