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Background: Poly (ADP-ribose) polymerase-inhibitors (PARPis) showed antitumour activity in BRCA1/2-mutated cancers, with more heterogeneous outcomes in tumours harbouring mutations that impair other genes involved in the DNA homologous recombination repair (HRR) or wild-type (wt). Methods: We conducted a systematic review and meta-analysis to better assess the role of PARPis in the treatment of metastatic solid tumours, with and without BRCA1/2 mutations. The primary end-point was progression-free survival (PFS). The secondary end-points were overall response rate (ORR) and overall survival (OS). A random-effects model was applied. Results: Twenty-nine studies (8,839 patients) were included. PFS was significantly improved (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.51-0.68, p < 0.001), without being affected by BRCA mutational status (p = 0.65). Significant subgroup differences were observed with regard to the tumour site (p = 0.001), line of therapy (p = 0.002), control arm (p < 0.001), type of PARPi (p < 0.001) and trials' phase (p = 0.006). PARPis were associated with ORR (relative risk: 1.35, 95% CI: 1.16-1.56, p < 0.001), with significant subgroup differences observed with regard to treatment line (p = 0.03), control arm (p = 0.04) and PARPis (p < 0.001) and independent of mutational status (p = 0.44), tumour site (p = 0.86) and trials' phase (p = 0.09). OS was significantly improved by PARPis (HR: 0.86, 95% CI: 0.80-0.92, p < 0.001), regardless of mutational status (p = 0.57), tumour site (p = 0.82), treatment line (p = 0.22), control arm (p = 0.21), PARPis (p = 0.30) and trials' phase (p = 0.26). Finally, an exploratory subgroup analysis showed a significant PFS improvement (HR: 0.51, 95% CI: 0.43-0.60, p < 0.001) with PARPis in BRCA-wt/HRR-deficient tumours. Conclusion: Our results confirm the efficacy of already approved PARPi-based treatments in BRCA1/2-mutant solid tumours, support their role also in BRCA-independent HRR-deficient tumours and suggest a potentially broader efficacy in some wt tumours, perhaps with appropriate therapeutic partners. Prospective studies are warranted.

Introduction: Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. Methods: We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Results: Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. Conclusions: The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.

Background: Recently, CDK4/6i proved to improve the efficacy of HT of pts affected by luminal MBC. However, the best sequence of HT is still unclear and it is still uncertain if pts with lobular histology derive the same benefit of ductal when receiving second line CDK4/6i. Particularly in lobular MBC, the dysregulation of the AKTpathway with the overexpression of cyclin E potentially represents an important mechanism of acquired resistance to HT, finally providing an intrinsic resistance to subsequent CDK4/6i. Thus, a multicentric retrospective study was conducted to determine the efficacy of PALBO-FUL versus EVE-EXE as second line HT of MBC with Lobular histology.Methods: Pts affected by Lobular MBC receiving PALBO-FUL or EVE-EXE for second line HT from 2013 to 2018 in 6 Italian centers were considered eligible. The primary endpoint was progression free survival (PFS). A propensity score (PS) adjustment for baseline characteristics was further accomplished for survival analysis. Results: Seventy-four of 376 screened pts were diagnosed for Lobular MBC; 46pts received PALBO-FUL, whereas 28 were treated with EVE-EXE, without imbalance in clinical characteristics. PFS resulted to be significantly longer for pts receiving EVE-EXE in comparison with PALBO-FUL (6.1 vs. 4.5 months, HR 0.58, 95% CI 0.35-0.96; p=0.025). Previous chemotherapy exposure resulted to be significantly associated with PFS at the multivariate analysis (HR 0.41, 95% CI 0.24-0.72, p=0.002). At the PS analysis, adjusted for previous chemotherapy exposure and synchronous/metachronous metastatic status, PFS was confirmed to be significantly longer for pts receiving EVE-EXE in comparison with PALBO-FUL (6.0 vs. 4.6 months, p=0.04)Conclusion: This retrospective real-world analysis generates the hypothesis of a potential benefit of EVE-EXE in comparison with PALBO-FUL for second line HT of MBC with Lobular histology. Nevertheless, the small pts’ sample calls for a larger and adequately sized prospective validation. However, these data allow to speculate on the best hormonal therapeutic sequence in MLBC. Indeed, in this setting a late exposure to CDK4/6i might not allow to exploit its efficacy, while once hormonal resistance is acquired the inhibition of AKT/m-TOR pathway may represent the best option. Citation Format: Armando Orlandi, Elena Iattoni, Laura Pizzuti, Agnese Fabbri, Andrea Botticelli, Carmela Di Dio, Antonella Palazzo, Giovanna Garufi, Giulia Indellicati, Daniele Alesini, Luisa Carbognin, Ida Paris, Angela Vaccaro, Luca Moscetti, Alessandra Cassano, Patrizia Vici, Valentina Magri, Giuseppe Naso, Diana Giannarelli, Paolo Marchetti, Emilio Bria, Giampaolo Tortora. Palbociclib-fulvestrant (PALBO-FUL) and everolimus -exemestane (EVE-EXE) for second line hormonal treatment (HT) of metastatic breast cancer (MBC) with lobular histology: A propensity score matched analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-43.

Despite recent advances in the molecular characterization of triple-negative breast cancer (TNBC), the standard treatment for early-stage TNBC is represented by the historically used anthracycline and taxane-based chemotherapy. In this modern era of precision medicine, several new therapeutic strategies and novel agents have been investigated in the neoadjuvant setting of TNBC, in order to individualize treatment.This review provides a comprehensive overview of the currently available evidence regarding the activity and efficacy of platinum agents, PARP- and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, highlighting the available data on potential predictive biomarkers of response or resistance to such treatments.The genomic and immune landscape of TNBC has encouraged the exploration of drugs that interfere with the DNA repair mechanism and that modulate immune response. Overall, these drugs seem to improve the pCR rate in TNBC, despite preliminary and heterogeneous results. Taking into account the economic issues and the side effects of these drugs, it is crucial to further explore the potential predictive role of BRCA mutational status and homologous recombination deficiency score, for platinum agents and PARP-inhibitors, and tumor infiltrating lymphocytes and other immune biomarkers for checkpoint inhibitors, respectively.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non‐pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first‐line phase III trials in HER2‐negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2‐negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms., SCOPUS: re.j, info:eu-repo/semantics/published

The new Coronavirus infection, called COVID-19, has appeared on the world stage with significant implications for patients suffering from cancer and their caregivers. Patients with oncological diseases are particularly at risk, both for morbidity and lethality related to respiratory virus infections and are exposed to a higher risk of severe events. The assistance to these types of patients had to deal with the consequences and damage that arise from a state of health emergency and has therefore undergone a remodeling. While the threat of slowdowns threatens patients and all people who risk being diagnosed late, many oncologists face severe occupational burnout. This situation has repercussions on an emotional level: a shared path is desirable to protect the patient himself and the health professionals who take responsibility for the therapeutic care process of such fragile patients. Our model of assistance is based on coaching pointed towards patients affected by cancer, their caregivers and healthcare professionals with the aim of addressing the crisis through an operational process aimed at helping to integrate the experience of illness in order to rebuild the continuity of the existence and give it an evolutionary sense.

IntroductionOlaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.MethodsPatients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.Results27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (pBRCA status and type of response.ConclusionsEarly-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

Background: The effect of germline BRCA mutations on the outcomes of patients with triple-negative breast cancer (TNBC) is not well understood and the expanding access to genetic testing could provide further information about drug sensitivity and patients’ prognosis. In this retrospective study, data collected from TNBC patients with locally advanced disease and susceptible to neoadjuvant chemotherapy (NAC) were used in order to define whether the presence of germline BRCA pathogenic variants could help defining clinical features, prognosis and outcome of this population. Materials and Methods: Seventy-four women with newly diagnosed locally advanced TNBC from July 1, 2014 to July 30, 2017, were enrolled. DNA derived from whole-blood specimens was available for all the TNBC-NAC cohort. We investigated the presence of gBRCA mutations by employing next generation sequencing (NGS) techniques. Tumor and patients’ characteristics, genetic testing results, and outcomes were collected by patients’ medical records. Statistical calculations were performed using the SPSS 24.0 software. Pearson χ2- test for frequencies was used to compare the demographics, tumor characteristics and response to treatment between pathogenic and not pathogenic BRCA variants. Two-sided p-values were considered to be statistically significant if &lt 0.05. Results: Of our 74 TNBC-NAC cohort, 23 patients (31.1%) tested positive for a pathogenic BRCA variant, 4 (5.4%) tested VUS (variant of uncertain significance) and 47 (63.5%) tested negative. Patients were divided in two group according to the presence of pathogenic or not pathogenic BRCA variants. There were no significant differences between the two group respect to the age at cancer diagnosis (median age in BRCA positive women: 50.6, in VUS: 42.2, in BRCA negative: 47.6), the rate of pathologic response after neoadjuvant anthracycline taxane based chemotherapy and the disease recurrence. Conclusion: In our preliminary study, for the first time all the 74 TNBC-NAC patients have been genetically screened for the presence of BRCA variants. Although larger cohort and longer follow-up are needed in order to fully understand if BRCA variants can assess TNBC patients prognosis, our results showed that the BRCA status does not correlate with response to chemotherapy and disease-free survival of TNBC patients. Citation Format: Ida Paris, Roberta Rizza, Carmela Paolillo, Luisa Carbognin, Alessandra Calegari, Giovanni Scambia, Emilio Bria, Ettore Capoluongo, Riccardo Masetti, Andrea Urbani, Mariangela Pasqualoni, Concetta Santonocito. Impact on outcome and response to neoadiuvant chemotherapy in triple negative breast cancer patients and BRCA mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-06.

Background. Alopecia (A) is a common and emotionally traumatic adverse effect for breast cancer (BC) patients (pts) undergoing chemotherapy (CT). Food and Drug Administration (FDA) cleared the DigniCap® SCD, for patients with breast cancer in 2015. This device was designed to reduce hair loss during chemotherapy. However, the impact of SCD in pts undergoing anthracycline and taxane-based sequential regimen is not entirely established. Thus, the aim of this analysis was to prospectively explore the role of SCD in a cohort of pts including also this regimen. Methods. From February 2016 to June 2018 patients with early/locally advanced breast cancer treated with neoadjuvant/adjuvant CT including anthracycline, taxane or both in sequential regimen were enrolled. The estimate of hair-loss was evaluated by photographs of the head using the Dean scale during and one month after the end of chemotherapy. Alopecia was graduated according to Dean scale: G0 = no A; G1 < 25% A; G2 = 25–50% A; G3 = 50–75% A; G4 > 75%. A score of 0-2 (≤ 50% hair loss) was defined as treatment success. Tolerability was defined as the percentage of patients who completed all chemotherapy cycles using the SCD. All patients received the Patient Symptoms Survey (self-reported). A database for individual data and information was appropriately fulfilled. Descriptive statistics was adopted. Results. Overall 121 pts were enrolled; 118 pts were evaluable for efficacy of Dignicap® SCD. Median age was 44 years (range: 24-74 years). CT regimens included docetaxel/cyclophosphamide (37 pts), epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2 iv) three weekly followed by 12 courses of paclitaxel (80 mg/m2 iv weekly) (84 pts). Alopecia all grade was showed in 52.5% (n=62): G1 in 35 pts (29.6%)and G2 in 23 pts (19.5%). No hair loss in 42 pts (35.6 %). Treatment success was seen in 103 pts (87.3%). Toxicity included grade 1/2 headache in 56 pts (47.4%), cervical discomfort in 36 pts (30.5%), pain of skin in one pts (8.5%). Discontinuation of SCD was seen in 28 pts (23.7%) primarily for headache G3 (4 pts – 3.4%), hair loss G3 in 15 pts (12.7%), discomfort in 8 pts (6.8%), use of head cover in one pt (0.8%). Conclusions. This prospective observational study suggests that SCD is effective in preventing A in a relevant number of patients (87.3%), undergoing also anthracyclines followed by taxanes regimen in sequential schedule. Citation Format: Paris I, Accetta C, Carbognin L, Di Giorgio D, Magno S, Terribile D, Franceschini G, Sanchez M, Ferrandina G, Pasciuto T, Fulvi A, Scambia G, Masetti R. Impact of scalp cooling device (SCD) in preventing alopecia in women undergoing chemotherapy for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-03.

Background: Despite the sequential E therapy is recognized as the preferred approach for HR+/HER2- MBC, no data from clinical trials support the choice between the different sequential strategies. Methods: In this retrospective study descriptive statistics are reported using the median (Interquartile range, IQR) or frequency. Progression Free Survival (PFS) curves were estimated with the Kaplan-Meier method and compared with the log-rank test. Analysis were performed by SPSS version 21.0 (SPSS Inc., Chicago, IL). Results: From January 2006 to December 2017, 240 patients (pts) with HR+/HER2- MBC receiving at least two consecutive E therapies as first approach were selected from 12 italian cancer centers. The median age at the time of metastasis onset was 63.5 (IQR: 55-72.5) years; 184 (76.7%) pts were in menopausal status; 38 (16%) had de novo stage IV disease and the remaining 202 (84%) had recurrent BC with a median time of 78 months (5-396 months). At the beginning of MBC diagnosis, 148 (62%) pts had a single site of distant disease, 108 (45%) of whom had bone only disease and 45 (18.8%) presented visceral involvement too. The aromatase inhibitor (AI) was chosen as I-line therapy in 146 (60.9%) pts, followed by Fulvestrant (F) in 62 (25.8%) pts; the alternative I-line options were everolimus-exemestane (Eve-Exe), tamoxifene (T), Palbociclib (P)+AI and F+AI in 13 (5.4%), 14 (5.8%), 1 (0.4%) and 4 (1.7%) pts, respectively. The most favourite II-line option resulted F for 111 (46.2%) pts while the Eve-Exe combination was chosen in 70 (29.2%) pts, AI in 30 (12.5%) pts; T, AI+F, P+F and antiprogestincwere administered in 4 (1.7%), 4 (1.7%), 19 (7.9%) and 2 (0.8%) pts, respectively. For I and II-line, the AI followed by F (40%) and F followed by Eve-Exe (18%) were the most common sequential therapeutic approaches; the several alternative options were scanty used (in less than 10%). The median Progression-Free Survival (PFS) from first and second-line E therapies resulted 15.7 (95% CI 13.3-18.1) and 10.3 months (95% CI 8.7-11.9), respectively. Among 194 pts with disease progression after second-line E therapy, 87 (44.8%) received further E therapies with a median PFS 9.4 months (95% CI 7.9-10.9). The remaining 70 (29.2%) pts was treated with palliative chemotherapy. Interestingly, the median Overall Survival (OS) was even longer for pts receiving more lines of E therapies compared to the group with earlier introduction of chemotherapy (204.3 vs 92.8; p=0.007). Finally, in the subgroup analyses a longer PFS benefit was observed in pts with disease recurrence over 12 months from initial diagnosis (38.1 vs 30.3 months p=0.04) and limited sites of disease involvement at the time of MBC diagnosis (37.6 vs 28.3 months, p=0.03) Conclusions: The sequential use in first and second-line setting of E therapies for HR+/HER2- MBC improves median PFS up to 32.3 months. According to real practice experience the optimal sequences could be AIs followed by F and F followed by Eve-Exe. A role for these compounds should be redefined in the light of recently introduction of CDK 4/6 inhibitors in combination with AIs or F for the first or later lines. Citation Format: Fabi A, Giannarelli D, Botticelli A, Scagnoli S, Pellegrino A, Fabbri A, Corsi D, Magri V, Pizzuti L, Paris I, Bruni V, Pace R, Lanzetta G, Stani S, Moscetti L, Marchetti P, Piesco G, Cognetti F, Rossi V. SEQUERPLUS: A multicenter real practice observational study investigating the endocrine-based (E) therapies sequential approach in hormonal receptor positive (HR+) HER2 negative (-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-07.

Breast cancer (BC) is the most frequent cancer among women and represents the second leading cause of cancer-specific death. A subset of patients with metastatic breast cancer (MBC) presents limited disease, termed ‘oligometastatic’ breast cancer (OMBC). The oligometastatic disease can be managed with different treatment strategies to achieve long-term remission and eventually cure. Several approaches are possible to cure the oligometastatic disease: locoregional treatments of the primary tumor and of all the metastatic sites, such as surgery and radiotherapy; systemic treatment, including target-therapy or immunotherapy, according to the biological status of the primary tumor and/or of the metastases; or the combination of these approaches. Encouraging results involve local ablative options, but these trials are limited by being retrospective and affected by selection bias. Systemic therapy, e.g., the use of CDK4/6 inhibitors for hormone receptor-positive (HR+)/HER-2 negative BC, leads to an increase of progression-free survival (PFS) and overall survival (OS) in all the subgroups, with favorable toxicity. Regardless of the lack of substantial data, this subset of patients could be treated with curative intent; the appropriate candidates could be mostly young women, for whom a multidisciplinary aggressive approach appears suitable. We provide a global perspective on the current treatment paradigms of OMBC.

Neoadjuvant chemotherapy is increasingly being employed in the management of breast cancer patients. Efforts and resources have been devoted over the years to the search for an optimal strategy that can improve outcomes in the neoadjuvant setting. Today, a multidisciplinary approach with the application of evidence-based medicine is considered the gold standard for the improvement of oncological results and patient satisfaction. However, several clinical complications and psychological issues due to various factors can arise during neoadjuvant therapy and undermine outcomes. To ensure that health care needs are adequately addressed, clinicians must consider that women with breast cancer have a high risk of developing “unmet needs” during treatment, and often require a clinical intervention or additional care resources to limit possible complications and psychological issues that can occur during neoadjuvant treatment. This work describes a multidisciplinary model developed at “Fondazione Policlinico Universitario Agostino Gemelli” (FPG) in Rome in an effort to optimize treatment, ease the application of evidence-based medicine, and improve patient quality of life in the neoadjuvant setting. In developing our model, our main goal was to adequately meet patient needs while preventing high levels of distress.

Introduction Sentinel node biopsy (SNB) is the standard of care in women with breast cancer (BC) and clinically non suspicious axillary lymph nodes (LNs), due to its high negative predictive value (NPV) in the assessment of nodal status. SNB has significantly reduced complications related to the axillary lymph node dissection, such as lymphedema and upper limb dysfunction. Evidence acquisition The gold standard technique for SNB is the blue dye (BD) and technetium labelled nanocolloid (Tc-99m) double technique. However, nuclear medicine is not available in all Institutions and several new tracers and devices have been proposed, such as indocyanine green (ICG) and superparamagnetic iron oxides (SPIO). All these techniques show an accuracy and detection rate not inferior to that of the standard technique, with different specific pros and cons. The choice of how to perform a SNB primarily depends on the surgeon's confidence with the procedure, the availability of nuclear medicine and the economic resources of the Institutions. In this setting, new tracers, hybrid tracers and imaging techniques are being evaluated in order to improve the detection rate of sentinel lymph nodes (SNs) and minimize the number of unnecessary axillary surgeries through an accurate preoperative assessment of nodal status and to guide new minimally invasive diagnostic procedures of SNs. In particular, the contrast-enhanced ultrasound (CEUS) is an active field of research but cannot be recommended for clinical use at this time. Evidence synthesis The ICG fluorescence technique was superior in terms of DR, as well as having the lowest FNR. The DR descending order was SPIO, Tc, dual modality (Tc/BD), CEUS and BD. Conclusions This paper is a narrative review of the most common SNB techniques in BC with a focus on recent innovations.

Simple Summary The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to endocrine therapy have remarkably improved the outcome of patients with HR+ advanced breast cancer. However, some points of reflections are still undiscussed. To answer these questions, we revised the mechanism of action of CDK4-6 inhibitors, clinical data available from pivotal studies, and summarized potential future strategies to overcome resistance to CDK4-6 inhibitors, thus improving patient’s survival. Abstract Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

Clinical trials in cancer treatment are imperative in enhancing patients’ survival and quality of life outcomes. The lack of communication among professionals may produce a non-optimization of patients’ accrual in clinical trials. We developed a specific platform, called “Digital Research Assistant” (DRA), to report real-time every available clinical trial and support clinician. Healthcare professionals involved in breast cancer working group agreed nine minimal fields of interest to preliminarily classify the characteristics of patients’ records (including omic data, such as genomic mutations). A progressive web app (PWA) was developed to implement a cross-platform software that was scalable on several electronic devices to share the patients’ records and clinical trials. A specialist is able to use and populate the platform. An AI algorithm helps in the matchmaking between patient’s data and clinical trial’s inclusion criteria to personalize patient enrollment. At the same time, an easy configuration allows the application of the DRA in different oncology working groups (from breast cancer to lung cancer). The DRA might represent a valid research tool supporting clinicians and scientists, in order to optimize the enrollment of patients in clinical trials. User Experience and Technology The acceptance of participants using the DRA is topic of a future analysis.

Breast cancer (BC) heterogeneity is composite in nature, with a wide variety of factors concurring to define several pathological entities, which differ by clinical presentation, pathologic features, therapy administered, and inherent outcomes1. Additional sources of breast cancer heterogeneity may raise during the disease course. In BC patients whose disease was initially diagnosed in the early stage and subsequently progressed with metastatic involvement of one single or multiple site/s, the molecular characteristics of metastatic lesions do not necessary mimic those of the disease initially diagnosed. A well-depicted molecular landscape is crucial for subtype definition, prognostic evaluation and appropriate therapeutic decisions. Accordingly, current guidelines suggest repeating the immunohistochemical (IHC) assessment in patients with metastatic spread and at least one secondary lesion amenable to biopsy2. Discordance in human epidermal growth factor receptor 2 (HER2) status between the tumor and metastatic lesions is widely acknowledged, and not yet completely unraveled in their biologic meaning and prognostic relevance3–11. The overexpression of HER2 or amplification of the related gene is extensively recognized as a feature associated with more aggressive biological behavior12,13. However, the extent to which changes in HER2 status may affect patients’ prognosis is still a matter of debate14. We herein propose an observational study of HER2-positive metastatic breast cancer (mBC) patients treated with the anti-HER2 targeted agents pertuzumab and/or trastuzumab emtansine (T-DM1). Our research question is whether relevant differences exist in long-term outcomes of patients with concordant HER2 status between the primary tumor and its secondary lesion/s compared to patients whose disease revealed HER2-positivity gain at the IHC assessment of metastatic lesions. In our historical cohorts, we also sought to identify factors associated with HER2-positivity gain at the IHC reassessment, for which an impact on prognosis may be foreseen.

BackgroundHER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines.MethodsThe biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.ResultsWe herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients.Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively).ConclusionsOur data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

The emergency caused by COVID-19 pandemic has imposed a sudden reorganization of the healthcare structures and has created consequences in cancer patients management. General clinical recommendations for cancer patients were released, even if limited clinical cancer-specific data were available. A number of critical issues have come out during COVID-19 pandemic in the management of patients with metastatic breast cancer (MBC). To explore the changes in the treatment of patients with MBC during COVID-19 pandemic, we promoted a survey to the oncologists operating in the Italian breast units. The results of this survey show that Italian oncologists have tried to ensure continuity of care for patients with MBC. De-escalation of cancer treatments, especially monotherapy administration, and greater use of oral anticancer drugs are the main changes that emerge from this survey. Some subgroups of patients, especially the elderly and endocrine-responsive patients, have been undertreated during the COVID-19 pandemic.

Radiogenomics is a specific application of radiomics where imaging features are linked to genomic profiles. We aim to develop a radiogenomics model based on ovarian US images for predicting germline BRCA1/2 gene status in women with healthy ovaries. From January 2013 to December 2017 a total of 255 patients addressed to germline BRCA1/2 testing and pelvic US documenting normal ovaries, were retrospectively included. Feature selection for univariate analysis was carried out via correlation analysis. Multivariable analysis for classification of germline BRCA1/2 status was then carried out via logistic regression, support vector machine, ensemble of decision trees and automated machine learning pipelines. Data were split into a training (75%) and a testing (25%) set. The four strategies obtained a similar performance in terms of accuracy on the testing set (from 0.54 of logistic regression to 0.64 of the auto-machine learning pipeline). Data coming from one of the tested US machine showed generally higher performances, particularly with the auto-machine learning pipeline (testing set specificity 0.87, negative predictive value 0.73, accuracy value 0.72 and 0.79 on training set). The study shows that a radiogenomics model on machine learning techniques is feasible and potentially useful for predicting gBRCA1/2 status in women with healthy ovaries.

Background: ErbB2-targeting agents have dramatically changed the therapeutic landscape of ErbB2+ advanced breast cancer (ABC). However, their optimal sequence of administration deserves further investigation.Methods: The biology of ErbB2 was investigated through sequential treatments in vitro, in ErbB2+ breast cancer cell lines resistant to trastuzumab, pertuzumab, and their combination. We analyzed data from 555 ErbB2+ ABC patients treated with trastuzumab emtansine (T-DM1) and explored the efficacy of T-DM1 in the 371 patients who received it in second-line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models.Results: We show here lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Reduced T-DM1 efficacy is associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. Membrane-HER2 downregulation was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p=0.0006 and 0.03 for OS and PFS2, respectively). Conclusions: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 to cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

The diagnosis of breast cancer (BC) during pregnancy is uncommon. It has varied among different studies from 1:10,000 to 1:3000 of all pregnancies, with a median age of 33 years. Pregnancy-associated BC represents a challenge in terms of clinical management to guarantee both maternal and fetal security in choosing the right treatment. This situation is complex and requires a multidisciplinary approach, including the surgeon, anesthesiologist, oncologist, radiotherapist, psychologist, and maternal-fetal medicine specialist. In the present review, we examined the management of pregnancy-associated BC, focusing on pathophysiologic background, risk factors, diagnosis, staging procedures, anesthesia, surgical management, and systemic treatment.

Background NEPA is an oral fixed-dose combination of netupitant, a new highly selective neurokinin-1 receptor antagonist, and palonosetron. This study was conducted to evaluate whether the efficacy of NEPA against chemotherapy-induced nausea and vomiting (CINV) in cycle 1 would be maintained over subsequent chemotherapy cycles in breast cancer patients receiving adjuvant anthracycline plus cyclophosphamide (AC). The study also describes the relationship between efficacy on day 1 through 5 (overall period) and control of CINV on day 6 through 21 (very late period) in each cycle. Methods In this multicentre, phase II study, patients received both NEPA and dexamethasone (12 mg intravenously) just before chemotherapy. The primary efficacy endpoint was overall complete response (CR; no emesis and no rescue medication use) in cycle 1. Sustained efficacy was evaluated during the subsequent cycles by calculating the rate of CR in cycles 2–4 and by assessing the probability of sustained CR over multiple cycles. The impact of both overall CR and risk factors for CINV on the control of very late events (vomiting and moderate-to-severe nausea) were also examined. Results Of the 149 patients enrolled in the study, 139 were evaluable for a total of 552 cycles; 97.8% completed all 4 cycles. The proportion of patients with an overall CR was 70.5% (90% CI, 64.1 to 76.9) in cycle 1, and this was maintained in subsequent cycles. The cumulative percentage of patients with a sustained CR over 4 cycles was 53%. NEPA was well tolerated across cycles. In each cycle, patients with CR experienced a significantly better control of very late CINV events than those who experienced no CR. Among the patients with CR, the only predictor for increased likelihood of developing very late CINV was pre-chemotherapy (anticipatory) nausea (adjusted odds ratio = 0.65–0.50 for no CINV events on cycles 3 and 4). Conclusion The high anti-emetic efficacy seen with the NEPA regimen in the first cycle was maintained over multiple cycles of adjuvant AC for breast cancer. Preliminary evidence also suggests that patients achieving a CR during the overall period gain high protection even against very late CINV events in each chemotherapy cycle. Trial registration This trial was retrospectively registered at Clinicaltrials.gov identifier (NCT03862144) on 05/Mar/2019.

Background Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups. Methods We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP). Results Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%). Conclusions CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.

We analyzed data from 738 HER2‐positive metastatic breast cancer (mbc) patients treated with pertuzumab‐based regimens and/or T‐DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression‐free survival at first‐line (mPFS1) was 12 months. Pertuzumab as first‐line conferred longer mPFS1 compared to other first‐line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second‐line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T‐DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs‐negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T‐DM1 in second‐line after pertuzumab were significantly lower compared to pertuzumab‐naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment‐related outcomes of HER2‐positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2‐positive (mbc) patients., What's new? About half of breast cancers positive for human epidermal growth factor (HER2) also express hormone receptors but the impact of hormone receptor status on the success of HER2‐directed treatments is not fully explored. Here the authors retrospectively assessed tumor behavior and treatment outcomes in 738 women with HER2+ metastatic breast cancer treated with new generation anti‐HER2 agents. Distinct hormone receptor expression patterns significantly affected the progression free and overall survival, justifying further studies to define optimal treatment regimens and the interplay between hormone receptor and HER2 signaling.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) show meaningful efficacy and tolerability in patients with metastatic breast cancer (MBC), but the optimal sequence of ET has not been established. It is not clear if patients with lobular breast carcinomas (LBC) derive the same benefits when receiving second line CDK4/6i. This retrospective study compared the efficacy of palbociclib plus fulvestrant (PALBO&ndash, FUL) with everolimus plus exemestane (EVE&ndash, EXE) as second-line ET for hormone-resistant metastatic LBC. From 2013 to 2018, patients with metastatic LBC positivity for estrogen and/or progesterone receptors and HER2/neu negativity, who had relapsed during adjuvant hormonal therapy or first-line hormonal treatment, were enrolled from six centers in Italy in this retrospective study. A total of 74 out of 376 patients (48 treated with PALBO&ndash, FUL and 26 with EVE&ndash, EXE) with metastatic LBC were eligible for inclusion. Progression-free survival (PFS) was longer in patients receiving EVE&ndash, EXE compared with PALBO&ndash, FUL (6.1 vs. 4.5 months, univariate HR 0.58, 95% CI 0.35&ndash, 0.96, p = 0.025). On the propensity score (PS) analysis, PFS was confirmed to be significantly longer for patients treated with EVE&ndash, EXE compared to PALBO&ndash, FUL (6.0 vs. 4.6 months, p = 0.04). This retrospective analysis suggests that EVE&ndash, EXE is more effective than PALBO&ndash, FUL for second line ET of metastatic LBC, allowing us to speculate on the optimal therapeutic sequence.

ObjectiveSince vulvar cancer is such a rare disease, the international experience with electrochemotherapy has been derived from only a few centers. The aim of this study was to evaluate clinical outcome and side effects profile with the use of electrochemotherapy in patients with primary or recurrent vulvar cancer.MethodsData were retrospectively collected from November 2017 to November 2019 in two major Italian oncologic institutes: Regina Elena Institute and Fondazione Policlinico Universitario Agostino Gemelli IRCCS. Electrochemotherapy was offered in a palliative setting to patients with a primary or recurrent vulvar cancer who were not candidates for surgery or any other treatment, because of poor performance status or previous delivered treatments. All patients underwent general anesthesia. Electrical pulses were delivered using a pulse generator. Intravenous bleomycin was administered in conjunction with electrochemotherapy. Follow-up examinations were performed at 1, 3, and 6 months. Primary endpoint was to assess the response rate of electrochemotherapy as palliative treatment in patients with vulvar cancer.ResultsA total of 15 patients were included in the study. Fourteen patients (93.3%) had a squamous cell carcinoma and one patient had vulvar carcinosarcoma. Ten patients (66.7 %) had a single lesion and 5 patients (33.3%) had multiple lesions. Median number of electrical pulses was 22 (range 3–42) and median operative time was 13 (range 7–20) min. No intra-procedure complications occurred. One patient had pneumonia during their post-operative stay. Overall response rate after 1 month was 80%. At the 3-month follow-up, 3 patients (20%) had disease progression, 3 patients (20%) had died from ongoing disease, 1 patient (6.7%) died for other reasons, whereas the other patients maintained their 1-month clinical response. A total of 8/13 patients (61.5%) were alive at 6-month follow-up, whereas 6/12 patients (50%) were alive at 1-year follow-up.ConclusionsElectrochemotherapy is a feasible, easy to perform, and reproducible procedure in patients with primary or recurrent vulvar cancer who are unable to undergo surgery. Survival after 1 year in this population was 50%. Electrochemotherapy may have a role in the management of vulvar cancer, especially as palliative treatment when other therapies are no longer applicable.

Pathogenic variants (PVs) carriers in BRCA1 or BRCA2 are associated with an elevated lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). The prevalence of BRCA1 and BRCA2 germline alterations is extremely variable among different ethnic groups. Particularly, the rate of variants in Italian BC and/or OC families is rather controversial and ranges from 8% to 37%, according to different reports. By In Vitro Diagnostic (IVD) next generation sequencing (NGS)-based pipelines, we routinely screened thousands of patients with either sporadic or cancer family history. By NGS, we identified new PVs and some variants of uncertain significance (VUS) which were also evaluated in silico using dedicated tools. We report in detail data regarding BRCA1/2 variants identified in 517 out of 2351 BC and OC patients. The aim of this study was to report the incidence and spectrum of BRCA1/2 variants observed in BC and/or OC patients, tested in at Policlinico Gemelli Foundation Hospital, the origin of which is mainly from Central and Southern Italy. This study provides an overview of the variant frequency in these geographic areas of Italy and provides data that could be used in the clinical management of patients.

We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p

Background We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in ‘field-practice’ breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs). Methods The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement. Results Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1–55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4–8.6) in the BM group and 8 months (95% CI: 5.7–10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1–6.9) versus 11 (95% CI: 7.1–14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2–15.8) in the BM group and 32 months (95% CI: 24.4–39.6) in the non-BM group (p Conclusions T-DM1 is active in breast cancer patients with BMs.

Nowadays, the overall attention is focused on de-escalating treatments for breast cancer (BC) including surgery, radiotherapy and chemotherapy. The introduction of sentinel lymph node biopsy (SLNB) has led to less invasive surgical approaches for accurately staging the axilla, with axillary lymph node dissection (ALND) progressively confined to a limited group of patients. One of the goal of surgery in de-escalating approaches is to reduce surgical morbidity by restricting or avoiding axillary surgery with no effect on survival. In this context the importance of imaging study for preoperative identification of axillary metastasis, in order to reduce axillary surgery, is gradually improving while the role of intraoperative assessment of sentinel nodes is progressively becoming limited to restricted groups of patients. According to the results of the ACOSOG Z0011 and following the most important guidelines, ALND can be safely omitted in selected patients treated with breast conserving surgery (BCS) with one or two positive SLNB while the adoption of SLNB positive alone in patients undergoing mastectomy is not yet defined. The increased employment of neoadjuvant chemotherapy (NAC) and the use of SLNB in patients after NAC plays an important role in de-escalation of axillary surgery in this group of patients. However current studies on this topic are still controversial, mainly about clinically positive lymph nodes (cN+) pre NAC patients or how to manage positive SLNB in post NAC patients. Some authors have collected predictive factors of positive non sentinel lymph nodes (NSLNs) in nomograms, considered an useful tool to avoid unnecessary further surgery. Elderly women represent specific group of patients where the axillary approach needs to be properly resized. The management of axilla in BC is in continuous evolution and ongoing studies could make even SLNB useless in the next future.

Ductal carcinoma in situ (DCIS) represents a disease that includes different risk categories and does not necessarily turn into invasive cancer. The 20% of all newly diagnosed breast cancers consist in DCIS, with an incidence increased due to the widespread diffusion of screening programs. Once upon a time, mastectomy was considered the gold standard in treatment of DCIS, but over the years, breast-conserving surgery (BCS) has been included as the treatment of choice for patients with small lesions. Several randomized trials demonstrated that adjuvant treatment as radiation and ET reduce the risk of local recurrence, including invasive recurrences. Therefore, in patients with DCIS susceptible to conservative surgery, the key decision for management is represented by the addition of radiotherapy (RT) or ET. With the variety of surgical and adjuvant treatment options available, there has been great interest in tailoring therapies to the individual, with the goal of optimizing the balance of risks and benefits. From the observation of the first data showing how such treatments are not clearly associated with an improvement in disease specific mortality, the upcoming hypothesis is to consider omitting some of such treatments or to plan close surveillance for low risk lesions. Prospective studies on women treated with BCS alone have identified low risk lesions. Actually, the main challenge is how to recognize cases that will not progress to invasive lesions. Despite all the studies carried out and the many available data, there are no unique and universally accepted treatment criteria, so some issues of controversy are still open.

Pathogenic mutations in two autosomal dominant genes, BRCA1 and BRCA2 , with high penetrance are supposed to be the cause for an approximated 5–7% risk of all breast cancer (BC) and ovarian cancer (OC). Compared to sporadic BC, BRCA mutated ( BRCAmut ) BC differs for lifetime risk of onset and sensitivity to systemic therapies. A hereditary BC syndrome should be taken into account when there are numerous relatives with BC early-onset (typically before menopause). Moreover, BRCAmut carriers showed a lifetime possibility of manifesting OC. When a BC diagnosis is made in young patients or in suspicious personal relatives’ anamnesis, be aware of being carriers of a BRCA mutation may influence the decision making-process about surgical procedure and prevention strategies. In this review, we examined surgical treatment choice for BRCAmut BC, risk of ipsilateral breast recurrence (IBR) and contralateral breast cancer (CBC). We examined the role of breast-conserving therapy (BCT), risk-reducing mastectomy (RRM) and preventive risk-reducing salpingo-oophorectomy (RRSO) with a special consideration about advantage in terms of mortality reduction for both conservative and prophylactic measures. We also reviewed the sensitivity of mutated BC to platinum-based antineoplastic drugs and poly (ADP-ribose) polymerase inhibitors (PARPi) by emphasizing the results of clinical trials recently published.

Background: Ado-trastuzumab emtansine (T-DM1) is a drug-antibody conjugate whose activity has been confirmed in HER2+ advanced breast cancer (BC) patients by the phase 3 EMILIA trial (Verma et al, NEJM 2012). Within the 991 patients enrolled in this trial, about 10% were affected with brain metastases (BM); in this subgroup, safety and efficacy of T-DM1 were confirmed although without any PFS improvement. Patients and methods: In an Italian, multicenter, retrospective analysis involving 303 patients with advanced BC treated with T-DM1 (Fabi et al, Oncotarget 2017), we analyzed 87 patients with BM (BM-group). The study wanted to evaluate the efficacy of T-DM1 on BM; furthermore we compared BM-group with the remaining 216 patients without BM (nBM-group) in order to study outcome of disease. MRI was used as assessment imaging. The number of extracranial metastatic sites in the BM-group and in the nBM-group was 1 for 10 (11.5%) and for 74 patients (34.3%), 2 for 23 (26.4%) and 93 (43%) patients, 3 for 25 (28.7% and 38 (17.6%) and 4 or more for 29 (33%) and 11 (5%), respectively. In the BM-group, 5 patients (5.7%) had received surgery alone as local treatment for brain metastases, 13 (14.9%) surgery plus stereotactic radio-surgery (SRS), 4 (4.7%) surgery plus whole-brain radiotherapy (WBRT), 23 (26.5%) SRS alone, 40 (45.9%)WBRT alone and 2 (2.3%) WBRT followed by SRS. Twenty-eight patients (32.9%) and 89 (42.4%) in the BM-group and nBM-group, respectively, received T-DM1 as second line, 24 (28.2%) and 49 (23.3%) as third line and 33 (38.8%) and 72 (34.3%) as fourth line. Mean number of cycles was 6 in both groups. Results:Among BM-group, 53 patients (60.9%) were evaluable for response. Two (3.8%) obtained brain complete response, 14 (26.4%) partial response and 13 (24.5%) stable disease [brain disease control rate: 54.7%); 24 (45.3%) progressed during T-DM1. Regarding extracranial metastases, overall response rate was 35.1% in the BM-group and 38.3% in the nBM-group; 6 months-clinical benefit was 50.6% and 52.3%, respectively. Median PFS was 7 months in the BM-group and 8 months in the nBM-group; when T-DM1 was given as second line, median PFS was 5 months in the BM-group and 11 months in nBM-group (p=0.01) while as third, line in which 76% of patients received lapatinib/capacitabine before TDM1, median PFS was 12 and 13 months (p=NS), respectively. Conclusions: T-DM1 showed a good activity on BM in BC patients. A better outcome was shown in patients previously treated with lapatinib. The identification of clinical and biological prognostic factors could be needed to better select more responder patients with BM to T-DM1. Citation Format: Fabi A, Alesini D, Valle E, Carbognin L, Arpino G, Montemurro F, Ciccarese M, Cannita K, Paris I, Cursano MC, Moscetti L, Ferretti G, De Laurentiis M, Zambelli A, La Verde N, Nisticò C, Gasparro S, Giannarelli D, Cognetti F. Ado-trastuzumab emtansine (TDM-1) treatment and brain metastases in HER2 positive metastatic breast cancer patients: Final analysis of an italian multicenter study [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 P1-17-02.

Objectives: Breast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information. Material and methods: In this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome. Results: We describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC). Conclusion: Data regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members. (C) 2017 Elsevier Ltd. All rights reserved.

Background: Worldwide, breast cancer (BC) is the most common malignancy in the female population. In recent years, its diagnosis in young women has increased, together with a growing desire to become pregnant later in life. Although there is evidence about the detrimental effect of chemotherapy (CT) on the menses cycle, a practical tool to measure ovarian reserve is still missing. Recently, anti-Mullerian hormone (AMH) has been considered a good surrogate for ovarian reserve. The main objective of this paper is to evaluate the effect of CT on AMH value. Methods: A systematic review and meta-analysis were conducted on the PubMed and Scopus electronic databases on articles retrieved from inception until February 2021. Trials evaluating ovarian reserves before and after CT in BC were included. We excluded case reports, case-series with fewer than ten patients, reviews (narrative or systematic), communications and perspectives. Studies in languages other than English or with polycystic ovarian syndrome (PCOS) patients were also excluded. AMH reduction was the main endpoint. Egger’s and Begg’s tests were used to assess the risk of publication bias. Results: Eighteen trials were included from the 833 examined. A statistically significant decline in serum AMH concentration was found after CT, persisting even after years, with an overall reduction of −1.97 (95% CI: −3.12, −0.82). No significant differences in ovarian reserve loss were found in the BRCA1/2 mutation carriers compared to wild-type patients. Conclusions: Although this study has some limitations, including publication bias, failure to stratify the results by some important factors and low to medium quality of the studies included, this metanalysis demonstrates that the level of AMH markedly falls after CT in BC patients, corresponding to a reduction in ovarian reserve. These findings should be routinely discussed during oncofertility counseling and used to guide fertility preservation choices in young women before starting treatment.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this ‘field-practice’ study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively. In conclusion, in this ‘real-word’ study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatinib.

Background: T-DM1 showed remarkable activity in metastatic HER-2 positive breast cancer (mBC) and it was recently approved for clinical use in patients (pts) who previously failed Trastuzumab- and Taxanes-based therapies. Currently, little is known on the performance of T-DM1 in a “real life” scenario. Therefore, we investigated effectiveness and safety of T-DM1 in Italian daily practice. Methods: Pts baseline characteristics and clinical outcome of pts with HER-2 positive mBC treated with T-DM1 between 2013 and 2015 at 20 Italian Institutions were retrospectively collected and analyzed. Results: 300 pts were included in our analysis. Median age was 51 years (27-78); visceral metastases were present in 204 (68%) pts and brain metastases in 86 (29%). It is noteworthy that 111 (37%) pts received T-DM1 as pure second line, 83 (28%) as third line and 96 (32%) as further lines. Moreover 10 (3%) pts had T-DM1 as first line because disease recurrence occurred during or adjuvant trastuzumab of within 6 months of its completion. The overall response rate (ORR) was 40%, global disease control rate (gDCR) 64%, median progression-free survival (PFS) 7.0 months (C.I.95%: 5.6-8.4) and overall survival (OS) at 2 years 63%. Pts with 1, 2 and 3 or more metastatic site had OS at 2 years of 87%, 67% and 46%, respectively (p Conclusions: To our knowledge, this is the first real life, multicenter retrospective analysis evaluating efficacy and safety of T-DM1 in pretreated HER-2 positive mBC pts. We observed remarkable results in terms of PFS and OS, especially when T-DM1 was given early in the course of metastatic disease. Shortened PFS in patients progressing after pertuzumab suggest further analyses to better define possible molecular mechanisms of cross-resistences between two molecules. As a whole there was no evidence of significant or unexpected toxicities. Although these findings should be taken with caution due to the retrospective analysis and the different lines of previous treatment considered, we confirmed the potential therapeutic role of T-DM1 across a heterogeneous population of HER-2 positive mBC patients. The final analysis will be presented to the meeting. Citation Format: Fabi A, De Laurentiis M, Caruso M, Valle E, Moscetti L, Santini D, Cannita K, Carbognin L, Ciccarese M, Rossello R, Arpino G, Leonardi V, Montemurro F, La Verde N, Generali DG, Zambelli A, Scandurra G, Russillo M, Paris I, D'Ottavio AM, Filippelli G, Giampaglia M, Stani S, Fabbri A, Alesini D, Giannarelli D, Cognetti F. T-DM1 in HER2 positive advanced breast cancer patients: Real world practice from a multicenter observational 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 P4-21-11.

Objective To assess the accuracy of preoperative ultrasound examination for predicting lymph-node (LN) status in patients with vulvar cancer. Methods This was a single-institution retrospective observational study of all women with a histological diagnosis of vulvar cancer triaged to inguinal surgery within 30 days following ultrasound evaluation between December 2010 and January 2016. For each groin examined, 15 morphological and dimensional sonographic parameters associated with suspicion for LN involvement were examined. A morphometric ultrasound pattern (MUP) was expressed for each groin, classifying the inguinal LN status into five groups (normal; reactive-but-negative; minimally suspicious/probably negative; moderately suspicious; and highly suspicious/positive) according to subjective judgment, followed by stratification as positive or negative for metastasis according to morphometric binomial assessment (MBA). In cases of positive MBA, fine-needle aspiration cytology was performed. Combining the information obtained from MUP and cytologic results, a binomial final overall assessment (FOA) was assigned for each groin. The final histology was considered as the reference standard. Comparison was performed between patients with negative and those with positive LNs on histology, and receiver-operating-characteristics curves were generated for statistically significant variables on univariate analysis, to evaluate their diagnostic ability to predict negative LN status. Results Of 144 patients included in the analysis, 87 had negative inguinal LNs and 57 had positive LNs on histology. A total of 256 groins were analyzed, of which 171 were negative and 85 showed at least one metastatic LN on histology. The following parameters showed the greatest accuracy, with the best balance between specificity and sensitivity, in predicting negative LN status: cortical (C) thickness of the dominant LN (cut-off, 2.5 mm; sensitivity, 90.0%; specificity, 77.9%); short-axis (S) length of the dominant LN (cut-off, 8.4 mm; sensitivity, 63.9%; specificity, 90.6%); C/medulla (M) thickness ratio of the dominant LN (cut-off, 1.2 mm; sensitivity, 70.4%; specificity, 91.5%), the combination of S length and C/M thickness ratio (sensitivity, 88.9%; specificity, 82.4%); and the FOA analysis (sensitivity, 85.9%; specificity, 84.2%). Conclusions Preoperative ultrasound assessment, with or without the addition of cytology, has a high accuracy in assessing inguinal LN status in patients with vulvar cancer. In particular, the combination of two ultrasound parameters (S length and C/M thickness ratio) provided the greatest accuracy in discriminating between negative and positive LNs. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Data from 423 human epidermal growth factor receptor 2-negative (HER2−), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane (p = 0.002) and favorably influenced by early line-treatment (p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

The characterization of tumor biology and consequently the identification of prognostic and predictive biomarkers represent key issues for the translational research in breast cancer (BC). Phosphatase and tensin homolog deleted on chromosome ten (PTEN), the negative regulator of the proto-oncogenic phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, constitutes one of the most intriguing tumor suppressor genes involved in a series of biological processes, such as cell growth and survival, cellular migration and genomic stability. Loss of PTEN activity, due to protein, genetic or epigenetic alterations, was reported in up to almost half of BC cases. Recently, besides the role of PTEN in the pathogenesis of BC, investigated for over 20 years after the PTEN discovery, several retrospective and prospective translational studies, in the early and advanced setting, reported controversial results regarding the association between PTEN functional status and both clinical outcome and response to various BC treatments. This review explores the pre-clinical and clinical role of PTEN in BC with regard to the potential association of PTEN with prognosis and treatment response or resistance, underlying the complexity of the interpretation of available results and suggesting potential future perspectives.

Objective To evaluate the timing and pattern of relapse, and duration of response to second line chemotherapy in advanced ovarian cancer (AOC) patients treated with first line carboplatin-paclitaxel chemotherapy with or without bevacizumab. Patients and methods This is a case-control study including 222 AOC patients. Seventy-four women treated with first line carboplatin-paclitaxel-bevacizumab chemotherapy (Cases) were matched based on laparoscopic predictive index value, and residual tumor at first surgery with 148 AOC patients treated with carboplatin-paclitaxel. Distribution of pattern of relapse, and response to second line chemotherapy was compared between the two groups. Time to Progression (TTP) for second line chemotherapy was also analyzed for study purpose. Results Median platinum-free interval (PFI) was 16months (range 2–65) in Cases, compared with 9months (1–83) in Controls (p-value=0.001). Twenty patients (51.3%) among Cases showed recurrence in multiple anatomic sites, compared with 31 (31.9%) in the Control group (p-value=0.035). Peritoneal recurrence occurred as diffuse in 30 Cases (96.8%), and 60 Controls (82.2%; p-value=0.046). Secondary cytoreductive surgery (SCS) was successfully completed in 53.5% of Controls compared to 10.0% of Cases (p-value=0.016). In women with fully platinum-sensitive relapse, response rate to second line chemotherapy was 85.2% in Controls, compared to 38.4% in Cases (p-value=0.002). Finally, Cases showed a shorter TTP, compared to Controls (5months vs 8months; p-value=0.041). Conclusions Incorporation of bevacizumab into upfront regimens prolongs PFI in AOC patients, but is associated with wider presentation of relapse, lower rate of complete SCS, and shorter TTP to second line chemotherapy in women with platinum-sensitive disease.

Background: The primary objective of this phase IIIb, single arm trial is to study circulating tumor DNA (ctDNA) alterations, their evolution during treatment and association with clinical outcome in patients receiving ribociclib and letrozole as first-line therapy for aBC. Here we report baseline ctDNA mutational status and its correlation with clinical-pathological characteristics and response to treatment on the basis of first imaging evaluation. Methods: From February to December 2018, 287 post-menopausal patients (pts) with hormone receptor positive (HR+) and HER2 negative aBC were enrolled in 47 Italian Centers; 271 pts were suitable for biomarker analysis (Biomarker Analysis Set- BAS). Data on first imaging evaluation were available for 225 pts. Baseline liquid biopsies were analyzed both for Copy Number Variation (CNV) by Oncomine Pan-Cancer Cell-Free Assay (Thermo Fisher Scientific) and for Single Nucleotide Variant (SNV) using 533 amplicon custom AmpliSeq HD panel optimized for the detection of low abundance events in ctDNA. Variants were analyzed as both individual genes and as pre-defined pathways (n=10). Results: At BAS, median age was 66 years (range 47-86). At study entry, 60% (109) and 40% (162) of pts had recurrent and de-novo disease, respectively, with 43% (117) of pts with visceral and 24% (64) with bone-only involvement. At least one CNV alteration or a hotspot mutation was detected in 51% of patients. The most frequently altered genes were PIK3CA (22.14%), TP53 (15.50%), FGFR1 (6.64%), CCND1 (4.80%), CCND2 (4.80%), KMT2C (4.43%), MYC (4.06%), CDK4 (3.69%) AKT1 (3.32%), PTEN (3.32%), ERBB2 (2.58%), CCND3 (2.58%), APC (2.21%) and MAP2K4 (2.21%). More than one alteration was observed in 28% pts (either CNV or hotspots). Mutation in KTM2C or alterations in genes belonging to the “Estrogen Receptor nuclear function” (ERnf) pathway (i.e. KTM2C, ESR1, GATA3 and MYC) were more frequent in patients with recurrent vs. de novo disease (Odds Ratio [OR] =7.69, p=0.0499 for KTM2C; OR=2.70, p=0.0381 for ERnf). MYC copy number gain or alterations in the ERnf genes were more frequent in Estrogen Receptor positive (ER+)/Progesteron Receptor negative (PgR-) compared to ER+/PgR+ tumors (OR= 4.07, p=0.0361 for MYC; OR=3.36, p=0.0073 for ERnf). Copy number gain of FGFRs (FGFR1, 2 and 3) were more frequent in patients with visceral versus bone-only disease (OR=5.26, p=0.0144 for FGFRs) and in pts with more than three metastatic sites (OR=8.05, p=0.0052). At first imaging, the Clinical Benefit Rate (CBR, defined as CR + PR + SD) was 90%, with only 10% of pts showing early disease progression (PD). Thirty pts (11%) had at least one alteration in genes belonging to the CDK4/6 pathway (CCND1, RB1, CDK4 and 6, CDKN2A). These alterations were more frequent in the group of patients with early PD (OR=3.23, p=0.0272). MYC gain, TP53 mutations and alterations in the HER family genes (EGFR, ERBB2, 3 and 4) were also more frequent in pts with early PD compared with pts with CBR (OR 5.16, p=0.0280, OR 3.87, p=0.0058 and OR 4.40, p=0.0426, respectively). Conclusion: At the present analysis, alterations in KTM2C and ERnf seem to characterize recurrent vs de novo aBC while FGFRs are prevalent in patients with more aggressive disease. Interestingly, MYC gain, TP53 mutations, alterations in genes of the HER family and CDK4/6 pathway were more likely detected in patients with early PD suggesting these as potential markers of intrinsic resistance to first-line treatment with ribociclib and letrozole. Further analyses for biomarker dynamics and pharmacogenomics are ongoing. Citation Format: Michelino De Laurentiis, Luca Malorni, Giampaolo Bianchini, Roberta Caputo, Mario Giuliano, Alberto Zambelli, Fabio Puglisi, Lucia Del Mastro, Marco Colleoni, Filippo Montemurro, Giulia Bianchi, Ida Paris, Giacomo Allegrini, Laura Amaducci, Marina Elena Cazzaniga, Michele Orditura, Claudio Zamagni, Vincenzo Adamo, Valentina Guarnieri, Nicola Battelli, Maria Rosaria Valerio, Saverio Cinieri, Sara Bianchetti, Donatella Grasso, Daniela Castelletti, Diletta Valsecchi, Ettore Cotroneo, Grazia Arpino. Bioitalee - Biomarker analysis on liquid biopsies of patients treated with ribociclib and letrozole as first-line therapy for advanced breast cancer (aBC) (NCT03439046) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-07.

Introduction: In advanced epithelial ovarian cancer patients, the standard of care is primary debulking surgery, followed by first-line chemotherapy often with bevacizumab addiction. In this context, some experiences have shown that a comprehensive treatment approach to surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) could improve the prognosis. Objective: This is a study aimed to explore the feasibility of primary debulking surgery and HIPEC upfront followed by first-line therapy with bevacizumab. Study Design: Phase II monocentric, open label, non-randomised and single-arm study. Forty patients affected by advanced ovarian cancer submitted to primary debulking surgery with HIPEC were enrolled in the study. After surgery, all patients underwent systemic chemotherapy with bevacizumab addiction. Results: Complete cytoreduction (RT = 0) was achieved in all cases. Treatment-related early complications were observed in 23 patients and in 15 cases were G1–G2. Major complications were reported in 8 patients. No postoperative death was recorded. Subsequent chemotherapy was administered in all cases. Median time between surgery and first cycle of chemotherapy was 42 days (range 30–76). Concomitant bevacizumab was administered in 34 patients (85%). Maintenance with bevacizumab was feasible in 33 patients (82.5%) and its withdrawal was necessary for 1 patient (2.5%) due to G3 hypertension. Conclusion: Our data suggest that HIPEC can be safely introduced in the upfront therapy of advanced ovarian cancer.