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Massimo Gion,1 Giulia Cardinali,2 Stefano Guzzinati,3 Paolo Morandi,4 Chiara Trevisiol,5 Aline SC Fabricio,5 Massimo Rugge,3,6 Manuel Zorzi3 1Regional Center for Biomarkers, Department of Clinical Pathology, Azienda ULSS 3 Serenissima, Venice, Italy; 2Management Control Unit, Azienda ULSS 3 Serenissima, Venice, Italy; 3Veneto Tumour Registry, Azienda Zero, Padua, Italy; 4Medical Oncology Unit, Azienda ULSS 3 Serenissima, Venice, Italy; 5Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; 6University of Padova, Department of Medicine DIMED, Padua, ItalyCorrespondence: Massimo Gion, Regional Center for Biomarkers, Department of Clinical Pathology, Azienda ULSS 3 Serenissima, Ospedale SS. Giovanni e Paolo – Castello, Venezia, 6777 – 30122, Italy, Tel +39 041 5294260, Fax +39 041 5295603, Email massimo.gion@aulss3.veneto.itPurpose: Clinical practice guidelines (CPGs) recommend against intensive follow-up in asymptomatic women with breast cancer (BC). The present study assessed the adherence to CPGs of diagnostic tests ordering during BC follow-up by exploring routinely collected health data through an algorithm developed to distinguish patients according to their status at follow-up.Patients and Methods: A retrospective population-based cohort study was performed monitoring the diagnostic tests ordered during 5 years of follow-up in all BC cases incident in 2013 in the Veneto Region, Italy. Data were extracted from the Veneto Tumour Registry, the Hospital Discharge Records and the Outpatients’ Records of Diagnostic and Therapeutic Procedures. The algorithm was developed using information on infusion of anticancer agents, imaging exams ordered, and death.Results: The algorithm classified patients by status at follow-up in four groups: (i) probably no-evidence-of-disease (NED), (ii) suspicious signs of relapse not confirmed, (iii) increased risk of relapse and (iv) advanced disease at presentation or progressive disease. A total of 3930 consecutive incident cases were followed-up for 5 years, corresponding to 17,184 person-years, 15,345 of which pertaining to NED cases. In NED cases, 32,900 tumour markers and 15,858 imaging exams were ordered. Liver ultrasonography and chest radiography were most frequently ordered.Conclusion: In contrast with recommendations of CPGs, a substantial overordering of tumour markers and imaging exams occurred in NED BC patients. The developed algorithm can be repeatedly applied to routine health datasets for regular monitoring of the adherence to CPGs and of the impact of interventions to improve appropriateness.Keywords: tumour markers, imaging exams, adherence to guidelines, routinely collected health data

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality. Standard treatment for TNBC primarily relies on cytotoxic agents, such as taxanes, anthracyclines, and platinum compounds for both early and advanced stages of the disease. Several targeted therapies, including bevacizumab and sunitinib, have failed to demonstrate significant clinical benefit in TNBC. The emergence of immune checkpoint inhibitors (ICI) has revolutionized cancer treatment. By stimulating the immune system, ICIs induce a durable anti-tumor response across various solid tumors. TNBC is a particularly promising target for treatment with ICIs due to the higher levels of tumor-infiltrating lymphocytes (TIL), increased PD-L1 expression, and higher mutational burden, which generates tumor-specific neoantigens that activate immune cells. ICIs administered as monotherapy in advanced TNBC yields only a modest response; however, response rates significantly improve when ICIs are combined with cytotoxic agents, particularly in tumors expressing PD-L1. Pembrolizumab is approved for use in both early and advanced TNBC in combination with standard chemotherapy. However, more research is needed to identify more potent biomarkers, and to better elucidate the synergism of ICIs with other targeted agents. In this review, we explore the challenges of immunotherapy in TNBC, examining the mechanisms of tumor progression mediated by immune cells within the tumor microenvironment, and the signaling pathways involved in both primary and acquired resistance. Finally, we provide a comprehensive overview of ongoing clinical trials underway to investigate novel immune-targeted therapies for TNBC., Competing Interests: Authors AL, JP-G, and JC were employed by the company Scientia Innovation Research (MEDSIR), Oncoclínicas & Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Serrano García, Jávega, Llombart Cussac, Gión, Pérez-García, Cortés and Fernández-Murga.)

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2 + ) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 + mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 + mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 ., Competing Interests: Competing interests: N.H. has received lecture honoraria from Art Tempi, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pierre Fabre, Roche, Sanofi, Seagen, Viatris and Zuellig Pharma; has received consulting or advisory honoraria from Aptitude Health, Gileadn Sciences, Pfizer, Sandox-Hexal, Sanofi and Seagen; has received research funding from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, Merck Sharp & Dohme, Roche, Seagen, TRIO and WSG; has participated on independent data monitoring committees/steering committees for Eli Lilly, Pierre Fabre and Roche; and has ownership interest in the West German Study Group. E.C. has received lecture, consulting or advisory honoraria from AstraZeneca, Daiichi Sankyo, Eli lilly, Gilead Sciences, Menarini, Merck Sharp & Dohme, Novartis, Pfizer, Reveal Genomics and Roche; has received support for attending meetings and/or travel from AstraZeneca, Pfizer and Roche; has received research funding from Daiichi Sankyo, Pfizer and Roche; and has participated on steering committees for AstraZeneca, Daiichi Sankyo, Gilead Sciences, Novartis, Reveal Genomics and Roche. G.J. has received consulting honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Diaccurate/Evexta Bio, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, Roche and Seagen; has received support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Gilead Sciences, Novartis, Pfizer and Roche; and has received medical writing support from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Novartis and Roche. V.M. has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eisai, Gilead Sciences, high5 Oncology, iMED Institut, Eli Lilly, Medac, Medscape, Merck Sharp & Dohme, Novartis, Onkowissen, Pfizer, Pierre Fabre, Roche and Seagen; has received consulting or advisory honoraria from ClinSol, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pierre Fabre, PINK, Roche and Menarini Stemline; and has received research funding from AstraZeneca, Genentech, Novartis, Roche and Seagen. N.N. has received consulting or advisory honoraria from AstraZeneca, Chugai Pharmaceutical and Daiichi Sankyo; has received lecture honoraria from AstraZeneca, Chugai Pharmaceutical, Eisai, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan; and has received research funding from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Nippon Kayaku and Pfizer Japan. G.V. has received research grants from Dako/Agilent Technologies, Roche/Genentech and Ventana Medical Systems and has received honoraria from AstraZeneca, Daiichi Sankyo, Dako/Agilent Technologies, Gilead Sciences, Merck Sharp & Dohme Oncology, Pfizer, Roche and Ventana Medical Systems. R.B. has held advisory roles at AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Seagen and Menarini Stemline; has received lecture honoraria from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, Grünenthal, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche and Seagen; and has received research support from Daiichi Sankyo, Merck Sharp & Dohme, Novartis and Roche. C.K. has received lecture honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Novartis, PharmaMar, Pfizer and Roche; has received consulting or advisory honoraria from AstraZeneca, Eli Lilly, Genomic Health/Exact Sciences, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, PharmaMar and Roche; and has participated on steering committees for AstraZeneca. M.J.H. has received lecture honoraria from AstraZeneca. R.M.C. received an unrestricted educational grant from Pfizer; has received research support from AstraZeneca, Daiichi Sankyo, MSD Ireland and Pfizer; has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead Sciences and Seagen; and has received support for attending meetings and/or travel from Gilead Sciences, Novartis and Roche. M.G. has received support for attending meetings and/or travel from AstraZeneca, Gilead Sciences, Roche and Pfizer and has received honoraria from AstraZeneca, Gilead Sciences and Pfizer. V.G. has received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Olema Oncology, Pierre Fabre and Roche; has received lecture honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead Sciences, GlaxoSmithKline, Menarini Stemline, Novartis, Roche and Zentiva; and has received expert testimony honoraria from Eli Lilly. G.B. has received honoraria from Agendia, Amgen, AstraZeneca, Chugai Pharmaceutical/Roche, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Helsinn Lilly, Menarini Stemline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi and Seagen and received a research grant from Gilead Sciences. H.W. has received lecture honoraria from Seagen; has received consulting or advisory honoraria from AstraZeneca, Augustine Therapeutics, Daiichi Sankyo, E Squared Communications, Eli Lilly, Gilead Sciences, Immutep, MediMix, Menarini Stemline, Novartis, NV Hict, Pfizer, PSI CRO and Roche; has received support for attending meetings and/or travel from Daiichi Sankyo and Pfizer; has received research funding from Novartis, Roche and Syneos Health; and has received subscription fees from Gilead Sciences. S.E.-d.-R. has received honoraria from AstraZeneca, COR2ED, Daiichi Sankyo, Jazz Pharmaceuticals, Medistream, Pierre Fabre, Roche and Seagen; has received research funding from AstraZeneca, Byondis, Daiichi Sankyo, Jazz Pharmaceuticals, MEDSIR, Roche, SOLTI and Zymeworks; and has received support for attending meetings and/or travel from AstraZeneca, Daiichi Sankyo, Kern Pharma, Pfizer, Seagen and SOLTI. M.P., H.B., N.K.-C., N.S. and S.V. are employees of AstraZeneca. N.K.-C. holds stocks in AstraZeneca and AbbVie. N.U.L. has received honoraria from AstraZeneca and has received research funding from AstraZeneca. The other authors declare no competing interests., (© 2024. The Author(s).)

The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-value < 0.05), shedding light on an aspect of breast cancer biology warranting further investigation. These findings challenge CDH1 methylation as a CDH1 inactivation mechanism in ILC and highlight TILs as a potential confounding factor in gene methylation., (© 2024. The Author(s).)

Introduction: Tumor-infiltrating lymphocytes (TILs) have predictive and prognostic value in breast cancer (BC) and exert a protective function against tumor growth, indicating that it is susceptible to treatment using adoptive cell transfer of TILs or T cell receptor (TCR)-based therapies. TCR can be used to identify naturally tumor-reactive T cells, but little is known about the differences in the TCR repertoires of CD4+ and CD8+ TILs., Methods: TCR high-throughput sequencing was performed using TILs derived from the initial cultures of 11 BC biopsies and expanded and sorted CD4+ and CD8+ TILs as well as using PBMCs from healthy donors expanded and sorted using the same methodology., Results: Physicochemical TCR differences between T cell subsets were observed, as CD4+ TILs presented larger N(D)Nnt TRB sequences and with a higher usage of positively charged residues, although only the latest was also observed in peripheral T cells from healthy individuals. Moreover, in CD4+ TILs, a more restricted TCR repertoire with a higher abundance of similar sequences containing certain amino acid motifs was observed., Discussion: Some differences between CD4+ and CD8+ TCRs were intrinsic to T cell subsets as can also be observed in peripheral T cells from healthy individuals, while other were only found in TILs samples and therefore may be tumor-driven. Notably, the higher similarity among CD4+ TCRs suggests a higher TCR promiscuity in this subset., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Aran, Lázaro, Marco, Molina, Abancó, Peg, Gión, Garrigós, Pérez-García, Cortés and Martí.)

Background: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished., Methods: To investigate the molecular alterations of BC and their CM, a total of 66 samples (33 BC and 33 CM) from 33 patients were analyzed by immunohistochemical and massive parallel sequencing analyses. In addition, the clinicopathological characteristics of patients and tumors were analyzed., Results: Triple negative (TN) BCs were overrepresented (36.4%) among tumors that developed CM. A change of tumor surrogate molecular type in metastases was found in 15% of patients and 48.5% of the CM presented some additional molecular alteration with respect to the primary tumor, the most frequent were amplification of MYC and MDM4 , and mutations in TP53 and PIK3CA . Survival was related to histological grade, tumor surrogate molecular type and TP53 mutations in the univariate analysis but only the tumor surrogate molecular type remained as a prognostic factor in the multivariate analysis., Conclusions: The TN molecular type has a greater risk of developing skin metastases. There are phenotypic changes and additional molecular alterations in skin metastases compared to the corresponding primary breast tumors in nearly half of the patients. Although these changes do not follow a specific pattern and varied from patient to patient, they could impact on the treatment. More studies with larger patient and sample cohorts are needed.

Introduction: Patients with head and neck cancer (HNC) submitted to radiotherapy alone or combined chemoradiotherapy present a high prevalence of malnutrition at baseline. Prophylactic use of gastrostomy has been suggested for these patients for delivering enteral nutrition. On the other hand, other authors have failed to demonstrate the effectiveness of this measure over nasogastric tube feeding., Material and Methods: We studied 40 patients with HNC with moderate or severe malnutrition who were offered either prophylactic percutaneous gastrostomy before starting oncologic treatment or close follow-up with nutritional counseling with the placement of a nasogastric tube when necessary., Results: There were no significant changes throughout the study period in weight (p = 0.338), body mass index (BMI) (p = 0.314) or serum proteins (p = 0.729), and these changes showed no differences between the gastrostomy vsnasogastric tube feeding groups. The amount of delivered energy was above the estimated energy needs with both gastrostomy and nasogastric tube feeding, but there were no differences in the total energy provided by enteral nutrition between groups. Patients in the gastrostomy group received enteral nutrition support for a longer period of time (p = 0.007)., Conclusions: Both gastrostomy and nasogastric tube feeding are effective methods of delivering enteral nutrition in patients with HNC submitted to radiotherapy alone or combined chemoradiotherapy, with no differences between them in terms of avoiding further nutritional deterioration.