Background: a-Selective phosphatidylinositol 3-kinase (PI3K) inhibitors improve outcome in patients with PIK3CAmutated, hormone receptor-positive (HRþ)/Her2À metastatic breast cancer (mBC). Nevertheless, it is still unclear how to integrate this new drug family in the treatment landscape. Patients and methods: A total of 649 patients with mBC from the SAFIR02 trial (NCT02299999), with available mutational profiles were selected for outcome analysis. PIK3CA mutations were prospectively determined by nextgeneration sequencing on metastatic samples. The mutational landscape of PIK3CA-mutated mBC was assessed by whole-exome sequencing (n ¼ 617). Finally, the prognostic value of PIK3CA mutations during chemotherapy was assessed in plasma samples (n ¼ 44) by next-generation sequencing and digital PCR. Results: Some 28% (104/364) of HRþ/Her2À tumors and 10% (27/255) of triple-negative breast cancer (TNBC) presented a PIK3CA mutation (P < 0.001). PIK3CA-mutated HRþ/Her2À mBC was less sensitive to chemotherapy [adjusted odds ratio: 0.40; 95% confidence interval (0.22e0.71); P ¼ 0.002], and presented a worse overall survival (OS) compared with PIK3CA wild-type [adjusted hazard ratio: 1.44; 95% confidence interval (1.02e2.03); P ¼ 0.04]. PIK3CA-mutated HRþ/Her2À mBC was enriched in MAP3K1 mutations (15% versus 5%, P ¼ 0.0005). In metastatic TNBC (mTNBC), the median OS in patients with PIK3CA mutation was 24 versus 14 months for PIK3CA wild-type (P ¼ 0.03). We further looked at the distribution of PIK3CA mutation in mTNBC according to HR expression on the primary tumor. Some 6% (9/138) of patients without HR expression on the primary and 36% (14/39) of patients with HRþ on the primary presented PIK3CA mutation (P < 0.001). The level of residual PIK3CA mutations in plasma after one to three cycles of chemotherapy was associated with a poor OS [continuous variable, hazard ratio: 1.03, 95% confidence interval (1.01e1.05), P ¼ 0.007]. Conclusion: PIK3CA-mutated HRþ/Her2À mBC patients present a poor outcome and resistance to chemotherapy. Patients with PIK3CA-mutated TNBC present a better OS. This could be explained by an enrichment of PIK3CA mutations in luminal BC which lost HR expression in the metastatic setting. Trial registration: SAFIR02 trial: NCT02299999.

The generation of antibodies following exposure to therapeutic drugs has been widely studied, however in oncology, data in relation to their clinical relevance are limited. Antidrug antibodies (ADAs) can cause a decrease in the amount of drug available, resulting in some cases in decreased antitumor activity and a consequent impact on clinical outcomes. Several immunologic factors can influence the development of ADAs, and in addition, the sensitivity of the different testing methods used in different studies can vary, representing an additional potential confounding factor. The reported frequency of ADA-positive patients following treatment with immune checkpoint inhibitors varies from as low as 1.5% for pembrolizumab to 54% for atezolizumab. This latter drug is the only immune checkpoint inhibitor to have undergone an expanded analysis of the clinical implications of ADAs, but with discordant results. Given that immune checkpoint inhibitors can modify the immune response and potentially impact ADA formation, data from published as well as prospective trials need to be evaluated for a better understanding of the clinical implications of ADAs in this setting.

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Malignant melanoma represents the most aggressive type of skin cancer. Modern therapies, including targeted agents and immune checkpoint inhibitors, have changed the dismal prognosis that characterized this disease. However, most evidence was obtained by studying patients with frequent subtypes of cutaneous melanoma (CM). Consequently, there is an emerging need to understand the molecular basis and treatment approaches for unusual melanoma subtypes. Even a standardized definition of infrequent or rare melanoma is not clearly established. For that reason, we reviewed this challenging topic considering clinical and molecular perspectives, including uncommon CMs—not associated with classical V600E/K BRAF mutations—malignant mucosal and uveal melanomas, and some unusual independent entities, such as amelanotic, desmoplastic, or spitzoid melanomas. Finally, we collected information regarding melanomas from non-traditional primary sites, which emerge from locations as unique as meninges, dermis, lymph nodes, the esophagus, and breasts. The aim of this review is to summarize and highlight the main scientific evidence regarding rare melanomas, with a particular focus on treatment perspectives.

PURPOSE In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair–related genes. PATIENTS AND METHODS We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair–related genes (g BRCA1/2- ATM- CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS Among the total population (n = 217), 15 (6.9%) patients carried g BRCA1/2 (n = 10)- ATM (n = 4)- CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger ( P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group ( P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival ( P = .020) and overall survival ( P = .012). CONCLUSION In this retrospective real-world study, g BRCA1/ 2- ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

1056 Background: HER2-low expression, defined as HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization assay (FISH), accounts for 50% of breast cancers. There is limited and conflicting evidence regarding the efficacy of cyclin-dependent kinase (CDK) 4 and 6 inhibitors in patients with ER+ and HER2-low tumors. This study aimed to investigate the prognostic value of HER2-low expression in patients with ER+/HER2-negative advanced breast cancer treated with CDK 4/6 inhibitors. Methods: We retrospectively selected consecutive patients with ER+/HER2-negative advanced breast cancer treated with CDK 4/6 inhibitors plus endocrine therapy in our institution from May 2015 to Feb 2020. Two cohorts were compared, including HER2-0 (IHC score) and HER2-low (HER2 IHC score 1+ and 2+ [negative FISH]) tumors. Comparisons in progression-free survival (PFS) and overall survival (OS) were performed using a log-rank test. The prognostic value of HER2-low was investigated by the Cox regression model. Results: Among the 186 patients included, median age at treatment was 55 (r 27-84), and majority had ECOG 0 (126, 67.8%). Progesterone receptor was positive in 155 (83.3%) tumors. Of note, most patients received CDK4/6 inhibitors and endocrine therapy as first-line setting (131, 70.4%). Mostly received palbociclib (161, 86.6%), while ribociclib and abemaciclib were used in 23 (12.4%) and 2 (1.08%) patients, respectively. Overall, 27 patients (14.5%) had de novo metastatic disease, 68 (36.6%) had only bone metastases, and 69 (37.1%) had visceral disease. Of the total population, 64 (34.4%) tumors were HER2-low (43 [23.1%] HER2-1+, and 21 [11.3%] HER2-2+), and 122 (65.6%) were HER2-0. Median PFS among patients with HER2-0 and HER-low were 19 mo. (95% CI, 13.9-24.1), and 15.6 mo. (95% CI, 11.1-20.0), p = 0.074, respectively. In patients treated with CDK 4/6 in the first-line setting, no statistically significant differences were observed in terms of PFS and OS between HER2-0 and HER2-low (PFS HR 0.73 [95% CI, 0.47-1.13; p = 0.160], and OS HR 1.04 [95% CI, 0.51-2.14; p = 0.909]). Conclusions: In our study, HER2-low expression did not show a statistically significant impact on patients with ER+/HER2-negative advanced breast cancer treated with CDK 4/6 inhibitors. Our study supports the necessity of real-world evidence and the design of pooled analysis to understand the real implication of this biomarker in patients with ER+/HER2-negative tumors.

et al. 26PA combination of resistance mechanisms is frequent in nonsmall cell lung cancer (NSCLC) that progressed to EGFR tyrosine kinase inhibitors (TKIs).

Effective networking and mentoring are critical determinants of professional satisfaction and success in oncology. There are multiple benefits associated with established mentoring programs. However, these are scarce in Latin America (LATAM). The AAZPIRE project meeting was held to encourage the discussion of mentorship strategies in our region, to create new learning frameworks, and improve cancer care. A group of 30 young oncologists and investigators, together with seven members of LACOG and CLICaP experts of 8 LATAM countries, were reunited to share views and define opportunities, barriers, and possible solutions to implement mentorship programs in LATAM. For each of the mentioned topics, key points were obtained by consensus, and a literature review was conducted to support group conclusions. This article analyses mentoring in LATAM countries and its role on promoting leadership. It will address conceptual frameworks, limitations, and opportunities from the perspectives of both mentor and mentee. The creation of regional and international group stimulation programs and joint projects that impact health policies are attractive, starting points to implement mentorship scenarios.