Abstract Background: Approximately 47-65% of estrogen receptor-positive (ER+)/HER2-negative breast cancers (BC), although classified as HER2-negative due to the absence of HER2 gene amplification, exhibit low levels of HER2 expression (referred to as HER2-low BC) with immunohistochemistry (IHC) 1+ or 2+ without amplification scores. More recently, an additional subclass—HER2-ultralow—has been proposed for tumors with HER2 IHC-0 and <10% tumor cell staining. Emerging evidence indicates that HER2-low and HER2-ultralow BC may represent biologically distinct entities compared with HER2-null BC. Here, the latest updates of the NextGIM trail, a retrospective, multicenter translational study designed to comprehensively characterize ER+/HER2-low BC, are presented. Methods: Primary tumor samples from patients enrolled in three randomized clinical trials (GIM2, GIM4, and GIM10) of the GIM (Gruppo Italiano Mammella) Investigator Group, underwent re-assessment of HER2 expression and tumor-infiltrating lymphocytes (TILs) in accordance with ASCO/CAP and TILs Working Group guidelines. In parallel, gene expression profiling was performed using the nCounter Breast Cancer 360 Panel on the NanoString platform. Clinical and survival data will be updated and integrated to evaluate potential prognostic markers and to investigate mechanisms of treatment resistance. Results: To date, from a total of 283 patients selected at participating centres, 208 samples were deemed suitable for molecular analyses after pathological and RNA quality/quantity assessment. HER2 expression has been re-evaluated in 179 samples. At diagnosis, HER2 classification was: 45.8% HER2-negative (IHC not specified), 26.8% HER2-0, 19.6% HER2-1+, and 7.8% HER2-2+. After pathological reassessment, the distribution shifted to 58.7% HER2-null, 20.7% HER2-ultralow, 15.1% HER2 1+, 5.0% HER2 2+, and 0.6% HER2 3+. Notably, HER2-null BC resulted more prevalent in older archival samples (before 2011). TILs levels ≤1% were more frequently observed in HER2-null and HER2-ultralow tumors compared with HER2-1+ and HER2-2+ (59.1% & 67.6% vs. 25.9% & 55.6%).. Genomic profiling has been completed for 208 cases and data analyses are ongoing. An integrated analysis of molecular, pathological and clinical data will be conducted upon completion of the dataset. Conclusion: The results obtained so far from HER2 re-evaluation has indicated that the interval between sample collection and reassessment can affect tissue antigenicity and immunohistochemistry results, and should be considered when re-evaluating HER2 status for therapeutic purposes. Overall, the study is expected, integrating genomic, immunological, and clinical information, to validate HER2-low and -ultralow expression as prognostic/predictive biomarkers to support personalized treatment. Citation Format: Barbara Cardinali, Alice Stella, Chiara Molinelli, Marco Bruzzone, Yanina Lizet Castillo, Francesca Pitto, Barbara Massa, Simona Pigozzi, Andrea Sciutto, Giorgia Anselmi, Maria Dono, Virna Maltoni, Benedetta Conte, Giulia Buzzatti, Davide Soldato, Gaia Griguolo, Valentina Guarneri, Mario Giuliano, Caterina Marchiò, Fabio Puglisi, Lorenzo Gerratana, Francesca Poggio, Lucia Del Mastro. Genomic, immune, and clinical characterization of estrogen receptor-positive, HER2-low breast cancer: The NextGIM trial latest updates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7907.

Post-surgical pyoderma gangrenosum is a rare neutrophilic dermatosis that may occur after surgical procedures, mimicking a wound infection. Early recognition is crucial to prevent unnecessary debridement and worsening of lesions due to pathergy. We report the case of a 67-year-old woman who underwent nipple-sparing mastectomy for invasive breast carcinoma with immediate reconstruction using a tissue expander. In the early postoperative period, she developed an extensive sterile necrotic-ulcerative inflammation of the left breast, unresponsive to broad-spectrum antibiotics and repeated surgical revisions. Histopathology revealed an aseptic neutrophilic infiltrate, confirming the diagnosis of post-surgical pyoderma gangrenosum. The patient responded favorably to high-dose corticosteroid therapy, achieving complete wound healing and definitive reconstruction with a TRAM flap. This case highlights the importance of considering post-surgical pyoderma gangrenosum in the differential diagnosis of inflammatory postoperative complications in breast oncology surgery. Prompt diagnosis and early initiation of immunosuppressive therapy within a multidisciplinary approach are key to preserving tissues and ensuring optimal functional and aesthetic outcomes.

Background: The combination of LHRH analog (LHRHa) and aromatase inhibitors (AI) represents the standard adjuvant endocrine therapy (ET) for premenopausal women at intermediate and high risk of relapse. However, complete ovarian suppression may not be achieved through LHRHa, and international guidelines provide different indications on how to monitor these patients and how often to evaluate hormonal status. Methods: PREFER (NCT02895165) and GIM 23-POSTER (NCT05730647) are two Italian prospective, observational studies enrolling premenopausal women eligible to receive (neo)adjuvant chemotherapy and/or adjuvant ET. We conducted an exploratory analysis to investigate which factors were associated with suboptimal ovarian suppression during LHRHa treatment. We divided the enrolled patients into two groups: patients with suboptimal ovarian suppression (non-suppressed group) and patients with adequate ovarian suppression (suppressed group), based on estradiol levels (higher than 25.1 ng/L for non-suppressed) or resumption of menstruation at least 3 months after the start of ET plus LHRHa. Clinical features, treatment type and outcomes were compared between the two groups. Kaplan Meier method was used to estimate the percentage of patients with suboptimal suppression and Cox models were used to explore possible related factors. Results: As of June 2024, out of 1863 patients registered (827 in the PREFER and 1036 in the GIM 23), all subjects enrolled in the coordinating center (n=545) were included in the present analysis. Median follow-up was 44.4 months (interquartile range [IQR] 20.6-84). Among the patients undergoing adjuvant ET (n=343), 202 received LHRHa plus AI, and 141 LHRHa plus tamoxifen: 315 have been included in the suppressed group, while 28 in the non-suppressed group. Median age at diagnosis was 38 years (IQR 33-44) in the non-suppressed group compared to 39 years (IQR 36-43) in the suppressed group. Clinical characteristics, including age, BMI, baseline FSH, and estradiol levels, did not correlate with suboptimal ovarian suppression. Regarding treatment, no significant differences in developing suboptimal ovarian suppression were found between those who received LHRHa during chemotherapy, those who did not receive LHRHa during chemotherapy, and those who were not administered chemotherapy. On the contrary, the use of AI was associated with an increased risk of suboptimal ovarian suppression: HR 12.83 (95% CI 3.01-54.65; p=0.001). The proportion of patients not-suppressed was 5.1% (95% CI 3.2-8.2) in the first year of LHRHa treatment and 10.5% (95% CI 7.1-15.4) after five years. Conclusions: Among premenopausal women receiving LHRHa as part of adjuvant ET, approximately 10% did not achieve complete ovarian suppression. Since no baseline clinical or treatment features seem to be associated with suboptimal ovarian suppression, except for the combination with AI, all patients receiving this treatment should perform serial monitoring of hormonal profile throughout the years of adjuvant ET to identify those who are not adequately suppressed. Citation Format: Simone Nardin, Edoardo Chiappe, Chiara Lanzavecchia, Tommaso Ruelle, Irene Giannubilo, Maria Grazia Razeti, Roberto Borea, Lucrezia Barcellini, Diletta Favero, Marta Perachino, Luca Arecco, Chiara Molinelli, Davide Soldato, Maria Maddalena Latocca, Alessia Levaggi, Giulia Buzzatti, Claudia Bighin, Valentina Barbero, Michela Lia, Barbara Cardinali, Marco Bruzzone, Eva Blondeaux, Lucia Del Mastro, Matteo Lambertini, Francesca Poggio. Comparison of Suboptimal vs. Adequate Ovarian Suppression during Adjuvant Endocrine Therapy for Premenopausal Women with Breast Cancer: An Exploratory Analysis of the PREFER and GIM 23 Studies [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-18.

Breast cancer is the most frequent malignancy among young women, with unique challenges particularly for carriers of BRCA pathogenic or likely pathogenic variants (PVs). Among them, the indication for intensive surveillance and risk-reducing surgeries is critical. In addition, special considerations on systemic treatment should be considered, including the use of targeted treatments like poly (adenosine diphosphate (ADP)-ribose) polymerase inhibitors. Moreover, the impact of anticancer treatments and risk-reducing surgeries on their ovarian reserve, pregnancy wish, and breastfeeding is a crucial aspect to be considered. Proper management of long-term toxicities, such as bone and cardiovascular health, as well as menopause-related symptoms, requires proper multidisciplinary care to optimize quality of life. This review examines the biological, clinical, therapeutic, and survivorship implications of breast cancer in young BRCA carriers, emphasizing differences between carriers of PVs in the BRCA1 and BRCA2 genes. Personalized strategies integrating genetic counseling, tailored surveillance and survivorship programs, as well as innovative therapies, are essential for improving prognosis and well-being in these young patients. Multidisciplinary care and further academic research efforts are critical to improve the management of breast cancer in young BRCA carriers.

Breast cancer (BC) is the most common malignancy among women. Among 5%–10% of diagnoses are correlated with hereditary cancer syndromes, while the remaining cases are sporadic and linked to multiple factors. When a pathogenetic variant in one of the genes commonly associated with BC is detected, the patient is referred to a tailored surveillance program; otherwise, the standard follow-up guidelines are applied. We present a unique case of BC diagnosed in two monozygotic twins at the same age apparently unrelated to a hereditary syndrome known to date. Notably, despite comparable clinical–pathological features, the two neoplasms behaved differently to neoadjuvant chemo-immunotherapy, showing different outcomes and toxicities. Very little is known about the predictive mechanisms of response and toxicity to immunotherapy and this clinical case might be a starting point for further investigations.

Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 ( BRCA1 ) or BReast CAncer 2 ( BRCA2 ) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA 1/2 (g BRCA1/2 ) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young g BRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young g BRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment. Keywords Germline , pathogenic variants , anti-Müllerian hormone , oncofertility , fertility , pregnancy

Approximately 10% to 15% of breast cancer cases in young women are diagnosed in patients harbouring germline (g) pathogenic or likely pathogenic variants (PVs) in the BReast CAncer 1 ( BRCA1 ) or BReast CAncer 2 ( BRCA2 ) genes. Preclinical and clinical studies showed a potential negative effect of germline BRCA 1/2 (g BRCA1/2 ) PVs on ovarian reserve and reproductive potential, even before starting anticancer therapies. The aim of this article is to summarize the current literature on the fertility potential of young g BRCA1/2 PVs carriers with breast cancer and the risk of gonadotoxicity associated with anticancer treatments. Moreover, we describe the available evidence on the efficacy of fertility preservation techniques in young g BRCA1/2 PVs carriers and the safety data on having a pregnancy after breast cancer treatment.

The emerging era of precision medicine is characterized by an increasing availability of targeted anticancer therapies and by the parallel development of techniques to obtain more refined molecular data, whose interpretation may not always be straightforward. Molecular tumor boards gather various professional figures, in order to leverage the analysis of molecular data and provide prognostic and predictive insights for clinicians. In addition to healthcare development, they could also become a tool to promote knowledge and research spreading. A growing body of evidence on the application of molecular tumor boards to clinical practice is forming and positive signals are emerging, although a certain degree of heterogeneity exists. This work analyzes molecular tumor boards' potential workflows, figures involved, data sources, sample matrices and eligible patients, as well as available evidence and learning examples. The emerging concept of multi-institutional, disease-specific molecular tumor boards is also considered by presenting two ongoing nationwide experiences.

INTRODUCTION:We conducted an online survey to investigate oncologists' clinical practices and views on palliative care at the end of life in the Italian region of Liguria. METHODS:The survey included 29 items divided into three sections: participant characteristics (n=6), hospital resources and practices (n=11), participant practices and views (n=12). RESULTS:Twenty-one of the 41 medical oncologists invited completed the survey (51%). Although almost all reported the presence of palliative medicine physicians at their hospitals (90%), nearly half (48%) stated that palliative medicine physicians were not responsible for managing cancer patients at end of life, and 21% reported routine participation of palliative medicine physicians in multidisciplinary meetings. Thirty-eight percent of the respondents stated they never consulted psychologists regarding end of life patient care, and 43% reported they rarely did. Notably, a substantial proportion of participants stated that they administered active treatments to patients with six months life expectancy. Regarding integration between oncology and palliative medicine, an equal proportion felt it had been fully (48%) or partially achieved (48%) at their hospitals. CONCLUSIONS:Participants seemed fairly satisfied with the level of integration between oncology and palliative medicine at their hospitals, which contrasts with other findings regarding, for instance, the scant participation of palliative medicine physicians in multidisciplinary meetings. Exploring the impact of the novel regional clinical healthcare pathway for palliative care on practices at hospitals in Liguria will be crucial to ensure that cancer patients at end of life receive quality care.

Despite its clinical value, cascade genetic testing (CGT) in hereditary cancer syndromes remains underutilized for a number of reasons, including ineffective family communication of genetic risk information. Therefore, alternative strategies are being explored to improve CGT uptake rates; one such strategy is direct contact with at-risk relatives by healthcare professionals with proband consent. It is unclear how Italian laws and regulations pertaining to CGT—including the EU General Data Protection Regulation (GDPR)—should be understood and implemented in the context of such alternative strategies. The authors constructed a hypothetical case about CGT, reviewed laws and regulations on informed consent, privacy, and the right not to know, and analyzed how those laws and regulations might apply to different communicative strategies relevant to the case and aimed at supporting CGT. A constitutionally consistent reading of Italian law and of the GDPR, an integral part of the Italian privacy framework, suggests that multiple communicative approaches may be legally permissible in Italy to support the CGT process. This includes direct contact by healthcare professionals with proband consent, provided certain conditions are met. Understanding the effectiveness of such approaches in improving CGT uptake will require further research efforts.

OBJECTIVES:To better understand the type of care offered to Italian patients with advanced breast cancer at the End-of-Life (EoL), we conducted a retrospective observational study. EoL was defined as the period of six months before death.METHODS:One hundred and twenty-one patients with advanced breast cancer (ABC) treated at IRCCS San Martino Policlinic Hospital who died between 2017 and 2021 were included. Data about patient, disease, and treatment characteristics from breast cancer diagnosis to death, along with information about comorbidities, medications, imaging, specialist evaluations, hospitalization, palliative care and home care, hospice admissions, and site of death were collected.RESULTS:98.3% of the patients received at least one line of active treatment at EoL; 52.8% were hospitalized during the selected period. Palliative (13.9%), psychological (7.4%), and nutritional evaluations (8.2%) were underutilized. Palliative home care was provided to 52% of the patients. Most of the patients died at home (66.1%) and fewer than one out of five (18.2%) died at the hospital. Among the patients who died at home, 27.3% had no palliative support.CONCLUSIONS:Our findings indicate that palliative care in EoL breast cancer patients is still inadequate. Only a minority of patients had psychological and nutritional support While low nutritional support may be explained by the fact that typical symptoms of ABC do not involve the gastrointestinal tract, the lack of psychological support suggests that significant barriers still exist. Data on the site of death are encouraging, indicating that EoL management is increasingly home centered in Italy.

Endometrial cancer (EC) is the most frequent gynaecological malignancy. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and application for a better diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC), high (HGEC) and low (LGEC) grade endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, the tumor DNA was semi-automatically extracted and analyzed by NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k=0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required for use in clinical practice for a more precise diagnostic-therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.

Endometrial cancer (EC) is the most frequent gynecological cancer. The ESGO/ESTRO/ESP 2020 guidelines identify prognostic groups based on morpho-molecular characteristics. This study aims to evaluate the clinical applicability of NGS analysis to define an appropriate risk class and to improve the diagnostic and prognostic stratification of ECs. Cases of serous carcinoma (OHEC) and high- (HGEC) and low-grade (LGEC) endometrioid carcinoma diagnosed with the morphological and immunohistochemical (IHC) protocols were considered. After a standardized pre-analytical phase, tumor DNA was semi-automatically extracted and analyzed using NGS with a panel of 14 genes. A total of 63 cases were considered. NGS analysis was successful in 60 cases; all of these were classified according to the new diagnostic algorithm. The molecular risk classification showed a good correlation with the morphological (k = 0.8). The study showed that the protocols of the pre-analytical and analytical phases used are robust and can lead to molecular results that fall within the standards required, which can be used in clinical practice for more precise diagnostic–therapeutic management of patients. The implementation of the classification is particularly relevant for better prognostic stratification of HGECs. In addition, the identification of a suspicious VUS in POLE questions the classification of truncating variants.

Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4

Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk.Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%.The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed.The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain chal-lenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as sec-ondary prevention.

Several models of genetic counseling have been proposed to tackle the increasing volume of individuals requiring access to BRCA testing. Few data are available on patient experience and retention of information with nurse-driven genetic counseling. We evaluated the experience and retention of information in women with an uninformative BRCA test result and who were not considered at high risk due to their personal/family history of cancer who underwent geneticist-supervised nurse-driven genetic counseling and who received their test result by phone. Women who received an uninformative BRCA test result between May 2017 and September 2019 were administered a questionnaire exploring experience with genetic counseling and retention of information provided. Of 366 eligible women, 299 (273 breast cancer patients and 26 women without breast cancer) completed the interview. Overall, 280 women (93.6%) positively valued their experience with genetic counseling and 287 (96.0%) considered it helpful with 57.5% of them feeling reassured for themselves and their family. Information on the clinical implications of the test result was correctly retained and women acted accordingly. Overall, 252 women (87.8%) accurately reported their test result as normal/negative. Only 67 (22.4%) recognized that despite a normal BRCA test result, a low probability of a hereditary syndrome remains. Most women showed a poor ability to estimate cancer risk in BRCA mutation carriers and in the general population. Geneticist-supervised nurse-driven genetic counseling process for women with uninformative BRCA test result is associated with a positive patient experience and an adequate retention of information concerning the management of their personal and familial cancer risk. The design and implementation of nurse-driven genetic counseling models may contribute to efficient and timely access to BRCA genetic testing.