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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: The poor prognostic value of young age at diagnosis appears to vary according to breast cancer (BC) subtype, although this has been studied mainly in hormone receptor-positive (HR+) disease, with limited data in HER2-positive BC and short follow-up. Limited evidence exists on the benefit of anti-HER2 therapy in young women with BC. Considering that age has historically been a rationale for overtreatment, further research efforts to better investigate the prognostic and predictive value of age are needed. This exploratory analysis conducted within the APHINITY trial aimed to investigate the prognostic and predictive value of young age in patients with HER2-positive early BC treated with modern chemotherapy and concurrent anti-HER2 targeted treatment. Methods: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in patients with HER2-positive early BC investigating the benefit of adding pertuzumab to adjuvant chemotherapy plus trastuzumab. For the purpose of the present analysis, 40 years of age at enrolment was used as the cut-off to distinguish between young (≤40 years) and older (>40 years) cohorts. Invasive disease-free survival (IDFS) was the primary endpoint. IDFS irrespective of treatment arm and the benefit of adding pertuzumab were evaluated in all patients by comparing the young and older cohorts and then according to centrally-assessed hormone receptor status. Univariate and multivariable Cox proportional hazard models were used to assess the prognostic and predictive value of age on IDFS as a continuous and dichotomous variable (≤40 years and >40 years). A STEPP analysis was also conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results: Out of 4,804 patients in the ITT population, 768 (16.0%) were ≤40 years at enrollment. Patients in the young cohort were less overweight/obese (29.3% vs. 50.4%), underwent mastectomy more frequently (63.2% vs. 52.6%), had higher rates of node positive (66.4% vs. 61.8%) and HR+ (71.7% vs. 64.9%) BC as compared to those in the older cohort (all p Citation Format: Matteo Lambertini, Shona Fielding, Sibylle Loibl, Wolfgang Janni, Emma Clark, Maria Alice Franzoi, Debora Fumagalli, Carmela Caballero, Luca Arecco, Sharon Salomoni, Noam F Ponde, Francesca Poggio, Hee Jeong Kim, Cynthia Villarreal-Garza, Olivia Pagani, Shani Paluch-Shimon, Alberto Ballestrero, Lucia Del Mastro, Martine Piccart, Jose Bines, Ann H. Partridge, Evandro de Azambuja. Effect of young age at diagnosis on clinical outcomes and efficacy of anti-HER2 targeted therapy in patients with HER2-positive early breast cancer: Results from the APHINITY trial [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 P2-13-42.

Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors. A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status. Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT. HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12–1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15–2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80–1.77, p = 0.390). Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed.

Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/mBetween April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred.Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer.

Survivorship has become a crucial component in breast cancer care. For women who have not completed their family planning, conceiving at the end of anticancer treatments should not be discouraged but might be challenging. Oncofertility counseling should be offered at the time of diagnosis to all patients, in order to inform them about the potential treatment-induced gonadotoxicity as well as the available strategies for fertility preservation, thus allowing to increase the chances of a future pregnancy. This article reports an updated overview on the current state of the art on pregnancy in women with prior breast cancer diagnosis and treatment, with a main focus on the issues faced by patients with history of hormone receptor-positive disease and BRCA carriers.

Background Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. Methods APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. Results Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. Conclusions In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status.

Objective: Neoadjuvant chemotherapy has become the preferred treatment in HER2-positive early breast cancer. Several trials investigated the neoadjuvant efficacy of dual HER2 blockade with anthracycline-free chemotherapy, whereas few data are available on single-agent trastuzumab and anthracycline-based regimens, which represent the standard of care in the adjuvant setting. This phase II, single-arm trial assessed anthracycline-based chemotherapy and trastuzumab as neoadjuvant treatment for high-risk HER2-positive breast cancer. Methods: Forty-three patients with stage II–III HER2-positive breast cancer were treated with 4 courses of neoadjuvant 5-fluorouracil 600 mg/m2, epirubicin 90 mg/m2, cyclophosphamide 600 mg/m2 (FEC ×4) every 21 days, followed by 12 courses of weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/Kg IV (loading dose 4 mg/kg). Results: Pathologic complete response (pCR) was observed in 22 (51%) of 43 patients. After a median follow-up of 6 years, the 5-year disease-free survival and overall survival were 85.8% (95% confidence interval 75.9%–97%) and 89.6% (80.4%–99.8%), respectively. A temporary decrease in left ventricular ejection fraction was observed in two patients. No cardiac death or congestive heart failure occurred. One patient died due to febrile neutropenia. Conclusions: FEC ×4 followed by paclitaxel and trastuzumab was associated with high pCR rates and favorable long-term outcomes. However, this regimen was associated with relevant hematologic toxicity.

Summary Background The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen. Methods This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2–3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635. Findings Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed. Interpretation In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer. Funding Novartis and the Italian Ministry of Health. Translation For the Italian translation of the abstract see Supplementary Materials section.

Background We evaluated the efficacy and safety of the nontaxane microtubule dynamics inhibitor eribulin plus the humanized anti-VEGF monoclonal antibody bevacizumab in a novel second-line chemotherapy scheme in HER2-negative metastatic breast cancer (MBC) patients progressing after first-line paclitaxel and bevacizumab. Patients and methods This is a multicenter, single-arm, Simon's two-stage, phase II study. The primary endpoint was the overall response rate, considered as the sum of partial and complete response based on the best overall response rate (BORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Results A total of 58 of the 61 patients enrolled in the study were evaluable for efficacy. The BORR was 24.6% (95% CI 14.5-37.3). The clinical benefit rate was 32.8% (95% CI 21.3-46.0). The median PFS was 6.2 months (95% CI 4.0-7.8), and median OS was 14.8 months (95% CI 12.6-22.8). Overall, adverse events (AEs) were clinically manageable and the most common AEs were fatigue, paresthesia, and neutropenia. Quality of life was well preserved in most patients. Conclusions The results of this study suggest that second-line therapy with bevacizumab in combination with eribulin has a meaningful clinical activity and may represent a potential therapeutic option for patients with HER2-negative MBC., Highlights • Bevacizumab + chemotherapy improved progression-free survival in HER2-negative metastatic breast cancer (MBC) patients. • Eribulin monotherapy improved overall survival in patients with anthracycline- and taxane-pretreated MBC. • The GIM11-BERGI trial assessed the efficacy and safety of eribulin + bevacizumab as second-line treatment for HER2-MBC. • Eribulin + bevacizumab showed to be a safe and active treatment after progression to first-line paclitaxel + bevacizumab.

Introduction: The prognosis of patients with HER2-positive early breast cancer has radically improved after the introduction of (neo)adjuvant anti-HER2 targeted therapy. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate combining the anticancer properties of the anti-HER2 agent trastuzumab and the antineoplastic cytotoxic drug DM1. After demonstrating to be an effective and safe treatment for patients with HER2-positive advanced breast cancer, the development of T-DM1 has moved to the early setting.Areas covered: The aim of this review is to explore the current role of T-DM1 in the treatment landscape of HER2-positive early breast cancer, focusing specifically on the efficacy and safety data available in the adjuvant setting.Expert opinion: T-DM1 is an effective and safe treatment option in the adjuvant setting for patients with HER2-positive breast cancer without pathologic complete response after standard neoadjuvant chemotherapy plus anti-HER2 targeted therapy. With the availability of more effective anti-HER2 targeted agents, including T-DM1, there is an urgent need for more chemotherapy de-escalation research efforts in the early setting.

Simple Summary The diagnosis of cancer during pregnancy represents a challenging situation, leading to a complex management aimed at maximizing the curative approach to the patient while minimizing potential adverse events towards the baby. The different treatment strategies can be combined according to the gestational age. However, to date, data regarding breast cancer care occurring during pregnancy are mostly derived from retrospective reports, thus the inclusion of patients in dedicated registries is advisable. This review aims at reporting the updates on this topic, giving insights into practical aspects of the management of this uncommon and demanding situation. Abstract The diagnosis of breast cancer during pregnancy represents a challenging situation for the patient, her caregivers and physicians. Pregnancy adds complexity to oncological treatment planning, as many therapies can be potentially dangerous to the fetus. Therefore, a multidisciplinary approach is needed to offer a proper care for obtaining the best possible outcomes for the mother and the future child. Breast surgery is feasible throughout the pregnancy while radiotherapy should be postponed after delivery. Administration of chemotherapy is considered safe and can be given during the second and third trimesters, while it is contraindicated in the first trimester due to the high risk of fetal malformations. Endocrine therapy and targeted agents are not recommended during the whole pregnancy period; however, limited data are available on the use of the majority of new anticancer drugs in this context. The aim of the current review is to provide an update on the current state of art about the management of women diagnosed with breast cancer during pregnancy.

Background: During the COVID-19 outbreak oncological care has been reorganized to face the emergency Cancer patients have been reported to be at higher risk of severe events related to SARS-CoV-2 Moreover, there are concerns of a possible interference between immune checkpoint inhibitors (ICIs) and the pathogenesis of the infection Methods: A 22-item questionnaire was shared with Italian physicians managing ICIs, between May 6 and 16, 2020 This survey aimed at exploring the perception about SARS-CoV-2 related risks in cancer patients receiving ICIs, and whether the management of these patients has been modified during COVID-19 outbreak Results: Respondents were 104, with a median age of 35 5 years, mainly females (58 7%), mainly working in Northern Italy (71%) 47 1% of respondents were afraid that a synergism could exist between ICIs mechanism of action and SARS-CoV-2 pathogenesis, leading to worse outcomes 97 1% of respondents would not deny an ICI only for the possible occurrence of COVID-19 Measures for reducing hospital visits have been adopted by choosing the ICIs schedule with fewer administrations, adopting the highest labeled dose of each drug (55 8%) and/or choosing, among different ICIs for the same indication, the one with the longer interval between cycles (30 8%) 53 8% of respondents suggested the need to test for SARS-CoV-2 every cancer patient candidate to ICIs Regarding differential diagnosis between immune-related adverse events (irAEs) and COVID-19 manifestations, 71 2% of respondents declared to manage a patient with onset of dyspnea and cough like a COVID-19 patient until otherwise proven (ie, waiting for the result of SARS-CoV-2 test before doing other diagnostic or therapeutic procedures);however, 96 2% did not reduce the use of steroids to manage irAEs during the pandemic No major impact of COVID-19 on physicians’ attitudes towards the use of ICIs to manage specific clinical situations in different cancer types (ie, lung, breast, melanoma, urothelial) was observed Conclusions: These results highlight the uncertainty of physicians dealing with ICIs in cancer patients during COVID-19 outbreak, supporting the need of dedicated studies on this regard Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: M Tagliamento: Travel/Accommodation/Expenses: Roche, Bristol-Myers Squibb, Astra Zeneca, Takeda F Poggio: Travel/Accommodation/Expenses: Takeda, Ely Lilly;Honoraria (self): Merck Sharp & Dohme, Ely Lilly, Novartis L Del Mastro: Honoraria (self): Roche, Pfeizer, Ipsen, Eli Lilly, Novartis, Takeda, Merck Sharp & Dohme, Genomic Health, Seattle Genetics;Non-remunerated activity/ies: Celgene M Di Maio: Advisory/Consultancy: Eisai, Takeda, Janssen, Astellas, Pfizer, AstraZeneca M Lambertini: Advisory/Consultancy: Roche and Ely Lilly;Speaker Bureau/Expert testimony: Roche, Takeda and Theramex All other authors have declared no conflicts of interest

Background: Coronavirus disease 2019 (COVID-19) outbreak is changing the approach of medical oncologists to cancer management However, the real impact on cancer care and its potential negative consequences are currently unknown Methods: A 29-multiple choice question anonymous online survey was shared with members of the Italian Association of Medical Oncology and the Italian Breast Cancer Study Group on April 3, 2020 The objectives of the survey were to investigate the attitudes and practice of Italian oncologists before and during COVID-19 outbreak on three relevant areas in breast cancer care: 1) (neo)adjuvant setting;2) metastatic setting;3) research activities Results: The survey was completed by 165 oncologists, of whom 121 (73 3 %) worked in Breast Units In the (neo)adjuvant setting, compared to before the emergency, a lower rate of oncologists adopted during COVID-19 outbreak weekly paclitaxel (68 5% vs 93 9%, P< 001) and dose-dense schedule for anthracycline-based chemotherapy (43% vs 58 8%, P< 001) In the metastatic setting, compared to before the emergency, a lower number of oncologists adopted during COVID-19 outbreak first-line weekly paclitaxel for HER2-positive disease (41 8% vs 53 9%, P= 002) or CDK4/6 inhibitors for luminal tumors with less aggressive characteristics (55 8% vs 80 0%, P< 001) A significant change was also observed in terms of delaying the timing for monitoring CDK4/6 inhibitors therapy, assessing treatment response with imaging and flushing central venous devices Clinical research and scientific activities were reduced in 80 3% and 80 1% of respondents previously involved in these activities, respectively Conclusions: Most of the changes in the attitudes and practice of Italian oncologists were reasonable responses to the current health emergency without expected major negative impact on patients’ outcomes, although some potentially alarming signals of undertreatment were observed These data invite developing cautious recommendations to help oncologists ensuring continuous effective and safe cancer care Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: F Poggio: Travel/Accommodation/Expenses: Takeda;Honoraria (self), Travel/Accommodation/Expenses: Ely Lilly;Honoraria (self): Merck Sharp & Dohme;Novartis M Tagliamento: Travel/Accommodation/Expenses: Roche;Bristol-Myers Squibb;AstraZeneca;Takeda;Honoraria (self): Novartis M Di Maio: Research grant/Funding (institution): Tesaro GSK;Honoraria (self), Advisory/Consultancy: AstraZeneca;Janssen;Astellas;Eisai;Pfizer;Merck Sharp & Dohme;Takeda L Del Mastro: Advisory/Consultancy: Roche;Novartis;Eisai;Pfizer;AstraZeneca;Ipsen;Eli Lilly;MSD;Seattle Genetics;Genomic Health M Lambertini: Advisory/Consultancy: Roche;Honoraria (self): Theramex, Eli Lilly All other authors have declared no conflicts of interest

On 11 March 2020, WHO declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to be a pandemic, and the related syndrome was then named coronavirus disease 2019 (COVID-19). As of 6 April 2020, 1 211 203 confirmed cases and 67 596 deaths have been recorded worldwide, Italy being one of the worst affected countries so far. Frail patients, such as elderly people or those with underlying conditions, are at higher risk of complications related to COVID-19.1 The burden of SARS-CoV-2 infection among patients with cancer has not been established yet, but their potential immunocompromised state is of concern.2 Preliminary data suggest an increased risk of developing infection-related severe events (ie, admission to the intensive care unit, mechanical ventilation or death) in the case of antitumour treatment administration within two weeks before COVID-19 diagnosis. Therefore, the authors suggested that treatment strategies likely to cause immunosuppression should be avoided or retained at decreased dosages.3 The Italian directives for the management of onco-haematological patients on therapy during the …

Background: Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes. Methods: Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%. Results: Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]). Conclusions: No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.

Breast cancer is the most frequent malignancy diagnosed in premenopausal women. In this age group, breast tumors tend to be diagnosed at more advanced stages and to harbor more aggressive biological features. In addition, specific age-related issues including genetic counseling, fertility preservation, impact on social and couple relationships, working life, and management of long-term side effects should be considered highly relevant when managing early breast cancer in premenopausal women. Therefore, the care of these patients is particularly complex and a multidisciplinary approach is mandatory. The present review summarizes the current state of art in the adjuvant systemic treatment of premenopausal women with early breast cancer focusing on the optimal chemotherapy, endocrine therapy, and targeted therapy approaches in this specific patient population.

PURPOSE: To investigate the impact of the COVID-19 outbreak on the attitudes and practice of Italian oncologists toward breast cancer care and related research activities. METHODS: A 29-question anonymous online survey was sent by e-mail to members of the Italian Association of Medical Oncology and the Italian Breast Cancer Study Group on April 3, 2020. Only medical oncologists (both those in training and specialists) were invited to complete the questionnaire. RESULTS: Out of 165 responding oncologists, 121 (73.3.%) worked in breast units. In the (neo)adjuvant setting, compared with before the emergency, fewer oncologists adopted weekly paclitaxel (68.5% v 93.9%) and a dose-dense schedule for anthracycline-based chemotherapy (43% v 58.8%) during the COVID-19 outbreak. In the metastatic setting, compared with before the emergency, fewer oncologists adopted first-line weekly paclitaxel for HER2-positive disease (41.8% v 53.9%) or CDK4/6 inhibitors for luminal tumors with less-aggressive characteristics (55.8% v 80.0%) during the COVID-19 outbreak. A significant change was also observed in delaying the timing for monitoring therapy with CDK4/6 inhibitors, assessing treatment response with imaging tests, and flushing central venous devices. Clinical research and scientific activities were reduced in 80.3% and 80.1% of respondents previously implicated in these activities, respectively. CONCLUSION: Medical oncologists face many challenges in providing cancer care during the COVID-19 outbreak. Although most of the changes in their attitudes and practice were reasonable responses to the current health care emergency without expected major negative impact on patient outcomes, some potentially alarming signals of undertreatment were observed.

Background In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease (a € trastuzumab-free interval', TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models. Results Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred 12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233). Conclusions TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: In HER2-positive breast cancer patients, timing from the end of (neo)adjuvant trastuzumab (T)-based therapy to diagnosis of metastatic breast cancer is the key factor in determining the optimal first-line treatment. There is currently lack of clear evidence to support the possible prognostic role of this interval and 12 months has been mostly empirically used. The present analysis aimed to investigate patterns of relapse, first-line choice and survival outcomes of patients with HER2-positive early breast cancer who relapsed after adjuvant T-based therapy depending on T-free interval (TFI, i.e. timing from end of adjuvant T to diagnosis of distant metastases). Methods: In ALTTO, HER2-positive early breast cancer patients were randomized to 1 year of either T alone, lapatinib (L) alone, their sequence (T–>L) or their combination (T+L). This exploratory analysis included only pts in the T or T+L arms who experienced a distant disease-free survival (DDFS) event. Two cohorts of patients were defined depending on TFI: group A (TFI of 12 months). Baseline characteristics, patterns of relapse, first-line choice and overall survival (OS) were compared. OS was defined as time between date of DDFS event to death; age at diagnosis, tumor size and hormone receptor status were the variables included in the final multivariate models. Results: Out of 8,381 patients included in ALTTO, 404 patients in the T and T+L arms developed a DDFS event, of whom 201 occurred 12 months (group B) after the end of adjuvant T. Patients in group A were older (p=0.013), had larger tumors (p=0.004) and more frequently hormone receptor-negative disease (p Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. 12 months) following adjuvant T-based therapy had inferior OS after the diagnosis of distant recurrence. Given its prognostic value, TFI can help to individualize clinical recommendations and to design future trials in the metastatic setting for patients relapsing after prior exposure to anti-HER2 therapy for early disease. Citation Format: Matteo Lambertini, Dominique Agbor-Tarh, Otto Metzger-Filho, Noam Ponde, Francesca Poggio, Florentine Hilbers, Larissa A Korde, Saranya Chumsri, Olena Werner, Lucia Del Mastro, Rafael Caparica, Volker Moebus, Alvaro Moreno-Aspitia, Martine Piccart, Evandro de Azambuja. Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-04.

// Claudia Bighin 1 , Beatrice Dozin 2 , Francesca Poggio 1 , Marcello Ceppi 2 , Paolo Bruzzi 2 , Alessia D’Alonzo 1 , Alessia Levaggi 1 , Sara Giraudi 1 , Matteo Lambertini 1 , Loredana Miglietta 1 , Marina Vaglica 1 , Vincenzo Fontana 2 , Giuseppina Iacono 1 , Paolo Pronzato 1 and Lucia Del Mastro 1 1 Department of Medical Oncology, IRCCS Azienda Ospedaliera Universitaria San Martino – Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 2 Department of Clinical Epidemiology, IRCCS Azienda Ospedaliera Universitaria San Martino – Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy Correspondence to: Claudia Bighin, email: // Keywords : advanced breast cancer, hormone-responsive breast cancer, first-line treatment, hormonal therapy, chemotherapy Received : November 30, 2016 Accepted : January 10, 2017 Published : January 18, 2017 Abstract Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy. Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy. Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CT-first group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group. Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CT-first group had a superimposable OS than those in the HT-first group.

PURPOSE OF REVIEW Adjuvant chemotherapy for breast cancer significantly reduces the risk of recurrence and improves overall survival (OS). The purpose of the current article is to review available evidence on dose-dense chemotherapy, also focusing on special population, including premenopausal women and those with HER2-positive disease. RECENT FINDINGS A recent patient-level meta-analysis showed that the use of dose-dense chemotherapy is associated with significant reduction in disease recurrence, breast cancer mortality and improvement in OS. The benefit of dose-dense chemotherapy is irrespective from HER2 status, although women with HER2-positive disease enrolled in trials included in the meta-analysis did not receive the current standard of treatment with anti-HER2 agents. Among premenopausal women, dose-dense chemotherapy improved OS, and thus should be considered standard of care for them. SUMMARY In conclusion, high-risk early stage breast cancer patients should be treated with (neo)adjuvant dose-dense anthracycline-based chemotherapy followed by paclitaxel. In the era of trastuzumab, the benefit of dose-dense chemotherapy is still unclear for patients with HER2-positive breast cancer.

Background Adjuvant chemotherapy is the standard of care in high-risk early breast cancer patients. Dose-dense should be the preferred schedule of administration. However, its long-term benefit is unknown. Methods In the Italian multicentre Phase 3 randomised MIG-1 trial, node-positive and high-risk node- negative breast cancer patients were randomised to receive six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide regimen administered every 3 (FEC21) or 2 (FEC14) weeks. The primary endpoint was overall survival (OS), and the secondary endpoint was event-free survival (EFS). Results From 1992 to 1997, 1214 patients were included. Median follow-up was 15.8 years. In all, 15-year OS was 71% and 68% in the FEC14 and FEC21 groups, respectively (HR = 0.89; p = 0.25). In all, 15-year EFS was 47% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.87; p = 0.18). In a pre-planned subgroup analysis, among patients with hormone receptor-negative tumours, 15-year OS was 70% and 65% in the FEC14 and FEC21 groups, respectively (HR = 0.73; 95% CI: 0.51–1.06); 15-year EFS was 58% and 43% in the FEC14 and FEC21 groups, respectively (HR = 0.70; 95% CI: 0.51–0.96). Conclusions Updated results from the MIG-1 study are numerically in favour of dose-dense chemotherapy, and suggest a long-term benefit of this approach in high-risk early breast cancer patients.

Background T-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy. Patients and Methods Eligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer ( ClinicalTrials.gov Identifier: NCT02284581 ). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS. Results Of 445 patients with HER2+ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%. Conclusions Our results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.

The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation.

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive 4 cycles of (fluorouracil)epirubicin/cyclophosphamide followed by 4 cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p=0.698) and OS (p=0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52-1.89; OS: HR, 0.95; 95% CI 0.37-2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab. This article is protected by copyright. All rights reserved.

Background: Fertility and pregnancy-related issues are major concerns for young breast cancer patients. Limited data are available on physicians’ knowledge, attitudes and practice in these fields. Methods: A 26-item questionnaire exploring 3 different topics (fertility preservation, pregnancy after breast cancer and breast cancer during pregnancy) was sent by email to physicians attending the 2016 3rd European School of Oncology (ESO) – European Society for Medical Oncology (ESMO) Breast Cancer in Young Women Conference (BCY3) and the 15th St. Gallen International Breast Cancer Conference 2017 (BCC 2017). Given the selected sample, survey respondents were expected to have a higher than average interest in the management of breast cancer patients. Descriptive analyses were performed. Results: A total of 273 physicians (105 at BCY3 and 168 at BCC 2017) completed the survey; 37.0%, 46.9% and 34.8% reported never having consulted the available international guidelines on fertility preservation, pregnancy after breast cancer and management of breast cancer during pregnancy, respectively. Up to 18.3% of respondents did not know if the different fertility preservation options were available in their country; 22.3% suggested that controlled ovarian stimulation should not be considered safe in patients with hormone receptor-positive disease. A total of 30.4% of respondents agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence. Regarding breast cancer during pregnancy, 23.8% and 38.1% disagreed or were neutral on the statements that endocrine therapy and anti-HER2 agents should be avoided during pregnancy, respectively. Conclusions: Further educational initiatives are needed to improve physicians’ knowledge and adherence to available guidelines when addressing fertility and pregnancy-related issues in young breast cancer patients., SCOPUS: ar.j, info:eu-repo/semantics/published

516 Background: Current guidelines recommend GnRH agonist (GnRHa) use during chemotherapy (CT) as a strategy to reduce the risk of premature ovarian insufficiency (POI) in premenopausal patients with early breast cancer (EBC). However, no long-term safety data are available raising some concerns on concurrent use of GnRHa during CT in patients with hormone receptor-positive disease. In addition, there is no evidence on the protective role of this strategy in patients with germline BRCA mutations ( mBRCA). Here, we report the final analysis of the PROMISE-GIM6 phase III randomized study, the largest trial addressing the role of GnRHa use during CT in premenopausal EBC patients (Del Mastro et al, JAMA 2011 & Lambertini et al, JAMA 2015). Methods: From October 2003 to January 2008, 281 premenopausal patients aged 18 to 45 years with stage I-III EBC candidates for (neo)adjuvant CT were randomized to receive CT alone or combined with the GnRHa triptorelin. Primary endpoint was incidence of CT-induced POI (defined as amenorrhea and post-menopausal FSH/estradiol levels 1 year following CT). This final analysis reports on post-treatment pregnancies, disease-free survival (DFS) and overall survival (OS). An exploratory descriptive analysis in mBRCA patients is also reported. (ClinicalTrial.gov: NCT00311636) Results: Of the 281 randomized patients (CT+GnRHa arm = 148; CT alone arm = 133), 80% had hormone receptor-positive disease. At the time of this final analysis, 38 (13.5%) patients were lost to follow-up. Median follow-up was 12.4 years (IQR: 11.3-13.2 years). In the CT+GnRHa and CT alone arms, respectively, 9 (10-year cumulative incidence of pregnancy 6.5%, 95% CI 3.5%-12.3%) and 4 (10-year cumulative incidence of pregnancy 3.2%, 95% CI 1.2%-8.3%) patients had a post-treatment pregnancy (HR 2.14, 95% CI 0.66-6.92). No differences in 10-year DFS (72.4% in CT+GnRHa arm vs. 71.2% in CT alone arm: HR 1.16, 95% CI 0.76-1.77) nor in 10-year OS (82.0% in CT+GnRHa arm vs. 85.9% in CT alone arm: HR 1.17, 95% CI 0.67-2.03) were observed. There was no interaction between treatment effect and hormone receptor status. In patients with hormone receptor-positive disease, HR was 1.02 (95% CI 0.63-1.63) for DFS and 1.12 (95% CI 0.59-2.11) for OS. Out of 43 patients tested for BRCA, overall incidence of POI, irrespective of treatment arm, was 20% in mBRCA patients (n = 10) and 12% in patients without mBRCA (n = 33). In mBRCA patients, incidence of POI was 0% and 33% in the CT+GnRHa and CT alone arms, respectively. One post-treatment pregnancy was described in a patient with mBRCA1 in the CT alone arm. Conclusions: The final analysis of the PROMISE-GIM6 trial at a median follow-up of 12.4 years provides reassuring evidence on the safety of GnRHa use during CT as a strategy to preserve ovarian function in premenopausal patients with hormone receptor-positive EBC. Clinical trial information: NCT00311636.

12067 Background: Improvements in breast cancer (BC) care have led to increased survival of patients; hence, more attention to long-term treatment-related adverse events and quality of life (QoL) is required. Symptoms of spontaneous and treatment-induced menopause significantly affect the QoL and adherence to endocrine therapy among BC survivors, with potential negative implications on outcome. Use of systemic hormone replacement therapy (HRT) to mitigate menopause-associated symptoms is not recommended to reduce the burden of these side effects being historically associated with an increased risk of disease recurrence. This systematic review and metanalysis aimed to estimate the effect of HRT on risk of disease recurrence in BC survivors. Methods: A systematic search of Pubmed and Embase libraries up to January 15, 2021, was conducted in order to identify randomized controlled trials (RCTs) investigating the risk of disease recurrence with the use of HRT in BC survivors. We used the random-effect model to calculate the overall risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). Moreover, we performed a subgroup analysis to estimate the risk of recurrence according to hormone receptor status. The Higgins I2 index was computed to assess the heterogeneity between studies. The likelihood of publication bias was assessed by Egger’s test. Results: Four RCTs were found and three were included in the metanalysis (n = 3.973 patients); one study (n = 100 patients) was excluded due to the impossibility to extract the HR for disease recurrence. Overall, 1.990 patients were randomized to receive HRT (estrogen-progesteron combination or tibolone), while 1.983 patients were included in control groups (placebo or no HRT). As compared to control group, HRT significantly increased the risk of BC recurrence (HR 1.49, 95% CI 1.15-1.93, p = 0.002). The heterogeneity between the studies was low (39%, p = 0.194), and no publication bias was found ( p = 0.537). Two studies reported the HR according to hormone receptor status. At the subgroups analysis, the risk of BC recurrence with the use of HRT was significantly increased in hormone receptor-positive patients (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.25, 95% CI 0.83-1.88, p = 0.290). Conclusions: Use of HRT significantly increases the risk of recurrence in BC survivors, particularly in those with hormone receptor-positive disease. Therefore, this approach remains contraindicated in this setting. Alternative interventions to mitigate menopause-related symptoms should be proposed to these patients.

The cardiovascular effects of estrogen deprivation induced by aromatase inhibitors are unknown. We carried out a cross-sectional study to evaluate the effect of estrogen deprivation induced by aromatase inhibitors on markers of cardiovascular risk. We enrolled 410 postmenopausal women: 200 consecutive breast cancer patients treated with aromatase inhibitors for a median of 53 months (range 23–122) and 210 volunteer controls. Carotid intima-media thickness, presence of carotid stenosis, and presence of abdominal aortic aneurism were evaluated through an ultrasound examination. Average carotid intima-media thickness was 0.97 ± 0.02 mm and 1.08 ± 0.02 mm for breast cancer group and control group, respectively (p

Background In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab. Materials and methods In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics. Results Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval

Research question: This study explored the knowledge, attitudes and practice of physicians towards fertility and pregnancy-related issues in young BRCA-mutated breast cancer patients. Design: Physicians attending two international breast cancer conferences completed a 26-item questionnaire exploring fertility preservation, pregnancy during (BCP) or after breast cancer. A statistical comparison was carried out of the responses exploring the same issues in young breast cancer patients overall or specifically in those with BRCA mutations. Results: The survey was completed by 273 physicians. Ovarian tissue cryopreservation (33% versus 40%; P = 0.009) and gonadotrophin-releasing hormone analogues during chemotherapy (74% versus 81%; P = 0.001) were less commonly suggested in BRCA-mutated patients than in the overall breast cancer population. 42% of respondents agreed or were neutral on the statement that ovarian stimulation should not be considered safe in BRCA-mutated breast cancer patients. 45% and 30% agreed or were neutral on the statement that pregnancy in breast cancer survivors may increase the risk of recurrence in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 15% and 3% disagreed that transplanting the cryopreserved ovarian tissue can be considered safe in BRCA-mutated patients or in the overall breast cancer population, respectively (P < 0.001). 33.3% were against the addition of platinum agents as neoadjuvant chemotherapy in BRCA-mutated patients with BCP. Conclusions: Several misconceptions on fertility preservation and pregnancy-related issues in breast cancer patients persist even among physicians directly involved in breast cancer care. Focused research efforts to address these issues in BRCA-mutated breast cancer patients and education to improve physicians’ knowledge and adherence to available guidelines are urgently needed., SCOPUS: ar.j, info:eu-repo/semantics/published

Standard adjuvant chemotherapy for HER2-negative breast cancer consists generally in an anthracycline and taxane-based regimen (A+T). The TC (docetaxel and cyclophosphamide) regimen arises as a potential alternative, although individual randomized controlled trials (RCTs) could not demonstrate the non-inferiority of TC over A+T. This is a systematic review and meta-analysis of RCTs comparing 6 cycles of TC versus sequential A+T in the adjuvant treatment of HER2-negative breast cancer. A systematic literature search was performed to identify RCTs comparing TC versus A+T. Disease-free survival (DFS) and overall survival (OS) were assessed. Subgroup analyses of DFS according to hormone receptor status, lymph node involvement, and menopausal status were performed. Hazard ratios (HRs) and 95% confidence intervals (CI) for DFS and OS were extracted from each trial, and a pooled analysis was conducted using the random-effect model. The Higgins’ I-Squared Test was used to quantify heterogeneity. Seven RCTs were included (12,741 patients). Overall, no difference was observed between TC and A+T in DFS (HR 1.08, 95% CI 0.96–1.20) and OS (HR 1.05; 95% CI 0.90–1.22). A trend favoring A+T was observed in hormone receptor-negative (HR 1.12, 95% CI 0.93–1.34) and N2 patients (HR 1.25; 95% CI 0.82–1.90). Emesis/vomiting, mucositis, thrombocytopenia and sensory neuropathy were significantly more frequent with A+T. As adjuvant treatment of HER2-negative breast cancer, sequential A+T regimen was associated with increased risk of toxicities and no clear survival benefit as compared to 6 cycles of TC. Higher-risk patients may benefit the most from A+T, whilst TC may be an efficacious and less toxic alternative for lower-risk patients.