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Introduction: Cancer-related fatigue (CRF) is a common symptom in patients with metastatic breast cancer (MBC), who receive taxane-based chemotherapy, and is associated with poor outcomes. Current guidelines recommend regular screening for fatigue from the time of cancer diagnosis, during treatment, and after treatment is completed to identify CRF early, lessen its negative impact on quality of life, and prevent potential treatment interruptions. Fatigue is a subjective symptom and is assessed through patient questionnaires such as the FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) survey. However, there is currently no gold standard or recommended survey to assess CRF. Methods: A prospective, non-interventional, multicenter trial is ongoing to validate the FACIT-Fatigue scale in patients with locally advanced or metastatic breast cancer who are eligible to receive taxane-based chemotherapy. Adult patients who have documented locally advanced or metastatic breast cancer (not amenable to surgical resection), and mild-to-moderate CRF indicated by a score of 1 to 6 on a scale from 0 to 10 (10 being most severe), who are candidates to receive cycle one of taxane chemotherapy will be included. Patients who are unable to take oral medications, have other cancer-related causes of fatigue, are using oral morphine ≥60 mg/day, or are participating in another clinical trial will be excluded. The primary objective is to evaluate the change in FACIT-Fatigue scores at baseline and at the end of the study (16 weeks). Secondary endpoints include evaluation of quality-of-life outcomes. A subgroup of patients will participate in a phone-based cognitive interview at the end of study visit or within 2 weeks of this visit to explore fatigue factors deemed important to patients. Results: The total planned sample size is estimated to be 60 patients to allow for a minimum clinically important difference (MCID) with a minimum precision of 1.9 points, and standard deviation of 3 points. The qualitative assessment will be conducted as part of a substudy inclusive of data from 30 patients. Conclusions: This study is currently ongoing to determine the MCID in FACIT-Fatigue scores in patients with locally advanced or MBC receiving treatment with taxane-based chemotherapy. Contact usmedinfo@dompe.com for information related to clinical trial sites and this study. Citation Format: Alessandra Fabi, Steven Hager, Laura Lourdes, Rebecca Pedersini, Paola Malaguti, Elizabeth M. Gavioli, Renuka Wakade, Pier Adelchi Ruffini, Francesco Sergio, Manuela Leone, Flavio Mantelli, Marcello Allegretti, Anne Blaes. Trial In Progress: An Evaluation of FACIT-Fatigue in Patients with Locally Advanced or Metastatic Breast Cancer receiving Treatment with Taxane-based Chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-16-01.

Background: Up to 6% of patients (pts) with HER2 positive (pos) metastatic breast cancer (MBC) experience a radiologic complete response (rCR) to a first line of therapy, but these results mostly derive from dated and/or limited cohorts. Aim of this study was to define the clinico-pathological characteristics of HER2 positive (pos) MBC pts experiencing a rCR. Methods: Pts were selected from the database of the GIM14 study (NCT02284581) and classified according to the best radiologic response obtained to the first line chemotherapy (CT) and upon time-to-treatment-failure (TTF). rCR was defined as complete response (CR) with a TTF > 3 months. The association across variables was tested through logistic regression and their prognostic impact in terms of overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Of the 3,423 pts included in the GIM14 study, 814 had HER2 pos MBC. After exclusion of pts treated with first line endocrine therapy and/or with TTF < 3 months, 656 pts were included in the present analysis, of which 96 (14.6%) experienced a rCR. Instead, the best response was a partial response for 295 pts (45.0%), stable disease for 221 pts (33.7%), and progression for 44 pts (6.7%). Most pts (59.8%) presented de novo MBC; 379 pts (57.8%) had visceral metastases (mets), 609 pts (92.8%) did not have central nervous system (CNS) involvement and 318 pts (48.5%) had only 1 site of distant mets. Also, 445 pts (67.9%) had hormone receptor (HR) pos disease, a HER2 3+ score at immunohistochemistry (IHC) was present in 59.8% of cases versus 40.2% with HER2 2+ at IHC and in situ hybridization (ISH) + disease. Taxanes were the main CT backbone (489 pts, 74.5%), 341 pts (52.0%) had received a Trastuzumab-Pertuzumab doublet. At multivariable analysis, higher odds of experiencing a rCR were reported for presence of non-visceral mets (OR 1.87, 95%CI 1.10-3.17), low number of metastatic sites (OR 2.42, 95%CI 0.80-7.33 for 1 site only) and HER2 3+ score at IHC (OR 1.80, 95%CI 1.09-2.98). Disease-free interval (DFI) was associated to rCR at univariable but not at multivariable analysis. HR status, CT backbone and type of anti-HER2 regimen were not associated with rCR neither at univariable nor at multivariable analysis. Median follow-up was 76.2 months. Amongst pts with TTF>12 months, those with rCR had a significantly higher OS compared to those not experiencing a rCR (median OS 133 and 90 months, respectively; p=0.0191). OS rates in pts with TTF ≥ 12 months were 97.8% at 2-year follow-up and 59.4% at 5-year follow-up. Instead, in pts with TTF ≥ 60 months, OS rates were 76.7% at 10-year follow-up. Amongst the 96 pts experiencing a CR, 38 had a rCR with TTF between 12 and 60 months, while 22 pts had a rCR with a TTF ≥ 60 months. The remaining pts had a CR with a TTF < 12 months. Pts with HR negative (neg) disease were found to be more likely to experience a rCR with a with TTF between 12 and 60 months, whilst pts with HR pos disease had a higher probability to experience a rCR with a TTF ≥ 60 months (p=0.0074). Pts with HER2 3+ score at IHC had a higher probability to achieve a rCR with a TTF ≥ 12 months compared to pts with HER2 2+ score at IHC and ISH + (p=0.0216). Age at diagnosis, menopausal status, DFI, number and site of mets, CT backbone and anti-HER2 therapy did not influence the duration of the rCR obtained. Conclusions: This study characterized a real-world cohort of HER2 positive MBC patients experiencing radiologic complete response to a first line treatment. Based on these results a clinical trial focused on liquid biopsy-based minimal residual disease is being designed. Novel anti-HER2 agents are gaining momentum as ever increasingly effective treatments and future de-escalation strategies after complete response will represent a growing need. Citation Format: Linda Cucciniello, Eva Blondeaux, Claudia Bighin, Simona Gasparro, Stefania Russo, Arianna Dri, Palma Pugliese, Andrea Fontana, Giuseppe Naso, Antonella Ferzi, Ferdinando Riccardi, Valentina Sini, Luca Boni, Alessandra Fabi, Filippo Montemurro, Michelino De Laurentiis, Grazia Arpino, Lucia Del Mastro, Lorenzo Gerratana, Fabio Puglisi. Assessing the clinico-pathological characteristics of HER2 positive metastatic breast cancer patients experiencing radiologic complete response in a nationwide cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-04.

Background: A previous study on 22 metastatic breast cancer (mBC) patients (Allegretti et al. Mol Cancer 2021) has associated drug resistance to Ado-trastuzumab emtansine (T-DM1) with two sets of genomic events: a) reversal of HER2 amplification, b) ‘oncogenic replacement’ of HER2 by alternative cancer drivers. To expand on this, we designed GIM21 (Gruppo Italiano Mammella) study. Materials and Methods: GIM21 is a multicentre, prospective study; tumor and circulating total nucleic acids (tTNA and ctTNA) were obtained from primary and metastatic lesions (n=36 altogether), as well as plasma samples (n=501), the latter serially collected coincident with medical imaging re-evaluations. tCNAs/ctTNAs were sequenced by ultra-deep, largely overlapping 50-gene panels on Ion Torrent Gene Studio S5. Ortogonal dPCR validation was by dPCR (Quant Studio 3D). ctTNAs were correlated with clinical readouts and patient outcomes. Results: from September 2018 to January 2022, 50 HER2+ mBC patients receiving T-DM1 as second-line treatment. Median time to progression was 6.5 months (range 2.0-27.2). As previously shown, only a minority of patients (9/50 – 18%) retained residual HER2 amplification in blood at baseline, likely due to HER2 counterselection during previous therapy lines; all of them (9/9) underwent further neutralization during T-DM1 treatment, but an HER2-neutral blood status was reached in only 5 patients. In contrast, 2 HER2-neutral patients acquired HER2 amplification, suggesting either insufficient T-DM1 pressure or an unprecedented clonal escape mechanism. Overall, the circulating HER2 status did not correlate with progression free survival (PFS), further highlighting a loss of clinically relevant HER2 oncogenic dependence. At baseline, 24 circulating mutations were detected in 29/50 (58%) patients, 9 of which did not overlap with tissue mutations. Of note, carrying a given aberration in either blood or tissue resulted in outcome trends (p=0.16), but no clear association with therapeutic response. Rather, it was serial monitoring (appearance of any aberration in the blood) that predicted a dismal clinical outcome in 16/41 (39%) patients, with a median time to progression of 2.8 months (2.2-3.9). Unfortunately, liquid biopsy (LB) was confirmed to miss most patients developing brain (3/3 patients) or skin (2/3 patients) metastases. Most circulating alterations present at progression (40/60) were actionable (OncoKB level < 3B) in 34/41 (82.9%) patients, suggesting that LB may guide therapeutic strategies in post-T-DM1 settings. Conclusions: GIM21 trial showed that LB accurately predicts clinical outcome and reveals actionable drivers of T-DM1 escape. The final analysis are ongoing. Citation Format: Alessandra Fabi, Matteo Allegretti, Elena Giordani, Gianluigi Ferretti, Grazia Arpino, Alberto Zambelli, Claudia Omarini, Ida Paris, Andrea Botticelli, Emilio Bria, Antonella Palazzo, Stefania Gori, Francesco Cognetti, Patrizio Giacomini. Liquid biopsy and Ado-trastuzumab emtansine (T-DM1): drug-resistance traits in the blood of HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-22-01.

Introduction: Fatigue is a debilitating and persistent condition of exhaustion that interferes with usual functioning. It is the most reported symptom across all cancer patients, and when related to the malignancy itself or to the neoplastic treatment, is referred to as cancer-related fatigue (CRF). Fatigue occurs in nearly all patients with metastatic breast cancer and is associated with poor clinical outcomes and worse quality-of-life. It is subjective and can be assessed from patient self-reports, such as the FACIT-Fatigue scale or Brief Fatigue Inventory, with no current gold-standard, which may lead to under reporting and lack of treatment intervention. Only since 2016, fatigue has been considered as a syndrome and included in the International Statistical Classification of Diseases, 10th edition, Clinical Modification (ICD-10-CM) according to specific criteria. The aim of this real-world data analysis was to describe the prevalence of fatigue, as reported by physicians using ICD-10-CM codes, in patients with locally advanced (Adv) or metastatic (Mtx) breast cancer (BC) undergoing single-agent taxane-based chemotherapy (CT), and to assess whether relapsed subjects had a higher prevalence versus those diagnosed de novo at an advanced stage. Methods: Electronic health records (EHR) were analyzed from TriNetX, a global research network containing real-world data from approximately 150 million patients in 115 Health Care Organizations (72 in the United States and 42 in the European Union). Using ICD-10-CM codes and structured data only (no medical notes), subjects were identified with a diagnosis of Adv-Mtx BC who underwent CT with single-agent taxane in 2020, 2021 and 2022 (first quarter). After splitting the cohort based on “relapsed” (second- or further line treatment) vs “de novo” (first-line treatment), we assessed the prevalence of fatigue (any type, R53.x) and CRF (R53.0) within the first 3 months after initiation of taxanes. Results: Among 379,880 BC patients under follow-up in 2021 across the 115 sites, 50,490 (13%) had Adv-Mtx BC, of whom 16,170 (32%) were diagnosed de novo and 34,330 (68%) experienced relapse. The proportion of patients undergoing single-agent taxane-based CT was 7.5% (1,220) and 13.4% (4,590), respectively. Almost one third (28%) of relapsed patients had previously received taxanes. The prevalence of fatigue (any type) and CRF was similar between the “de novo” and “relapsed” groups (24.6% vs 25.7% and 6.6% vs 5.4%, respectively). Overall, 27% and 21% of all fatigue was coded as CRF in the “de novo” and “relapsed” groups, respectively. No relevant differences were observed between 2020, 2021 and 2022 results. Conclusions: This real-world analysis reveals that at least one in four patients with Adv-Mtx BC undergoing taxane based CT suffer from fatigue, independent of disease history and other factors. Fatigue is an unmet medical need in patients with BC, particularly in patients receiving taxanes. Table. Fatigue prevalence (as per ICD-10-CM codes) within the first 3 months of single-agent taxane-based CT in patients with locally advanced or metastatic BC diagnosed “de novo” or relapsed in 2021 Citation Format: Anne Blaes, Elizabeth M. Gavioli, Renuka Wakade, Santiago Miracle, Giovanna DiTuri, Maria DePizzol, Pier Adelchi Ruffini, Francesco Sergio, Manuela Leone, Flavio Mantelli, Marcello Allegretti, Alessandra Fabi. Fatigue in patients with locally advanced or metastatic breast cancer undergoing single-agent taxane-based chemotherapy: de novo versus relapsed [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-09.

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Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.Experimental Design: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.Results: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P = 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P = 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P = 0.01), as defined by SISH (k = 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P = 0.04).Conclusions: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC. Clin Cancer Res; 17(7); 2055–64. ©2011 AACR.

Background. Adjuvant denosumab treatment improved bone-health related outcomes in early breast cancer (BC) patients with discordant survival results. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods. PubMed, CENTRAL, Scopus, Embase, clinicaltrials.gov and key oncological meetings websites were screened to identify potentially eligible RCTs based on the PICOs model: P) Participant: pre and postmenopausal early BC patients; I) Intervention: adjuvant denosumab; C) Comparator: placebo; O) Outcomes: Disease-free survival (DFS), Bone Metastasis-free survival (BMFS), Overall Survival (OS), fracture incidence and time to first fracture were adopted as survival endpoints, and Adverse Events, Serious Adverse Events, Osteonecrosis of the Jaw (ONJ) and Atypical Femur Fractures (AFF) as safety endpoints; S) Study design: phase III RCTs. Risk of bias was assessed with Cochrane Collaboration Risk of Bias Tool. Pooled hazard ratios (HR), risk ratios (RR), risk differences (RD) and respective confidence intervals (CI) were computed using both a fixed and a random effect model. Subgroup analyses based on menopausal status, hormone receptor and HER2 status and immunophenotype were performed. Results. Two phase III RCTs were included (ABCSG-18, D-CARE), for an overall population of 7929 early BC patients receiving denosumab or placebo. Denosumab addition to standard of care anticancer treatment showed no difference in DFS (HR 0.93; 95% CI 0.75-1.16, p=0.53), BMFS (HR 0.90; 95% CI 0.75-1.07, p=0.23) and OS (HR 0.92; 95% CI 0.72-1.17, p=0.49). In hormone receptor-positive/HER2 negative patients, denosumab significantly prolonged both DFS (HR 0.88; 95% CI 0.78-0.99, p=0.04) and BMFS (HR 0.83; 95% CI 0.71-0.97, p=0.02). No interaction was found between denosumab addition and menopausal status. Fracture incidence (RR 0.79; 95% CI 0.70-0.89, p< 0.01) and time to first fracture (HR 0.76; 95% CI 0.66-0.87, p< 0.01) were also improved with denosumab. No association between denosumab addition and overall toxicity was seen and no difference was observed in terms of ONJ and AFF between the 60mg every 6 months schedule and placebo (RD 0.001, 95% CI from -0.001 to 0.002, p=0.48) Conclusions. Findings from this meta-analysis validate the role of denosumab as a highly effective anti-resorptive agent. We provide robust evidence that its addition to standard anticancer treatment significantly improves survival outcomes in hormone receptor-positive/HER2 negative early BC patients, suggesting that the implementation of denosumab use in combination with endocrine therapy in this patient population should be reconsidered. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022332787. Citation Format: Luca Mastrantoni, Giovanna Garufi, Elena Di Monte, Noemi Maliziola, Mariangela Pasqualoni, Letizia Pontolillo, Sergio Pannunzio, Maria Chiara Cannizzaro, Armando Di Bello, Alessandra Fabi, Antonella Palazzo, Emilio Bria, Giampaolo Tortora, Armando Orlandi. Adjuvant Denosumab treatment in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-06.

Background: Several randomized clinical trials clearly demonstrated that adding palbociclib (P) to endocrine therapies (ET), such as letrozole (LT) or fulvestrant (FLV), significantly improves outcome both in first-line/endocrine sensitive and second-line/endocrine resistant hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC) patients (pts). The aims of the present study were to assess efficacy, activity and toxicity of P combined with either LT or FLV in a real world setting, and to study the efficacy and activity of treatments administered after progression to P + ET. Methods: Records of 245 consecutive HR+/HER2- MBC patients from 14 Italian cancer centers were reviewed in this observational study. Primary end-point was progression-free survival (PFS) obtained with P+ET; secondary end-points were overall response rates (ORR) and clinical benefit rate (CBR) obtained with P+ET and with post-progression treatments, as well as overall survival (OS), PFS to subsequent treatment lines and post-progression survival (PPS). Results: Overall 245 pts were treated with P+ET from April 2014. Of them, 116 (47%) received it in first-line setting, 70 (28%) in second-line and the rest (68 pts, 25%) in subsequent lines. Median age was 60 (35-80) years and median ECOG performance status was 0. Seventy-three pts (30%) had more than two metastatic sites and 75 (31%) had visceral metastasis. Ninenty-one (37%) pts received P+LT and 92 (37%) were treated with P+FLV. For 15 (6%) premenopausal pts an LHRH analogue was added to P+ET. In 77 (41%) patients a biopsy of a metastatic lesion was performed. Among the 116 pts treated in first-line setting, median PFS was 14.7 (95% CI 12.0-17.3) and 15.1 (95%CI 8.6-21.6) months for pts receiving P+LT and P+FLV, respectively. ORR was 48% (95% CI: 39-57%) and CBR was 75% (95% CI, 66-82%). Four (3%) complete responses (CR), 52 (45%) partial responses (PR), 31 (27%) stable disease (SD) and 11 (9%) progression disease (PD) were observed as best response; 18 pts were not yet evaluable. Among the 70 pts treated in second-line setting, median PFS was 10.8 (95%CI 0-24.3) and 7.9 (95%CI 3.3-12.5) months, for pts receiving P+LT and P+FLV, respectively. The ORR was 26% (95% CI: 16-38) and the CBR was 66% (95% CI, 53-76). One CR (1%), 17 PR (24%), 28 SD (40%) and 13 PD (18.5%) were observed as best response, while 9 were not yet evaluable. Best response was achieved after a median of 5 cycle. At time of the current analysis, 50 pts experienced PD during P+ET. Of them, 38 (76%) received chemotherapy (capecitabine, eribulin, nab-paclitaxel, paclitaxel+bevacizumab, vinoreline) and 12 (24%) ET. To date, only 5 pts progressed during these therapies, preventing us for evaluating secondary end-points regarding efficacy and activity. The most frequent adverse event (AE) was grade 3-4 neutropenia (31%), with febrile neutropenia reported in 5 (2%) cases. Main non-hematological AEs were fatigue and gastrointestinal symptoms (diarrhea and stypsis). Conclusions: Our findings confirm the efficacy and safety of P+ET as first/second-line treatment for HR+/HER2- MBC pts, even in a non-selected, real world population. Since data regarding the efficacy and activity of post-progression therapies were not mature at the time of the current analysis, they will be subsequently presented. Citation Format: Alessandra Fabi, Michelangelo Russillo, Mariangela Ciccarese, Simone Scagnoli, Francesco Schettini, Giuseppe Buono, Vito Lo Russo, Grazia Arpino, Rosalba Rossella, Giuseppina Sarobba, Marianna Giampaglia, Patrizia Pellegrini, Simonetta Stani, Michela Palleschi, Vincenzo Adamo, Francesca Morelli, Maria Agnese Fabbri, Cecilia Nistico, Gianluigi Ferretti, Giovanna Catania, Simona Pisegna, Diana Giannarelli, Francesco Cognetti. Real-world evidence of efficacy and activity of palbociclib plus endocrine therapy and post-progression treatments in HR+/HER2- metastatic breast cancer patients: The PALPract 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 P5-11-18.

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: Metastatic breast cancer (MBC) is an incurable disease and its treatment focuses mainly on prolonging patients (pts) survival and improving their quality of life. As a consequence, management of treatment related adverse events (AE) is very important. Eribulin (E) is a microtubule inhibitor that has shown to increase overall survival in pre-treated MBC pts. Its most common AEs are asthenia, neutropenia and peripheral neuropathy (N). PATIENTS AND METHODS: PAINTER (Clinical trial registration: NCT 0286403) is a multicenter, interventional, single-arm, phase IV study, aimed at surveying the tolerability of E (dose 1.4 mg/m2 day 1, 8 every 21 days) in an unselected MBC pts population pre-treated with taxanes and antracyclines. The secondary objective was to investigate the relationship between specific polymorphisms and incidence and severity of peripheral N. Toxicity (T) was reported according to the NCI CTCAE v4.0. Genomic DNA was isolated from whole blood samples (Maxwell whole blood DNA kit-Promega). 15 SNPs (Single Nucleotide Polymorphisms) were genotyped by Taqman specific assays. For SNPs analysis, we selected pts with available genomic data and who started E treatment N was evaluated by medical examination. RESULTS: From May 2014 to June 2018, 180 pts were enrolled from 20 Italian centres and 170 were evaluable. Pts and tumors characteristics were as follows: median age 60 years, ductal carcinoma 76.3%, visceral disease 68.8%, luminal type 64.7%, Her2 positive 18.3%, triple negative 17%, median previous treatment lines for MBC 5, median years from first diagnosis 6.1. Pts received E for 4.5 median cycles (Q1-Q3: 3.0-7.0; min-max: 1-23); 48.8% of pts experienced dose reduction, due to neutropenia (23.9%) and liver injury (12%) and 5.2% of pts discontinued E for T or for pts refusal. Previous neuropathy was reported in 15.9% of pts. Table 1 shows the incidence of expected AEs. N (all grades) during E treatment was reported in 33.9% of patients (G2-G3-G4: 15%). The risk of N occurrence in the first 5 cycles was 32.5% (for any grade N) and 13.2% (for severe N). Other G1-G4 toxicities were: dermatological in 8.6% pts, liver injury in 13.6%, pulmonary in 13.6%. Interestingly, 40.7% of pts reported pain, especially osteo-muscular, abdominal and at tumor site. Ten serious AEs were reported and only two were E related. 159 pts were evaluable for the analysis of polymorphism. Among the selected SNPs, the allelic variant T of the polymorphism rs2233335 in NDRG1 gene (Fisher test p CONCLUSIONS: PAINTER study offers a wide spectrum of information about E tolerability. Asthenia, neuropathy and neutropenia were the most common T, but few pts experienced severe AEs. Schedule and dosage modifications were common, as expected in pre-treated pts, but T rarely led to treatment discontinuation. Importantly, we found for first time that the SNPs rs2233335 (G/T and T/T) in NDRG1 gene and rs7214723 (CC and CT) in CAMKK1 gene were associated with E induced N. These data on pharmacogenetic testing, if validated, could allow a tailored treatment with E. Table 1. Incidence of expected AEsAEsG1G2G3G4Severe T (G3+G4) N=170n (%)n (%)n (%)n (%)% [%95%CI]Neuropathy 31 (18.2)20 (11.8)5 (2.9)0 (0.0)14.7 [9.75 - 20.9] #Neutropenia 15 (8.8)11 (6.5)16 (9.4)10 (5.9)15.3 [10.2 - 21.6]Constipation 16 (9.4)8 (4.7)1 (0.6)0 (0.0)0.6 [0.02 - 3.23]Alopecia 25 (14.7)13 (7.6)N.A.*N.A.*7.6 [4.13 - 12.7]Asthenia 38 (22.4)38 (22.4)10 (5.9)0 (0.0)5.9 [2.86 - 10.6]Nausea 19 (11.2)6 (3.5)0 (0.0)0 (0.0)0.0#: G2 for neuropathy and alopecia were considered as severe T *N.A.: Not applicable Citation Format: Nicla La Verde, Giovanna Damia, Ornella Garrone, Loretta D'Onofrio, Alessandra Fabi, Mariangela Ciccarese, Daniele Generali, Martina Nunzi, Elena Poletto, Paolo Pedrazzoli, Elisabetta Cretella, Giuseppa Scandurra, Icro Meattini, Alessandro S Bertolini, Luigi Cavanna, Emanuela Romagnoli, Lorenzo Legramandi, Federica Guffanti, Eliana Rulli, Anna Moretti, Barbara Bocci, Gabriella Farina. Eribulin tolerability and correlation between neuropathy and a set of polymorphisms in metastatic breast cancer patients. Results from the PAINTER (Polymorphism And Incidence of Toxicity in ERibulin treatment) 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 P5-14-01.

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.

Background. The management of small (≤ 1 cm), node-negative, HER2+ve BC is controversial, since data from randomized clinical trials specifically addressing the benefit of adjuvant systemic treatment with or without Trastuzumab in this setting are still lacking. The aims of this retrospective study are to assess how pts are managed in routinary clinical practice in Italy, whether clinical or biological features may influence the choice of adjuvant systemic therapy and if there is any difference in the outcome between treated and not treated pts. Patients and methods. Data of 268 consecutive pts who underwent surgery from January 2007 to December 2012 for HER2+ve, pT1a-b pN0 BC, were collected from 25 Italian centres. Descriptive statistical analyses and multivariate logistic regression models were used, with the aim of investigating the relationship between the baseline clinical and biological features and the adjuvant treatment strategy. Results. Pts characteristics were: median age 57, 69% postmenopausal status, 77% had conservative surgery, 32% pT1a, 68% pT1b, 48% G3, 66% ER+ve, 75% Ki67 ≥14%. Ninety percent of pts received adjuvant systemic therapy: 19% hormone therapy (HT) alone, 3% chemotherapy (CT) +/- HT, 64% Trastuzumab + CT +/- HT and 4% Trastuzumab + HT. At the multivariate analysis, the odds of being treated with adjuvant systemic therapy with or without Trastuzumab, resulted higher in presence of conservative surgery (p=0.002), pT1b (p Conclusion. This preliminary analysis shows that in Italy the majority of these pts received systemic adjuvant treatment and about 2/3 were treated with Trastuzumab. Pathological tumor size (pT1b) and negative hormone receptor status represent the main factors influencing the choice of including Trastuzumab in the adjuvant treatment. Survival data are still not mature to drive definitive conclusions about outcome. Citation Format: Stefania Gori, Monica Turazza, Simona Duranti, Elena Fiorio, Jennifer Foglietta, Marcella Gulisano, Ilaria Marcon, Marta Gubbiotti, Maria Giovanna Cavazzini, Simon Spazzapan, Valeria De Simone, Giancarlo Bisagni, Chiara Saggia, Luigi Cavanna, Emilio Bria, Laura Iezzi, Elisabetta Cretella, Patrizia Vici, Daniele Santini, Alessandra Fabi, Ornella Garrone, Antonella Ferro, Silvana Saracchini, Lucia Evangelisti, Sandro Barni, Lucia Mentuccia, Lucio Laudadio, Alessandro Inno, Gianluigi Lunardi, Francesca Coati, Luca Boni. The Promher Study: An observational Italian study on HER2+ve, pT1a-b, pN0, M0 breast cancer (BC) patients (pts) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-18-05.

Background The combination of the dual HER1/HER2 inhibitor lapatinib (L) and capecitabine (C) is a therapeutic option for patients (pts) with HER2+MBC whose disease progresses after treatment with the monoclonal antibody trastuzumab. At present time, no clinical or pathological factors except HER2 status are clearly recognized as predictors of the activity of LC. We conducted a retrospective analysis of pts with HER2-positive metastatic breast cancer receiving LC after trastuzumab failure to identify factors associated with resistance to LC. Materials and methods We collected clinical and pathological data from 151 pts with HER2+ MBC receiving LC after failing a prior trastuzumab-based treatment (either adjuvant or for metastatic disease) treated at 13 Italian Institutions between March 2007 and December 2013. Time to progression (TTP) and overall survival (OS), calculated by the Kaplan Meier (KM) method, were from LC treatment beginning to disease progression or to death in the absence of progression (TTP), and to the date of death or to the date of last follow-up (OS), respectively. LC resistance was defined as TTP from treatment initiation lower or equal to the median TTP for the overall population. KM curves were compared by the Log-rank test. Logistic regression analysis was used to study predictors of TTP below the median value for patients receiving LC. Analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL). Results At a median follow-up of 41 months (IQR 23-62), median TTP to LC therapy was 7 months (IQR 5.5-8.5) and median OS was 18 months (IQR 10-28). Fifteen pts were excluded because of short follow-up (i.e. on LC treatment and Conclusions A short time to progression during capecitabine and lapatinib (LC-R) is associated with reduced OS in patients failing prior trastuzumab based therapy for HER2+ MBC. Patients who had modest clinical benefit from previous trastuzumab-based therapy could experience LC-R indicating the possibility of primary resistance to anti HER2-treatment. For these patients, alternative targeting strategies are urgently needed. Citation Format: Stefania Gori, Valentina Rossi, Monica Turazza, Elena Fiorio, Alessandra Fabi, Giancarlo Bisagni, Jennifer Foglietta, Daniele Santini, Ida Pavese, Alberto Zambelli, Patrizia Vici, Vita Leonardi, Sandro Barni, Silvana Saracchini, Giuseppe Bogina, Simona Duranti, Alessandro Inno, Gianluigi Lunardi, Filippo Montemurro. Multi-institutional retrospective analysis of clinical and pathological factors predicting resistance to lapatinib-based therapy in HER2 positive metastatic breast cancer (HER2+ MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-25.

Background: The antibody-drug conjugate Trastuzumab emtansine (T-DM1, Kadcyla®) is standard of care in HER2+ breast cancer patients on clinical progression after Trastuzumab/Pertuzumab and taxanes. Despite considerable clinical benefits, most patients rapidly develop progressive disease due to adaptive resistance, the molecular bases of which remain largely unknown and/or controversial. Next generation sequencing (NGS) and digital PCR (dPCR) applied to serial biological samples obtained through liquid biopsy (LB) and re-biopsy (RB) offer a unique opportunity to intercept mutational trajectories and uncover molecular patterns linked to primary as well as adaptive resistance. Materials and methods: Tumor tissues (n=14), either from primary or metastatic lesions, and plasma samples (n=99) were collected, upon informed consent, from 9 breast cancer patients undergoing T-DM1 administration. Tissue (tDNA) and circulating tumor DNA (ctDNA) were extracted by the QIAmp DNA FFPE and CNA kits (Qiagen), respectively, and analyzed by ultra-deep sequencing and dPCR (IonTorrent S5 and QuantStudio 3D, LifeTechnologies) with commercial 400-gene panel and custom-designed dPCR assays. Genomic data were correlated with clinical imaging (CT/PET). Results: Six out 9 (66.7%) patients experienced progression within 1 year of treatment (mean 192±97 days), whereas the remaining 3 were stable at the last follow up (> 400 days). No correlation was found between outcome and HER2, ER or PR status in the latest available (prior to T-DM1) archival tissue, in which NGS revealed several pre-existing mutations, including some associated with resistance to ERBB2 blockade. LB analysis detected increases in both baseline and de novo occurring aberrations in 5/6 (83.4%) relapsing patients. As compared to clinical imaging, progression disease was anticipated by an average lead time of 1.9 months (range 0.7-2.8). Surprisingly, the sixth relapsing patient underwent rapid progression (3 months) in spite of decreased PIK3CA p.E545K in blood, further confirmed in the re-biopsy, thus suggesting heterogeneous response to T-DM1 across multiple cancer cell populations. Of note, we observed progressive accumulation of ERBB2 p.L755S (associated with Lapatinib resistance) in multiple biopsies of serial metastatic foci from a patient over 18 years of multimodal ERBB2 blockade. However, a single administration of T-DM1 resulted in ultra-fast (within few weeks) clearance of ERBB2 p.L755S ctDNA, and stabilization of two distinct 'bystander' TP53 ctDNAs (p.R273H and p.S241T). Conclusions: Non-invasive LB monitoring of a small cohort of T-DM1-treated patients provides proof of principle of intersecting mutational trajectories, anticipation and classification of resistance, as well as de novo appearance/clearance of resistance mutations. Thus, LB and RB may hint at disease evolution and successive lines of medical treatment. This work was supported by AIRC (Nuvenia Fellowship to MA, IG 19052 to PG), EU commission (grant #633937 – ULTRAPLACAD), and Regina Elena National Cancer Institute intramural funding. Citation Format: Allegretti M, Giordani E, Casini B, Romania P, Gasparro S, Russillo M, Gallo E, Buglioni S, Pescarmona E, Cognetti F, Ciliberto G, Giacomini P, Fabi A. Liquid biopsy and re-biopsy: Tracking mutational trajectories in HER2+ breast cancer patients undergoing T-DM1 treatment [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 P4-01-19.

Background: The ErbB2-targeting monoclonal antibody trastuzumab has remarkable efficacy in metastatic breast cancer (MBC) patients (pts) with HER2 overexpression or amplification (HER2+), either alone or in combination with chemotherapy. However, the response rate to trastuzumab is modest and not all pts derive benefit from this treatment. Predictive mechanisms of sensitivity and/or resistance are largely unknown. Recently, preclinical and limited clinical data showed that aberrant MET expression in MBC is a predictor of poor prognosis and is involved in trastuzumab resistance. Aim of the present study was to investigate whether increased gene copy number of MET or its ligand, the hepatocyte growth factor (HGF), affect trastuzumab sensitivity. Patients and Methods: This retrospective study included 130 HER2+ MBC pts treated with trastuzumab as monotherapy (N=21) or in combination with chemotherapy (N=109). Main inclusion criteria were presence of at least one measurable lesion and availability of paraffin-embedded tumor tissue from primary cancer. MET and HGF gene copy number (GCN) were assessed by fluorescence in situ hybridization (FISH). Receiver operating characteristic (ROC) analysis was used for identifying the best MET and HGF mean GCN cut-off. Results: In the whole population response rate (RR), including complete (CR) and partial response (PR) was 49.2%, disease control rate, including CR+PR+ stable disease (SD) was 76.2%, median time to progression (TTP) 9.4 months, and median survival (OS) 28.3 months. MET FISH analysis was successfully performed in all 130 cases. Median MET mean GCN was 2.96 (range 1.66−8.40), with no gene amplification. ROC curve identified a mean of 3.72 MET GCN as the optimal cut-off value for discriminating between sensitive (CR+PR+SD) and refractory pts (pts with progressive disease [PD] at the first disease assessment). MET FISH+ (N=36, mean ≥3.72) had a significantly higher PD rate (44.4% versus 16.0%; p=0.001) and a significantly shorter TTP (5.7 versus 9.9 months; HR 1.74 95% C.I. 1.16−2.62; p=0.006) than MET FISH- pts (N=94, mean Conclusions: High GCNs of MET or HGF associate with an increased risk of trastuzumab failure in HER2+ MBC. These data support a further development of combining anti-HER2 with anti-MET strategies in MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-07.

To the Editor: Nikkola et al. ([1][1]), examining pretreatment serum levels of matrix metalloproteinase 9 (MMP)-9 in 71 patients and MMP-1 and MMP-13 in 48 patients with advanced melanoma, showed that MMP-1, MMP-9, and MMP-13 “play important roles at different phases of metastatic melanoma spread

Abstract #4088 BACKGROUND PALO is a selective and potent serotonin antagonist, with a pharmacologically different structure and binding affinity compared to older 5-HT3 receptors antagonists. Multiple studies with PALO have demonstrated better efficacy in preventing emesis throughout the 5 days after moderately and highly emetogenic chemotherapy (CT) compared to ondansetron, dolasetron or granisetron. METHODS This was a phase 4, double-blind, randomized, multicenter, parallel study, in 300 CT naïve patients with breast cancer receiving cyclophosphamide Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4088.

To the Editors: In a recent issue of Clinical Cancer Research , Santini and co-workers ([1][1]) assert that zoledronic acid (ZA) may inhibit several antiangiogenic-related cascades and its metronomic administration could represent a new potential therapy targeting the endothelial-tumor-stroma