The aim of the study was to analyze the modification of total and regional body composition in early breast cancer patients treated with aromatase inhibitors (AIs). This is a prospective, single-center, observational, longitudinal study. Four-hundred and twenty-eight patients treated with adjuvant aromatase inhibitors were enrolled at the Medical Oncology and Breast Unit of Spedali Civili Hospital in Brescia from September 2014 to June 2022. Several body composition parameters including total and regional fat and lean body mass were investigated with dual-energy X-ray absorptiometry (DXA) scan at baseline and after 18 months of treatment with aromatase inhibitors. A significant increase in fat body mass (mean + 7.2

Women with early breast cancer (EBC) receiving adjuvant aromatase inhibitors (AIs) are frequently given denosumab (Den) with the aim to both reducing fracture risk and preventing disease recurrence. However, a proportion of these patients still experience fragility fractures despite Den, and risk factors in women treated with upfront AIs and Den have never been explored. Dual-X-ray absorptiometry (DXA) at baseline conditions and after 18 months was performed in 237 consecutive patients undergoing adjuvant therapy with AIs and Den (60 mg subcutaneously every 6 months), recruited at the Breast Unit of the ASST-Spedali Civili of Brescia. The following baseline parameters were evaluated to predict the risk of vertebral fracture (VF) as assessed by a morphometric approach on DXA images: age, body mass index (BMI), history of previous fractures, family history of fractures, smoking, alcohol consumption, FRAX score, DXA-derived bone mineral density (BMD), trabecular bone score (TBS), percentage fat body mass (%FBM), lean body mass (LBM), appendicular mass index (ALMI). Seventeen out of 237 (7%) reported incident VFs after 18 months of AIs therapy. At the univariate analysis, incident VFs were significantly associated with high FRAX score (Odd Ratio [OR]: 3.786, 95% Confidence interval [CI]: 1.039-13.790), previous VFs (OR: 3.217, 95% CI: 1.185-8.736), high %FBM (OR 5.174, 95% CI: 1.418-18.873, p=0.013), high android fat (OR 9.580, 95% CI: 1.174-78.209, p=0.035) and low ALMI/FBM ratio (OR 0.252, 95% CI: 0.078-0.818, p=0.022). Only high %FBM was independently associated to incident VFs at multivariate analysis. FBM is an independent risk factor for VFs in EBC patients treated with adjuvant AIs and Den. A supervised physical activity aiming at avoiding obesity and potentiating LBM could synergize with Den in preventing AI-induced bone fragility.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the standard of care treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- aBC). However, optimal treatment after progression on CDK4/6i has not been established and real-world data may help to fill this knowledge gap. Two hundred twenty-one patients with HR+/HER2- aBC treated with CDK4/6i plus ET at Medical Oncology and Breast Unit of ASST Spedali Civili Brescia from November 2017 to February 2023 were retrospectively evaluated. The main aim of the study was to evaluate clinical benefit rate (CBR) of the subsequent lines of therapy after CDK4/6i. Secondary aims were to report objective response rate (ORR) and progression-free survival (PFS). Median age was 60 years. CDK4/6i were administered as first-line therapy in 26.2%, as second-line in 40.3%, and as a third or further line in 33.5% of patients. After a median follow-up of 30.5 months, 126 patients (57%) experienced a disease progression and had a median PFS of 14.3 months: the most common sites of disease progression were liver (42%), bone (31.7%), and lungs (12%). A total of 112 patients received a further line of treatment: 13.4% received ET monotherapy (either fulvestrant or aromatase inhibitor), 13.4% ET plus target therapy (such as an mTOR inhibitor), 42% metronomic chemotherapy (CT), and 31.2% received intravenous CT (either anthracyclines, taxanes, eribulin, or other drugs). A higher CBR was noted in patients receiving metronomic CT, in comparison to intravenous CT and ET with or without target therapy (51.9% vs 31.5% vs 16.7%, respectively, p = 0.04). Median PFS after CDK4/6i was 9 months (5.93-12.06). Associations between ORR after CDK4/6i and patients' clinical characteristics will be presented at the meeting. These single-center retrospective data suggest that CT, in particular metronomic CT, may show better favorable outcomes after progression on CDK4/6i. Evidence from prospective, randomized clinical trial is warranted.

CDK4/6 inhibitors (CDK4/6-i) combined with endocrine therapy (ET) have become the standard of care for ER-positive HER2-negative metastatic breast cancer (mBC) and have significantly improved clinical outcomes. In long-term survivors, bone health is a crucial issue. The risk of fragility fractures associated to ET is well established. Preclinical data suggest that CDK4/6-i could have an effect on the bone microenvironment, however no clinical data are available. The aim of this study is to evaluate vertebral fractures (VFs) progression in mBC patients (pts) treated with CDK4/6-i combined with ET. A series of 211 ER-positive HER2-negative mBC pts treated with CDK4/6-i combined with ET and referred to Medical Oncology and Breast Unit of ASST Spedali Civili, Brescia, from 2017 to 2023 were enrolled. VFs were evaluated through CT scan at baseline and at subsequent CT restaging and were classified as mild, moderate and severe based on Genant classification. All pts were female, with a median age of 55.5 years (32-79). CDK4/6-i were administered as first, second and third line of treatment in 113 (53.6%), 65 (30.8%) and 6 (2.9%) pts, respectively. ETs were aromatase inhibitor and fulvestrant in 104 (49.3%) and 107 (50.7%) pts, respectively. At baseline, 141 patients (66.8%) had bone metastases. 102 (48.3%) pts were treated with bone-targeted agents (BTAs). VFs in healthy bone were detected in 22 (10.4%) pts at baseline and in 37 (17.5%) pts after a mFU of 24 months (p<0.001), with 21 (10.1%) pts experiencing VFs progression, defined as the onset of a new VF of the worsening of pre-existing VFs. Among pts receiving BTAs, VFs in healthy bone were detected in 6 (5.9%) pts at baseline and in 16 (15.7%) pts after a mFU of 24 months (p = 0.006). Correlations between fracture risk factors and VFs progression as well as the comparison between patients receiving and patients not receiving BTAs will be presented at the meeting. These data suggest a detrimental effect of CDK4/6-i and ET combination on bone health. Studies with a prospective design, a control arm with ET alone and longer follow-up are needed to better explore this issue.

The study of production and depletion of chemical species is vital for the understanding of composition and evolution of planetary atmospheres. We present an implementation of photoinduced isotopic effects into the PATMO code (Avila et al., 2021) code designed for the study of stable isotopes and photo-induced isotopic effects. With respect to the original code PATMO, where the photochemistry was not included, this report extends capability of the model to set photochemical processes for stable isotopes and thus enhancing its applicability. The PATMO code is flexible and allows the edition of new chemical reactions without need for hard code them. We also test how changes in spectral resolution affects the calculation of isotopic effects during the photodissociation of oxygen. We found that for a highly structured spectrum such as the Schumann-Runge band a spectral resolution larger than 0.005 nm is necessary for accurately modeling these isotopic effects. We also show that SO2 and SO photodissociation couples in a complex shielding fashion and significantly affects the photo-induced isotopic effects. The model was also benchmarked against today's Earth atmosphere, where the solar UV flux and the ozone profile of the US Standard atmosphere of 1976 was reproduced with the simple Chapman mechanism and improved with the implementation of NOx and HOx radicals.

Aromatase inhibitors (AIs) represents the standard adjuvant therapy of postmenopausal early breast cancer (EBC) survivors. AIs reduce estrogen and increase androgen levels through inhibition of aromatase enzyme, with possible consequent alterations in body composition (BC). The primary aim of the current study was to examine the impact of nutrition education intervention on BC in EBC patients (pts) treated with AIs. This is a retrospective, two-cohort single-center study. 194 EBC pts referred to the Oncology Department and Breast Unit of ASST Spedali Civili Brescia were enrolled (from 2017 to 2019): 97 patients received a nutrition education intervention by a trained dietician (cohort A) while 97 did not (cohort B). BC was measured by using Dual-Energy X-ray Absorptiometry (DEXA) scan at baseline and after 18 months of AI therapy. The following data were also collected through validated questionnaires: dietary habits with food frequency questionnaire (FFQ), adherence to a Mediterranean diet with PREDIMED questionnaire, physical activity with IPAQ questionnaire, WCRF/AICR diet score was also calculated. Cohorts A compared to the cohorts B pts modified their diet through a reduction in consumption of animal fat, red meat, processed meat, added sugar, bread, cereals, and a rise in fruit and vegetables consumption. Moreover, cohort A pts were more adherent to the Mediterranean diet (PREDIMED score: 8.7 vs 7.2; p<0.001) and to the WCRF's recommendations (WCRF score: 4.4 vs 3.4; p<0.001), increasing slightly physical activity. A significant increase in body weight (65.2 vs 66.4, p<0.001) and BMI (24.8 vs 25.3, p<0.001) was observed only in cohort B. Regardless changing in dietary habits, an increase in adipose tissue and a reduction in lean body mass was observed in both cohorts at 18 months. A significant change in BC with loss of lean mass and an increase of fat body mass was observed during adjuvant AI-therapy despite the nutrition education intervention adopted in cohort A. These findings indicate that a diet, without prescription of tailored physical activity, is not sufficient to prevent change in BC during AI therapies.

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) represent the standard of care for HR-positive, HER2-negative metastatic breast cancer (mBC). ET increases the risk of bone fracture; moreover, it has been suggested that CDK6 plays a critical role in controlling osteoblast, osteoclast, and chondrocyte differentiation. The possible impact of ET combined with CDK4/6i on bone health has not already been explored. The main aim of the current study is to evaluate the proportion and the evolution of vertebral fractures (VFs) in mBC HR+ patients (pts) treated with ET combined with CDK4/6i. We retrospectively evaluated a series of 170 mBC HR+ treated with combination of CDK4/6i + ET at Medical Oncology and Breast Unit of ASST Spedali Civili, Brescia, from 2017 to 2020. VFs were evaluated through CT scan at baseline and at subsequent restaging CT and classified in mild, moderate, and severe based on Genant classification. Patients were all female, with a median age of 64 years (38-81). Endocrine treatments were Aromatase Inhibitor (AI) and fulvestrant in 44 and 66 % of pts respectively. CDKi treatments administered were palbocilib, ribociclib, and abemaciclib in 61.2, 22.9, and 15,9% of cases respectively. At baseline, 60.0% of pts had visceral metastases, 54.7% had bone metastases and 44.7% were receiving bone modified agents (BMA). More than half of pts experienced partial response as best response to CDK4/6i treatment and almost all (90%) had clinical benefit. VFs were detected at baseline in 22.9% of cases and after a median follow-up (mfu) of 27 months in 37.1% of pts. Nearly 20% of pts had a worsening of VFs in terms of new VFs or worsening of pre-existing VFs. Correlation between fracture risk factors with the onset of new or worsening of pre-existing VFs as well as the interaction with BMA will be present at the meeting. These preliminary data suggest a detrimental effect of the combination of CDK4/6i and ET on bone health after a mfu of 27 months. To our knowledge, this is the first study analyzing the impact of CDK4/6i on bone health. Studies with longer follow-up are needed to better explore this issue.

Background: Multigene assays (MGAs) are extremely useful tools for tailoring adjuvant chemotherapy (CT) in ER+/HER2- EBC. In July 2019, Lombardy was the first Region in Italy to reimburse MGAs for patients (pts) with formal indication to receive adjuvant CT after multidisciplinary discussion. Here, we report real-world MGAs experience in 6 referral Cancer Centers in Lombardy.

A free-floating planet (FFP) is a planetary-mass object that orbits around a non-stellar massive object (e.g. a brown dwarf) or around the Galactic Centre. The presence of exomoons orbiting FFPs has been theoretically predicted by several models. Under specific conditions, these moons are able to retain an atmosphere capable of ensuring the long-term thermal stability of liquid water on their surface. We model this environment with a one-dimensional radiative-convective code coupled to a gas-phase chemical network including cosmic rays and ion-neutral reactions. We find that, under specific conditions and assuming stable orbital parameters over time, liquid water can be formed on the surface of the exomoon. The final amount of water for an Earth-mass exomoon is smaller than the amount of water in Earth oceans, but enough to host the potential development of primordial life. The chemical equilibrium time-scale is controlled by cosmic rays, the main ionization driver in our model of the exomoon atmosphere.

Background: Late recurrences in postmenopausal women with hormone receptor-positive breast cancers remain an important challenge. Avoidance or delayed development of resistance represents the main objective in extended endocrine therapy (ET). In animal models, resistance was reversed with restoration of circulating estrogen levels during interruption of letrozole treatment. This phase III, randomized, open-label Study of Letrozole Extension (SOLE) studied the effect of extended intermittent letrozole treatment in comparison with continuous letrozole. In parallel, the SOLE estrogen substudy (SOLE-EST) analyzed the levels of estrogen during the interruption of treatment. Patients and methods: SOLE enrolled 4884 postmenopausal women with hormone receptor-positive, lymph node positive, operable breast cancer between December 2007 and October 2012 and among them, 104 patients were enrolled in SOLE-EST. They must have undergone local treatment and have completed 4-6 years of adjuvant ET. Patients were randomized between continuous letrozole (2.5 mg/day orally for 5 years) and intermittent letrozole treatment (2.5 mg/day for 9 months followed by a 3-month interruption in years 1-4 and then 2.5 mg/day during all of year 5). Results: Intention-to-treat population included 4851 women in SOLE (n 1/4 2425 in the intermittent and n 1/4 2426 in the continuous letrozole groups) and 103 women in SOLE-EST (n 1/4 78 in the intermittent and n 1/4 25 in the continuous letrozole groups). After a median follow-up of 84 months, 7-year disease-free survival (DFS) was 81.4% in the intermittent group and 81.5% in the continuous group (hazard ratio: 1.03, 95% confidence interval: 0.91-1.17). Reported adverse events were similar in both groups. Circulating estrogen recovery was demonstrated within 6 weeks after the stop of letrozole treatment. Conclusions: Extended adjuvant ET by intermittent administration of letrozole did not improve DFS compared with continuous use, despite the recovery of circulating estrogen levels. The similar DFS coupled with previously reported quality-of-life advantages suggest intermittent extended treatment is a valid option for patients who require or prefer a treatment interruption.

In the last years prognosis of cancer patients (pts) has been improved, but the develop of cardiotoxicity (CTX) in pts with low CV risk treated with cumulative doses of Anthracycline (ANT) considered safe, led to investigate the possible role of the genetic profile in the onset of CTX. To study the role of some single nucleotide polymorphisms (SNPs) as predictive genetic markers of individual susceptibility to CTX induced by anticancer treatment. We have enrolled women with non-metastatic breast cancer who had to start a therapy with ANT. The presence of a known heart disease, a previous mediastinal irradiation and a previous treatment with ANT, were the main exclusion criteria. All pts underwent complete cardiological evaluation (ECG, echo) before the beginning of the therapy (T0), after each ANT cycle and every 3 months up to 1 year of follow-up after the end of treatment. During each visit, we performed the determination of troponin I (TnI) and NT-proBNP. The genetic profile of each pts was also investigated, analyzing 6 SNPs belonging to 3 different genes (two for each genes) coding for enzymes or enzyme systems involved in the metabolism of ANT. DNA extraction from blood samples was performed using the QIAamp DNA Mini kit (QIAGEN). The DNA extracted was genotyped (by performing TaqMan SNP Genotyping assays) identifying 3 possible variants for each SNPs: homozygosity for the protective and “at risk” variant and heterozygosity. 179 pts finished the follow-up and from the analysis of the trend of biomarkers we found that 53 pts (30%) showed a significant increase in TnI (>0.04ng/mL) or less than this cut-off but persistently >0.015ng/mL in at least 2 measurements (“TnI+ group”), in the remaining 126 pts the TnI remained non-measurable (“TnI− group”); 76 pts (43%) showed NT-proBNP values ≥125 ng/L in at least two consecutive determinations (“NT-proBNP + group”),in the remaining 57% of pts this increase was not detected (“NT-proBNP - group”). Comparing “TnI+ group” to “TnI− group” we observed that only the genotyping of the SNPs rs1149222 (G/T) belonging to the ABCB4 gene is distributed differently in the two groups, in particular the homozygosity for the “at risk” variant (G/G) was present in 13% of the pts of the “TnI+ group” vs 5% in the “TnI− group” (p 0.06). The results of the comparison of “NT-proBNP+ group” vs “NT-proBNP− group”, showed that the genotyping of the SNPs rs6759892 (G/T) belonging to the UGT1A6 gene was distributed differently, the homozygosity for the “at risk” variant (G/G) was present in 28% of the “NT-proBNP+ group” vs 17% in the “NT-proBNP− group” (p 0.07). Together with the baseline clinical evaluation, genetic markers could contribute to the early identification of pts at high risk of developing CTX especially following treatment with ANT and they could support future therapeutic decisions and the planning of taylored strategies for the prevention of the CTX development. Type of funding source: None

Food habits change in early breast cancer (EBC) patients (pts) during chemotherapy has been poorly studied in literature. Primary aim of this study was to evaluate food preferences and consumption of EBC pts before and after adjuvant chemotherapy. We conducted a prospective cohort study at Medical Oncology Unit and Breast Unit of ASST Spedali Civili of Brescia (Italy). From April 2014 to June 2018 205 EBC pts were enrolled and interviewed by a dietician to assess quantity and frequency of several foods, soft drinks and alcoholic beverages intake. Additional 205 EBC patients, who were not interviewed by the dietitian, were selected as control group. A statistically significant reduction of the following foods and beverage was reported after chemotherapy: pasta or rice (p=0.009), bread (p<0.0001), breadsticks/crackers (p<0.0001), red meat (p<0.0001), fat salami (p<0.0001), lean salami (p<0.0001), fresh cheese (p=0.039), aged cheese (p=0.011), yogurt (p=0.022), sugar (p<0.0001), soft drinks (p=0.003), alcoholic beverages such as wine (p<0.0001), beer (p<0.0001), schnapps (p<0.001), and condiments such as oil (p=0.029) and butter (0.014). Conversely, fruit consumption consistently increased (p<0.0001). As a consequence of these food habits changes body weight did not increase, despite reduction in physical activity. Body weight remained stable also in the control group, indirectly suggesting that food habit variation was not influenced by the dietician. This prospective study shows that EBC patients tend to adopt “healthier dietary patterns” during adjuvant chemotherapy leading to a non-change in body weight, despite reduction of physical activity.

Objectives: Most research addressing needs and concerns of young patients with breast cancer (<40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns. Materials and methods: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern. Results: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039). Conclusions: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions. (C) 2019 Elsevier Ltd. All rights reserved.

Abstract Background: Alopecia is a common and distressing adverse effect in breast cancer (BC) patients (pts) receiving adjuvant chemotherapy. The aim of the study was to assess the effectiveness and safety of this device to prevent chemotherapy-induced alopecia in early breast cancer patients (EBCP) receiving adjuvant treatment. The quality of life of pts was also evaluated. Patients and methods: From January to December 2016, a sensor-controlled scalp cooling system (DigniCap:Sysmex Europe GmbH, Norderstedt, Germany) was proposed to a consecutive group of EBCP submitted to adjuvant chemotherapy at the Breast Unit of Spedali Civili Hospital of Brescia. Degree of hair loss was assessed by two nurse using Dean's alopecia scale by digital photographs at baseline and each chemotherapy cycle. EORTC QLQ-C30 questionnaire and self-reported visual analogical scale (VAS) of symptoms (anxiety, tone of mood, fatigue, nausea,well-being, activity) were collected at baseline and after the first two cycles of chemotherapy. Results: 70 pts were enrolled and 49 (70%) completed the chemotherapy plan and were evaluable. Median age was 51 years, 8 pts (16%) received neoadjuvant and 41 pts (84%) adjuvant chemotherapy, 21 (43%) were treated with 4 cycle of chemotherapy (TC, EC or paclitaxel alone), and 28 (57%) with sequential chemotherapy with antracycline and taxane +- trastuzumab. Fifteen pts (30%) stopped the treatment because of loss of hair in 9 pts, for headache in 4 pts and for other problems in 2 pts. At the end of chemotherapy, 13 pts (27%) had no loss of hair (Dean score 0), 25 pts (51%) had a minimal loss of hair (Dean score 1), 9 pts (18%) had a 50% hair loss (Dean score 2), 2 pts (4%) had a 75% hair loss (Dean score 3). No pts reported hair loss more than 75% (Dean score 4). There wasn't a significant difference between mean score value of QLQ-C30 at baseline and after chemotherapy and between the groups with and without hair loss. VAS documented an increase of fatigue and decrease of anxiety from baseline to final evaluation. The side effects presented with the use of DigniCap were the following: headache in 32% of pts and cold feeling in 57 % of pts. Conclusion: Scalp cooling with cold caps appears to be effective in preventing CIA among the majority of women undergoing treatment chemotherapy. The quality of life did not change in scalp-cooled patients. Acknowledgments: a thank you to the ESA association that donated Dignicap to Oncology Department. Citation Format: Vassalli L, Pedersini R, Romelli M, Claps M, Fornaro C, Conti E, Tagliani M, Baronchelli A, Ragni D, Lombardi E, Rodella F, Amoroso V, Berruti A, Simoncini EL. Efficacy and patient acceptability of the DigniCaP ScalpCooler to prevent hair loss in breast cancer patients receiving adjuvant chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-19.

Background The International Breast Cancer Study Group (IBCSG), in collaboration with Dana-Farber Cancer Institute, conducts the European (EU) cohort of the Helping Ourselves Helping Others (HOHO) study. HOHO is a prospective longitudinal cohort study investigating short and long-term treatment and fertility concerns in young women with breast cancer (BC): most previous studies have been retrospective. Patients and methods From Aug 2009-Jan 2016, 300 patients aged 18-40 yrs with early/advanced BC were enrolled within 6 mos of diagnosis in 18 Centers in Italy and Switzerland. Patients are surveyed every 6 mos the first 3 yrs and yearly for additional 7 yrs. 297 baseline surveys were evaluable. The baseline survey includes sociodemographic and treatment data, and a modified Fertility Issues Survey (including fertility concerns, preservation, outcome and impact on treatment decisions). Clinical data are collected yearly. We qualitatively compare the EU baseline data with the published US data (Ruddy et al, JCO 32:1151, 2014). Results Almost two thirds of women in both cohorts discussed future fertility with their doctors at diagnosis. Fertility concerns, desire for future pregnancy (both before disease onset and at time of survey) and steps to reduce infertility were all more common in the EU cohort. EU women were also more concerned about fertility when discussing treatment and about a possible relapse affecting their ability to care for future children. Conclusion Many young women with newly diagnosed BC have concerns about fertility, which may affect their treatment decisions. In the EU cohort fewer women had a stable relationship and children before diagnosis, potentially influencing their treatment decisions and encouraging fertility preservation. Concerns about a possible relapse could partly explain the decrease in their pregnancy desire after the disease. Differences between EU and US women seem to emerge: continued data collection will determine if they persist over time. The POSITIVE Trial (IBCSG 48-14/ALLIANCE 221405) will address safety and outcome of pregnancy after BC. Citation Format: Pagani O, Bagnardi V, Ruggeri M, Bianco N, Gallerani E, Buser K, Giordano M, Gianni L, Rabaglio M, Freschi A, Cretella E, Clerico M, Amadori D, Simoncini E, Ciccarese M, Rauch D, Glaus A, Berardi R, Franzetti A, Ruddy KJ, Gelber S, Partridge AH, Colleoni M. HOHO study: How European and US young women cope with breast cancer and fertility concerns [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 PD6-04.

Abstract Background:The expanded access “BALLET” study has been designed toevaluate the safety of EVE plus EXE combination in hormone receptor-positive (HR+), human epidermal growth factor-receptor-2-negative (HER2-) metastatic Breast Cancer (mBC). The Italian population was predominantly enrolled in trial. Patients and methods: Patients has been included according to the inclusion and exclusion criteria provided previously in the BALLET study. The aim of our analysis was the safety everolimus and exemestane analysed in two sets of population: a subpopulation including only patients who never received chemotherapy in metastatic setting (416 patients – 36.1% of the safety population) and a subpopulation including only patients who received at least one chemotherapy in metastatic setting, whatever the line of treatment (735 patients – 63.9%). Results:One thousand two hundred seventy nine (1279) Italian female patients were screened, 1153 (90.1% of the screened set) out of these were included in the analysis and 1151 (90.0% of the screened set) were included in the safety population. 1116 (97.0% of the safety population) prematurely discontinued the study drug and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%) and adverse event(s) (16.1%). The mean duration of study treatment exposure was 158.3±106.79 days (median 139.5) for exemestane and 153.9±108.48 days (median 135.0) for everolimus with a treatment compliance (higher than 90%) of 94.4% and 58.6% and (lower than 60%) of 0.1% and 15.1% for exemestane and everolimus, respectively. 92.5% of patients of the safety population (91.1% and . 93.3% patients without and with chemotherapy respectively) experienced at least one adverse event: gastrointestinal disorders” (67.3% vs. 64.6% in without and with chemo group); general disorders (48.6% vs. 48.3%); metabolism and nutrition disorders (35.6% vs. 37.4%) and skin and subcutaneous tissue disorders (32.2% vs. 27.5%). The incidence of everolimus related adverse events was higher (83.9%) when compared to those which occurred with exemestane. The most commonly reported adverse event was stomatitis (51.3% of patients) with 22.5% Grade 1; 18.2% Grade 2; 10.5% Grade 3; 0.2% Grade 4. The 49.7% of the patients experienced at least one stomatitis related to everolimus. No relevant difference was observed between the two groups of patients without and with chemo in metastatic setting. Conclusions: The administration of chemotherapy before starting EVE plus EXE combination did not affect the safety profile of EXE/EVE in the treatment of mBC. The stomatitis is the most frequent and relevant adverse event to be clinically focused on. Citation Format: Generali D, Bordonaro R, Febbraro A, Madoffa A, Romito S, Michelotti A, Savastano C, Mariani G, Tondini C, Piovano P, Iona MT, Bighin C, Roviello G, Ascione G, Goffredo F, Sartori D, Frassoldati A, Simoncini E. Safety of the combination of everolimus plus exemestane in the Italian cohort of patients enrolled in the expanded access “BALLET” 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 P4-22-17.

Background: In MONALEESA-2 (NCT01958021), patients (pts) with HR+, HER2– ABC who received first-line ribociclib (RIBO; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) had a significant improvement in progression-free survival (PFS) compared with placebo (PBO) + LET at the first analysis (Hortobagyi G, et al. N Engl J Med. 2016;375(18):1738-1748). Here we report updated efficacy and safety data from MONALEESA-2, with an additional 11 months follow-up (median follow-up duration of 26.4 months). Methods: MONALEESA-2 is a randomized (1:1) phase 3 trial evaluating RIBO (600 mg/day, 3-weeks-on/1-week-off) + LET (2.5 mg/day, continuous) vs PBO + LET in postmenopausal women with HR+, HER2– ABC with no prior therapy for advanced disease. The primary endpoint was locally assessed PFS. Secondary endpoints included overall survival (OS; key), overall response rate (ORR), clinical benefit rate (CBR), and safety. Results: 668 pts were enrolled (RIBO + LET: 334; PBO + LET: 334). The updated PFS analysis confirmed treatment benefit from the combination of RIBO + LET (hazard ratio = 0.568; 95% CI: 0.457-0.704; P = 9.63x10−8). Median PFS with RIBO + LET was 25.3 months (95% CI: 23.0-30.3) vs 16.0 months (95% CI: 13.4-18.2) with PBO + LET. Treatment benefit was consistent across all pt subgroups, including age, prior therapies, de novo ABC, and visceral metastasis. OS results remained immature. Common grade 3/4 adverse events (=15% of pts; RIBO + LET vs PBO + LET) included decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), and decreased lymphocytes (16.2% vs 3.9%). Conclusions: Despite a long median PFS with PBO + LET, the updated analyses confirmed that first-line treatment with RIBO + LET significantly prolongs PFS in postmenopausal women with HR+, HER2– ABC. The safety profile of RIBO + LET remains manageable.

Abstract Background The International Breast Cancer Study Group (IBCSG), in collaboration with Dana-Farber Cancer Institute, conducts the European (EU) cohort of the Helping Ourselves Helping Others (HOHO) study. HOHO is a prospective longitudinal cohort study investigating short and long-term treatment and fertility concerns in young women with breast cancer (BC): most previous studies have been retrospective. Patients and methods From Aug 2009-Jan 2016, 300 patients aged 18-40 yrs with early/advanced BC were enrolled within 6 mos of diagnosis in 18 Centers in Italy and Switzerland. Patients are surveyed every 6 mos the first 3 yrs and yearly for additional 7 yrs. 297 baseline surveys were evaluable. The baseline survey includes sociodemographic and treatment data, and a modified Fertility Issues Survey (including fertility concerns, preservation, outcome and impact on treatment decisions). Clinical data are collected yearly. We qualitatively compare the EU baseline data with the published US data (Ruddy et al, JCO 32:1151, 2014). Results Almost two thirds of women in both cohorts discussed future fertility with their doctors at diagnosis. Fertility concerns, desire for future pregnancy (both before disease onset and at time of survey) and steps to reduce infertility were all more common in the EU cohort. EU women were also more concerned about fertility when discussing treatment and about a possible relapse affecting their ability to care for future children. Conclusion Many young women with newly diagnosed BC have concerns about fertility, which may affect their treatment decisions. In the EU cohort fewer women had a stable relationship and children before diagnosis, potentially influencing their treatment decisions and encouraging fertility preservation. Concerns about a possible relapse could partly explain the decrease in their pregnancy desire after the disease. Differences between EU and US women seem to emerge: continued data collection will determine if they persist over time. The POSITIVE Trial (IBCSG 48-14/ALLIANCE 221405) will address safety and outcome of pregnancy after BC. USEUN (%)N (%)620 (100)297 (100)Age <35 yrs229 (37)95 (32)Married or in a significant relationship474 (76)192 (65)Had children before BC diagnosis409 (66)160 (54)Never pregnant158 (25)119 (40)Before BC wished to have future children230 (37)161 (54)At time of survey wished to have future children160 (26)120 (40)If wanted more children, concerned about: (some women indicated more than one)n=160n=120Caring for them if BC recurred27 (17)45 (38)Children having increased risk of developing cancer70 (44)38 (32)Pregnancy would increase risk of recurrence-56 (47)Reason(s) for not wanting more children: (some women indicated more than one)n=460n=177Caring for them if BC recurred18 (4)28 (16)Children having increased risk of developing cancer33 (7)22 (12)Pregnancy would increase risk of recurrence59 (13)16 (9)Concerned about fertility at time of treatment decision-making (a little, somewhat or a lot)319 (51)189 (64)Fertility concerns affected treatment decision (a little, somewhat or a lot)160 (26)115 (39)Took special steps to decrease infertility65 (10)79 (27)Discussed fertility issues with physician before starting therapy424 (68)198 (67) Citation Format: Pagani O, Bagnardi V, Ruggeri M, Bianco N, Gallerani E, Buser K, Giordano M, Gianni L, Rabaglio M, Freschi A, Cretella E, Clerico M, Amadori D, Simoncini E, Ciccarese M, Rauch D, Glaus A, Berardi R, Franzetti A, Ruddy KJ, Gelber S, Partridge AH, Colleoni M. HOHO study: How European and US young women cope with breast cancer and fertility concerns [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 PD6-04.

BACKGROUND This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2. PATIENTS AND METHODS Post-menopausal women aged ≥18 years with hormone receptor-positive, human epidermal growth factor-receptor-2-negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity. RESULTS The median treatment duration was 5.1 months [95% confidence interval (CI) 4.8-5.6] for EVE and 5.3 months (95% CI 4.8-5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related. CONCLUSIONS This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2. CLINICAL TRIAL REGISTRATION EudraCT Number: 2012-000073-23.