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INTRODUCTION: Breast cancer (BC) is a highly prevalent and heterogeneous disease, entailing different so-called intrinsic subtypes (IS) according to gene expression, namely Luminal A, Luminal B, HER2-Enriched (HER2E) and Basal-like, as well as a normal breast-like group. The HER2E is still a poorly understood entity, which needs further biologic characterization to improve therapeutic management. MATERIAL AND METHODS: Patients (pts) treated at Hospital Clinic (Barcelona, Spain) over 18 years with a diagnosis of metastatic BC, with available matched primary and metastatic tumor samples for gene expression analyses were retrospectively recruited. Using the nCounter® Breast Cancer 360 panel, we studied the expression of 776 genes pertaining to different tumor and immune pathway-related signatures, with a focus on HER2E vs. non-HER2E tumors. Significant changes were considered at a false discovery rate (FDR) < 5%. Main clinicopathological features were also compared. IS changes from primary to metastatic disease were assessed. RESULTS: Ninety-one pts with paired tumor samples were included. Briefly, primary tumors were 67.0% hormone receptor-positive (HR+)/HER2-negative (HER2-), 14.8% were HER2-positive (HER2+) and 18.2% were triple-negative (TNBC). IS distribution in primary tumors was the following: 25 Luminal A (28%), 22 Luminal B (24%), 24 HER2E (26%), 12 Basal-like (13%), and 8 Normal-like (9%). In contrast, IS distribution in metastatic tumors was the following: 13 Luminal A (14%), 22 Luminal B (24%), 34 HER2-E (37%), 16 Basal-like (18%), and 6 Normal-like (7%). The HER2E disease proved to be a relatively stable subtype, with 16 (66.7%) tumors not changing IS in the transition to metastatic disease (p=0.078). Particularly, within HR+/HER2-, HER2+ and TNBC, 8/12 (66.7%), 8/10 (80.0%) and 1/2 (50.0%) tumors remained HER2E. Conversely, an overall significant switch from Luminal to non-Luminal tumors at the metastatic progression was observed (p=0.031), with 14/19 (73.7%) new non-Luminal BC being HER2E. When considering all primary and metastatic tumors, HER2E were observed to be less frequently estrogen receptor (ER) positive than non-HER2E tumors (55.8% vs. 78.7%; p=0.002), with lower mean progesterone receptor (PR) levels (15.3% vs. 25.8%; p=0.027). Compared to the other subtypes (as a group), the PAM50 risk of recurrence score (ROR-P) was higher for HER2E tumors (59.1 vs. 41.7; p < 0.001), which were also more frequently HER2+ (36.5% vs. 5.8%) and less likely HR+/HER2- (50.0% vs. 73.6%) and TNBC (13.5% vs. 20.7%), compared to non-HER2E (p < 0.001). No significant differences in grade, TILs, Ki67 and histotype were observed. Overall, 140/776 genes were significantly downregulated in HER2E vs. non-HER2E tumors, including genes related to cell adhesion, migration, DNA damage repair, apoptosis, estrogen signalling pathway, senescence. Conversely, 178/776 genes were significantly upregulated, including the tyrosine-kinase receptor FGFR4, genes involved in nuclear activity, DNA transcription regulation, MAP-kinase signaling pathways, proliferation, cytokine response, epithelial-to-mesenchymal transition (EMT), cell cycle progression, and immune-related genes such as CD274 (PD-L1 gene). DISCUSSION: A switch towards more aggressive IS from primary to advanced disease was observed, with an increase in HER2E prevalence. HER2E tumors, which tend to maintain their IS at the metastatic disease, showed upregulation of genes related to proliferation, survival and EMT, coherently with their well-known worse prognosis. FGFR4 and CD274 upregulation, along with downregulation of genes involved in DNA damage repair suggest these tumors might benefit from targeted therapeutic approaches. Genomic higher risk was not convoyed by consistent clinicopathological features, except for lower PR levels and HER2 overexpression at IHC. Further characterization according to primary/metastatic and HR status is ongoing. Intrinsic subtype distribution across primary and metastatic breast tumors Citation Format: Francisco Javier Muñoz-Carrillo, Laia Paré, Benedetta Conte, Adela Rodríguez, Patricia Galván, Esther Sanfeliu, Blanca González-Farré, Claudette Falato, Isabel Garcia-Fructuoso, Barbara Adamo, Nuria Chic, Olga Martínez-Sáez, Tomás Pascual, Reinaldo Moreno, Montserrat Muñoz, Fara Brasó-Maristany, Aleix Prat, Francesco Schettini, Maria Vidal. Clinico-Pathological and Molecular Characterization of HER2-Enriched Breast Tumors Independently of HER2 Status [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-16.

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p p = 0.005). Time-to-best response (TTBR) and ORR (p p p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P

Oral SERDs are under extensive development to overcome fulvestrant main limitations, including intramuscular-only formulation and poor performance in early-stage hormone receptor-positive (HR+)/HER2-negative breast cancer. This review summarizes the most relevant evidence published so far and envisions the potential integration of oral SERDs in the therapeutic algorithm of HR+/HER2-negative metastatic breast cancer (MBC).Amcenestrant and giredestrant, two of the most promising oral SERDs, recently failed to show a significant improvement in progression-free survival (PFS) in pivotal trials. Conversely, elacestrant demonstrated significant PFS superiority over standard-of-care endocrine therapy (aromatase inhibitors or fulvestrant) in MBC. Additionally, it did not show unusual side effects observed with other oral SERDs, like bradycardia, hematotoxicity and vision impairment, and proved to be effective also in case of ESR1 -mutant endocrine-resistant breast cancer. Combination trials of oral SERDs with target agents, such as CDK4/6-inhibitors, are ongoing. Finally, some window-of-opportunity trials showed promising on-target activity in early-stage for this drug class.Promising results from early-phase trials are not translating into sufficient clinical benefit in pivotal trials of main oral SERDs in monotherapy, except for elacestrant. Whether oral SERDs might become the backbone for combination strategies in MBC or the preferred (neo)adjuvant endocrine agents is under evaluation.

Background: HoR+ breast cancer (BC) is an heterogeneous disease, comprising 4 molecular subtypes (i.e.Luminal A [LumA], Luminal B [LumB]), HER2-Enriched [HER2E] and Basal-like [BL]). In HoR+ MBC, non-LumA subtypes appear to be associated with poorer survival outcome compared to LumA. Here, we present a meta-analysis to validate the prognostic value of IS inHoR+ MBC. Methods: We performed a systematic review and trial-level meta-analysis of all available prospective phase II/III trials in HoR+ MBC where the prognostic role of the IS was assessed in terms of progression-free survival (PFS) or time-to-progression (TTP), if the former was not available. Hazard ratios (HR) and 95% confidence intervals (CI) had to be available or computable. Subgroup analyses according to treatment, menopausal and HER2 status were also performed. The random-effect model of Der Simonian and Laird was applied. Heterogeneity was assessed through Cochran’s Q and I2. Funnel plot with Egger’s and Begg’s test for publication bias, multiple sensitivity analyses and risk of bias analysis were also conducted. Revman 5.4 and R 3.6.1 for MacOS X were used for statistical analyses. Tests were two-sided and the threshold for significance was set at p Table 1.Included studies characteristicsStudy ReferenceTrial NameBreast CancerSubgroupMenopausal StatusTrial TypeTreatmentNon-Luminal ALuminal APrat A. et al. The Oncologist 2019BOLERO2HR+/HER2-negPostmenopausalRandomizedEverolimus+exemestane vs exemestane139122Jørgensen C.L.T. et al. Acta Oncologica 2014DBCGMainly HR+/HER2-negMixedRandomizedDocetaxel+gemcitabine vs docetaxel18684Prat A. et al. JAMA Oncol 2016EGF30008HR+/HER2+ and negPostmenopausalRandomizedLetrozole+lapatinib vs letrozole424377Prat A. et al. J Clin Oncol 2021MONALEESA 2HR+/HER2-negPostmenopausalRandomizedRibociclib+letrozole vs letrozole--Prat A. et al. J Clin Oncol 2021MONALEESA 3HR+/HER2-negPostmenopausalRandomizedRibociclib+fulvestrant vs fulvestrant618542Prat A. et al. J Clin Oncol 2021MONALEESA 7HR+/HER2-negPremenopausalRandomizedRibociclib+AI/TAM vs AI/TAM--Ciruelos E. et al. Clin Can Res 2020PATRICIAHR+/HER2+PostmenopausalNon-RandomizedPalbociclib+/-letrozole+trastuzumab3410 Citation Format: Francesco Schettini, Olga Martínez-Sáez, Nuria Chic, Fara Brasó-Maristany, Patricia Galván, Debora Martínez, Laia Paré, Maria Vidal, Barbara Adamo, Montserrat Muñoz, Tomás Pascual, Eva Ciruelos, Charles M Perou, Lisa A Carey, Aleix Prat. Prognostic value of intrinsic subtypes (IS) in hormone receptor-positive (HoR+) metastatic breast cancer (MBC): A systematic review and meta-analysis of prospective trials [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 P4-07-08.

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 In clinically node-negative (cN0) early stage breast cancer (EBC) undergoing primary systemic treatment (PST), post-treatment positive sentinel lymph node (SLN+) directs axillary lymph node dissection (ALND), with uncertain impacts on outcomes and increased morbidities. Patients and Methods We conducted an observational study on imaging-confirmed cN0 EBC, who underwent PST and breast surgery that resulted in SLN+ and underwent ALND. The association among baseline/postsurgical clinic–pathological factors and positive nonsentinel additional axillary lymph nodes (non-SLN+) was analyzed with logistic regression. LASSO regression (LR) identified variables to include in a predictive score of non-SLN+ (ALND-predict). The accuracy and calibration were assessed, an optimal cut-point was then identified, and in silico validation with bootstrap was undertaken. Results Non-SLN+ were detected in 22.2% cases after ALND. Only progesterone receptor (PR) levels and macrometastatic SLN+ were independently associated to non-SLN+. LR identified PR, Ki67, and type and number of SLN+ as the most efficient covariates. The ALND-predict score was built based on their LR coefficients, showing an area under the curve (AUC) of 0.83 and an optimal cut-off of 63, with a negative predictive value (NPV) of 0.925. Continuous and dichotomic scores had a good fit (p = 0.876 and p = 1.00, respectively) and were independently associated to non-SLN+ [adjusted odds ratio (aOR): 1.06, p = 0.002 and aOR: 23.77, p < 0.001, respectively]. After 5000 bootstrap-adjusted retesting, the estimated bias-corrected and accelerated 95%CI included the aOR. Conclusions In cN0 EBC with post-PST SLN+, non-SLN+ at ALND are infrequent (~22%) and independently associated to PR levels and macrometastatic SLN. ALND-predict multiparametric score accurately predicted absence of non-SLN involvement, identifying most patients who could be safely spared unnecessary ALND. Prospective validation is required.

Immunotherapy; PARP inhibitors; Pembrolizumab Immunoteràpia; Inhibidors de PARP; Pembrolizumab Inmunoterapia; Inhibidores de PARP; Pembrolizumab Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).

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.

BACKGROUND: In early-stage triple negative breast cancer (TNBC), the addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (CT) increases pathologic complete response (pCR) and relapsed-free survival. However, it is unclear whether CBDCA improves overall survival (OS). In addition, the prognostic and/or predictive role of pathogenic germline variants (PGV) in BRCA1/2 genes and other cancer risk in this setting is not fully understood. Here, we assessed the efficacy of (neo)adjuvant CBDCA and the prognostic and predictive role of a panel of 14 genes in patients (pts) with eTNBC. METHODS: This is a retrospective study on 117 pts diagnosed with early-stage TNBC between 2000-2021 at Hospital Clinic of Barcelona. Eighty-one pts (69%) were candidates for PGV testing. Overall, 14 genes (PGV) (BRCA1, BRCA2, PALB2, BRIP1, CHEK2, TP53, ATM, RAD51C, RAD51D, BARD1, MLH1, MSH2, MSH6 and PMS2) were assessed using the TruSight hereditary cancer panel (Illumina MySeq platform) according to local guidelines. Univariable and multivariable logistic regression and Cox regression analyses were performed to identify clinical and molecular predictors of pCR and relapse-free survival (RFS), respectively. Chi-squared or Fisher’s exact tests were used to assess characteristics’ distribution as appropriate. RESULTS: Of 117 pts, 83 (71%) received CT in the neoadjuvant setting and 28 (24%) in the adjuvant setting. CBDCA was added to standard CT in 68 pts (82%) in the neoadjuvant cohort and 7 pts (6%) in the adjuvant cohort. Among pts with germline testing, 32/81 (39%) harbored PGV. BRCA1 was the most frequently mutated gene (18/32, 56%), followed by BRCA2 (5/32, 16%), PALB2 (4/32, 13%), BRIP1 (2/32, 6%), CHEK2, TP53 and PMS2 (3/32, 6%). Percentages of pts receiving CBDCA were similar between patients with and without PGV (14/16,87% and wild type (53/67,79%)(p=0.120). In the neoadjuvant cohort (n=83), CBDCA was the only variable significantly associated with pCR at both univariate (pCR rates of 58.5% with CBCDA and 14.3% without CBCDA; odds ratio [OR]=8.2 [95% CIs 2.0-55.7], p=0.008) and remained statistically significant after adjusting for PGV, tumor size and nodal status (OR=6.9 [95% CIs 1.4-53.0], p=0.028). pCR rates according to PGV are reported in Table 1. In terms of RFS, addition of CBDCA to neoadjuvant therapy (hazard ratio [HR]=0.2 [0.1-0.45], p< 0.001), PGV (HR=0.2 [0.05-0.9], p=0.048), pCR (HR=0.2 [0.1-0.6], p=0.004) and nodal status (HR=5.1 [1.7-15.2], p< 0.003) were significantly associated with RFS in univariate analyses. In a multivariable model, CBDCA remained an independent predictor of improved RFS along with pCR. When the neoadjuvant and adjuvant cohort were pooled together (n=117), platinum-based CT remained significantly associated with better RFS (HR=0.2 [0.14-0.86], p=0.021) regardless of time of administration (i.e., neoadjuvant or adjuvant). With a median follow-up of 5 years, CBCDA use was not found associated with OS (HR=0.7 [0.3-1.8], p= 0.560). CONCLUSIONS: The addition of CBDCA to standard CT was significantly associated with pCR and RFS but not OS, consistent with the phase III data. The benefit in terms of RFS was independent of the presence and the type of pathogenic germline alterations. Table 1. pCR rates according to PGV Citation Format: Adela Rodríguez Hernández, Benedetta Conte, Laia Fernández, Fara Brasó-Maristany, Belén Pastor, Miriam Potrony, Lorena Moreno, Elia Grau, Joan Antón Puig-Butillé, Aurora Sánchez, Blanca González-Farré, Esther Sanfeliu, Olga Martínez-Sáez, Claudette Falato, Maria Vidal, Nuria Chic, Tomás Pascual, Francesco Schettini, Montserrat Muñoz, Francesc Balaguer, Aleix Prat, Barbara Adamo. Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-09.

Aim: To investigate the toxicity of nab-paclitaxel (wNP)/nonpegylated liposome-encapsulated doxorubicin (wNPLD) combination in HER2-negative metastatic breast cancer (MBC) patients as first-line treatment. Materials & methods: Phase I, single-arm study in metastatic breast cancer patients naive to previous chemotherapy for advanced disease. A 3 + 3 dose-escalation design was used to determine the safety. Primary endpoints were the identification of dose-limiting toxicity and maximum tolerated dose. Results: In total, 12 patients (mean age: 52 years; median metastatic sites: 2) were enrolled and 97 cycles were completed. Maximum tolerated dose was wNP + wNPLD 25 mg/m2. The most common adverse events were neutropenia, nausea, diarrhea and mucositis. The objective response rate was 68% (response mean duration: 12.6 months). Conclusion: wNP/wNPLD combination constitutes an active regimen with mild toxicity.

Purpose Obesity and insulin resistance have been associated with poor prognosis in breast cancer (BC). The present prospective study aimed to investigate the impact of metabolic syndrome (MetS) and its components on early BC (eBC) patients’ outcome. Methods MetS was defined by the presence of 3 to 5 of the following components: waist circumference > 88 cm, blood pressure ≥ 130/≥ 85 mmHg, serum levels of triglycerides ≥ 150 mg/dL, high density lipoprotein . Results Overall, 544 (75.9%) and 173 (24.1%) women were categorized as non-MetS and MetS, respectively. MetS patients were more likely to be older, postmenopausal, and insulin-resistant compared to non-MetS patients (p p = 0.07] and a significantly higher risk of death compared to non-MetS patients [overall survival (OS), HR 3.01, p p = 0.001]. Additionally, patients with 1 to 2 components of MetS had an increased risk of dying compared to patients with 0 components (OS, HR 4.90, p = 0.01; BCSS, HR 6.07, p = 0.02). Conclusions MetS correlated with poor outcome in eBC patients. Among patients without full criteria for MetS diagnosis, the presence of 1 or 2 components of the syndrome may predict for worse survival.

OBJECTIVE: The objective of this study was to evaluate the efficacy of rescue fractional microablative CO2 laser treatment in women with severe symptoms and sexual dysfunction related to lichen sclerosus not responsive to long-term ultra-potent topical corticosteroid treatment. METHODS: Consecutive eligible women with lichen sclerosus referred to our unit who received fractional microablative CO2 laser treatment after failure of ultra-potent topical corticosteroid treatment were enrolled in the study. The diagnosis was confirmed by histological assessment in all cases. Patients underwent two cycles of CO2 laser every 30 to 40 days. The severity of lichen sclerosus-related symptoms, sexual function, and procedure discomfort were evaluated with a visual analog scale in the same individual at baseline, after completion of each treatment cycle. Follow-up visits were scheduled during each treatment cycle and at least 1 month after completion of the treatment. The Friedman ANOVA test was used to evaluate differences in the visual analog scale scores of each symptom during treatment. RESULTS: A total of 100 patients with vulvar lichen sclerosus were screened, 40 of whom fulfilled the eligibility criteria. We found a significant improvement in vulvar itching (χ [2] = 31,182, P

Background: Several randomized clinical trials clearly demonstrated that adding palbociclib (P) to endocrine therapies (ET), such as letrozole (LT) or fulvestrant (FLV), significantly improves outcome both in first-line/endocrine sensitive and second-line/endocrine resistant hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC) patients (pts). The aims of the present study were to assess efficacy, activity and toxicity of P combined with either LT or FLV in a real world setting, and to study the efficacy and activity of treatments administered after progression to P + ET. Methods: Records of 245 consecutive HR+/HER2- MBC patients from 14 Italian cancer centers were reviewed in this observational study. Primary end-point was progression-free survival (PFS) obtained with P+ET; secondary end-points were overall response rates (ORR) and clinical benefit rate (CBR) obtained with P+ET and with post-progression treatments, as well as overall survival (OS), PFS to subsequent treatment lines and post-progression survival (PPS). Results: Overall 245 pts were treated with P+ET from April 2014. Of them, 116 (47%) received it in first-line setting, 70 (28%) in second-line and the rest (68 pts, 25%) in subsequent lines. Median age was 60 (35-80) years and median ECOG performance status was 0. Seventy-three pts (30%) had more than two metastatic sites and 75 (31%) had visceral metastasis. Ninenty-one (37%) pts received P+LT and 92 (37%) were treated with P+FLV. For 15 (6%) premenopausal pts an LHRH analogue was added to P+ET. In 77 (41%) patients a biopsy of a metastatic lesion was performed. Among the 116 pts treated in first-line setting, median PFS was 14.7 (95% CI 12.0-17.3) and 15.1 (95%CI 8.6-21.6) months for pts receiving P+LT and P+FLV, respectively. ORR was 48% (95% CI: 39-57%) and CBR was 75% (95% CI, 66-82%). Four (3%) complete responses (CR), 52 (45%) partial responses (PR), 31 (27%) stable disease (SD) and 11 (9%) progression disease (PD) were observed as best response; 18 pts were not yet evaluable. Among the 70 pts treated in second-line setting, median PFS was 10.8 (95%CI 0-24.3) and 7.9 (95%CI 3.3-12.5) months, for pts receiving P+LT and P+FLV, respectively. The ORR was 26% (95% CI: 16-38) and the CBR was 66% (95% CI, 53-76). One CR (1%), 17 PR (24%), 28 SD (40%) and 13 PD (18.5%) were observed as best response, while 9 were not yet evaluable. Best response was achieved after a median of 5 cycle. At time of the current analysis, 50 pts experienced PD during P+ET. Of them, 38 (76%) received chemotherapy (capecitabine, eribulin, nab-paclitaxel, paclitaxel+bevacizumab, vinoreline) and 12 (24%) ET. To date, only 5 pts progressed during these therapies, preventing us for evaluating secondary end-points regarding efficacy and activity. The most frequent adverse event (AE) was grade 3-4 neutropenia (31%), with febrile neutropenia reported in 5 (2%) cases. Main non-hematological AEs were fatigue and gastrointestinal symptoms (diarrhea and stypsis). Conclusions: Our findings confirm the efficacy and safety of P+ET as first/second-line treatment for HR+/HER2- MBC pts, even in a non-selected, real world population. Since data regarding the efficacy and activity of post-progression therapies were not mature at the time of the current analysis, they will be subsequently presented. Citation Format: Alessandra Fabi, Michelangelo Russillo, Mariangela Ciccarese, Simone Scagnoli, Francesco Schettini, Giuseppe Buono, Vito Lo Russo, Grazia Arpino, Rosalba Rossella, Giuseppina Sarobba, Marianna Giampaglia, Patrizia Pellegrini, Simonetta Stani, Michela Palleschi, Vincenzo Adamo, Francesca Morelli, Maria Agnese Fabbri, Cecilia Nistico, Gianluigi Ferretti, Giovanna Catania, Simona Pisegna, Diana Giannarelli, Francesco Cognetti. Real-world evidence of efficacy and activity of palbociclib plus endocrine therapy and post-progression treatments in HR+/HER2- metastatic breast cancer patients: The PALPract study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-18.

Introduction The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study. Patients and methods Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis. Results Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p, Highlights • The current multicenter analysis developed and validated a prognostic nomogram for early stage ILC. • A next-generation sequencing analysis was performed in prognostic ‘outlier’ patients. • CDK4 gain emerges as a potential negative prognostic factor in ILC patients. .

Background: Breast cancer is traditionally classified into three clinical subtypes based on hormone receptor and HER2 status (i.e., luminal-like, HER2-positive, and triple negative). Each subtype has distinct clinical-pathological and molecular characteristics and requires tailored treatments. Recent research efforts have been focusing on a new classification, identifying the so-called “HER2-low” category, including tumors characterized by a low level of HER2 expression (immunohistochemistry score 1+ or 2+ without in situ hybridization amplification). Emerging evidence shows that patients with HER2-low tumors can derive benefit from selected anti-HER2 therapies. This represents a major advancement in the field of breast oncology, where a broader proportion of patients with breast cancer can ultimately benefit from new effective targeted treatment strategies. Summary: The antibody-drug conjugate trastuzumab deruxtecan has proven impressive efficacy in patients with HER2-low breast cancer, and several other drugs are currently under investigation in this subset of patients. Additional investigation is needed to address open issues that exist in this field, including appropriate pathological assessment of HER2-low status, clarification of its prognostic implications, and global access to newly approved drugs. Key Message: Our review aims to summarize the available evidence regarding HER2-low breast cancer, illustrating the current challenges that are being addressed and the future perspectives in this exciting new field.

Neoadjuvant endocrine treatment (NET) associates to satisfactory rates of breast conservative surgery and conversions from inoperable to operable hormone receptor-positive (HR+)/HER2-negative breast cancer (BC), with less toxicities than neoadjuvant chemotherapy (NACT) and similar outcomes. Hence, it has been proposed as a logical alternative to NACT in patients with HR+/HER2- BC candidate to a neoadjuvant approach. Nevertheless, potential barriers to the widespread use of NET include the heterogeneous nature of patient response coupled with the long duration needed to achieve a clinical response. However, interest in NET has significantly increased in the last decade, owing to more in-depth investigation of several biomarkers for a more adequate patient selection and on-treatment benefit monitoring, such as PEPI score, Ki67 and genomic assays. This review is intended to describe the state-of-the-art regarding NET, its future perspectives and potential integration with molecular biomarkers for the optimal selection of patients, regimen and duration of (neo)adjuvant treatments.

Background: To date, a consensus has not yet been reached about the therapy sequence after disease progression (PD) on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer (MBC). Objectives: The present study assesses, in a real-world setting, the activity of different subsequent therapies in patients who experienced a PD on palbociclib (P) + endocrine therapy (ET), to evaluate the best therapy sequence. Methods: This is a multicenter retrospective observational study. Records of consecutive HR+/HER2- MBC patients from January 2017 to May 2019 were reviewed. The primary endpoint was the evaluation of progression-free survival (PFS) according to subsequent treatment lines after progression on P+ET. Toxicity data were also collected. Results: The outcomes were analyzed in 89 MBC patients that had progressed on previous P+ET: 17 patients were on hormone therapy (HT) and 31 patients on chemotherapy (CT) as second-line treatments; seven patients were on HT and 34 on CT as third-line therapies. PFS of patients treated with HT as second-line therapy is significantly improved when compared with patients treated with CT (p=0.01). Considering third-line settings, the difference in PFS was not statistically different between HT and CT. A better outcome in terms of toxicity is observed among HT patients for both second- and third-line therapies. Conclusions: patients who were progressive on P+ET could still benefit from a subsequent ET. In patients who experienced a good efficacy from prior ET, without visceral metastatic sites, HT seems the most suitable option, when compared to CT, also in terms of safety.

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