Cerebellar phenotypes in germline PTEN mutation carriers.

PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

Different Chemotherapy Regimens and Pathologic Complete Response in Triple-Negative Breast Cancer: An Updated Network Meta-Analysis of Phase 3 Trials.

Background and Objectives: Currently, the standard treatment for non-metastatic triple-negative breast cancer (TNBC) consists of a systemic neoadjuvant (or perioperative) anthracycline plus taxane-based chemotherapy, delivered either sequentially or concomitantly. We performed a network meta-analysis (NMA) to compare the relative efficacy of different neoadjuvant treatments for TNBC in terms of pathologic complete response (pCR). Materials and Methods: The MEDLINE, Embase, and Cochrane databases were searched from database inception to 1 November 2023. Randomized clinical trials were used that enrolled adults with stage I-III TNBC and provided data on pCR defined as residual ypT0/TisN0M0. Between-group comparisons were estimated using risk ratios (RRs) with 95% credible intervals (95% CrIs). The primary outcome was the pCR rate. Results: 1129 citations were screened, and 12 randomized clinical trials were included. In Bayesian comparisons, all regimens, except anthracycline/taxanes plus gemcitabine or capecitabine, resulted in a higher pCR than the standard regimen in both direct and indirect comparisons. In particular, immunotherapy-based regimens resulted in more than double the pCR compared to historical regimens (RR = 2.3, 95% CI 1.9-2.9) and ranked as being the optimal regimen with a probability of 97%. Disease-free survival was better for immune checkpoint inhibitor-based chemotherapy (HR = 0.36, 95% 1.21-2.09) than for historical regimens. Conclusion: This meta-analysis confirmed that incorporating immunotherapy with neoadjuvant platinum-based chemotherapy is the best option to guarantee remarkable pathologic downstaging and improve clinical outcomes.

The Contribution of Oxidative Stress to NF1-Altered Tumors.

The neurofibromatosis-1 gene (NF1) was initially characterized because its germline mutation is responsible for an inherited syndromic disease predisposing tumor development, in particular neurofibromas but also various malignancies. Recently, large-scale tumor sequencing efforts have demonstrated NF1 as one of the most frequently mutated genes in human cancer, being mutated in approximately 5-10% of all tumors, especially in malignant peripheral nerve sheath tumors and different skin tumors. NF1 acts as a tumor suppressor gene that encodes neurofibromin, a large protein that controls neoplastic transformation through several molecular mechanisms. On the other hand, neurofibromin loss due to NF1 biallelic inactivation induces tumorigenic hyperactivation of Ras and mTOR signaling pathways. Moreover, neurofibromin controls actin cytoskeleton structure and the metaphase-anaphase transition. Consequently, neurofibromin deficiency favors cell mobility and proliferation as well as chromosomal instability and aneuploidy, respectively. Growing evidence supports the role of oxidative stress in NF1-related tumorigenesis. Neurofibromin loss induces oxidative stress both directly and through Ras and mTOR signaling activation. Notably, innovative therapeutic approaches explore drug combinations that further increase reactive oxygen species to boost the oxidative unbalance of NF1-altered cancer cells. In our paper, we review NF1-related tumors and their pathogenesis, highlighting the twofold contribution of oxidative stress, both tumorigenic and therapeutic.

Updates on Lymphovascular Invasion in Breast Cancer.

Traditionally, lymphovascular invasion (LVI) has represented one of the foremost pathological features of malignancy and has been associated with a worse prognosis in different cancers, including breast carcinoma. According to the most updated reporting protocols, the assessment of LVI is required in the pathology report of breast cancer surgical specimens. Importantly, strict histological criteria should be followed for LVI assessment, which nevertheless is encumbered by inconsistency in interpretation among pathologists, leading to significant interobserver variability and scarce reproducibility. Current guidelines for breast cancer indicate biological factors as the main determinants of oncological and radiation therapy, together with TNM staging and age. In clinical practice, the widespread use of genomic assays as a decision-making tool for hormone receptor-positive, HER2-negative breast cancer and the subsequent availability of a reliable prognostic predictor have likely scaled back interest in LVI's predictive value. However, in selected cases, the presence of LVI impacts adjuvant therapy. This review summarizes current knowledge on LVI in breast cancer with regard to definition, histopathological assessment, its biological understanding, clinicopathological association, and therapeutic implications.

Thyroid findings in pediatric and adult patients with PTEN hamartoma tumor syndrome: A retrospective analysis, and literature review.

PURPOSE: PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients. METHODS: A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. RESULTS: We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years. CONCLUSIONS: Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.

Immune checkpoint inhibitor therapy for hepatocellular carcinoma.

Liver cancer is the third most common cause of cancer-associated death. Advances in the last decade have provided more options for treating hepatocellular carcinoma. The use of immune checkpoint inhibitors represents a leap forward and broadens the armamentarium for clinicians. In this article, we provide a state-of-the-art review of molecular therapy. We also detail the mechanisms of checkpoint inhibitor therapy, which blocks the interaction of programmed cell death receptor protein with programmed cell death ligand, reducing the immune checkpoint activity on regulatory T cells, thereby inhibiting tumor cell growth.

Lynch Syndrome: From Carcinogenesis to Prevention Interventions.

Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response.

Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting more often elderly patients, but sometimes even younger ones, particularly if immunocompromised or genetically predisposed. Specifically, the Gorlin-Goltz syndrome, an autosomal dominant genodermatosis, also known as nevoid basal cell carcinoma syndrome, characterizes for multiple early onset BCCs. It is caused by a germline mutation in PTCH1, a tumor suppressor gene whose product is the key component of Hedgehog (Hh) signaling pathway, which also appears somatically mutated in more than 85% of sporadic BCCs. Hh pathway inhibitors vismodegib and sonidegib are currently indicated for BCC, in adults with advanced or recurred tumor following surgery or radiation therapy. The principal mechanism of action of these drugs is the inhibition of Smoothened (SMO), a transmembrane protein involved in Hh signal transduction, that plays a role in both cellular differentiation and cancer development. Some studies have reported effects of Hh pathway inhibitors at different levels of the immune response, from cytotoxic T cells to a modified local cytokines pattern. Given the specific relation between immune system and BCC development in some conditions, we will review BCC with focus on immune system changes mediated by Hh signaling pathway and induced by the inhibitors vismodegib and sonidegib in the treatment of BCC. Thus, we will give an overview of their effects on the local immune response, as well as a brief note on the supposed function of Hh pathway inhibition on the systemic one.

Combined analysis of PTEN, HER2, and hormone receptors status: remodeling breast cancer risk profiling.

BACKGROUND: Phosphatase and tensin homolog (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker in these patients is controversial. We sought to determine whether the benefit of traditional biomarkers testing is improved by the analysis of PTEN status for the identification of high-risk breast cancer. METHODS: A cohort of 608 patients with breast cancer was included in this study. Based on the expression on the neoplastic cells compared to the normal internal controls by immunohistochemistry (IHC), cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on publicly available genomic data and included 4265 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher's exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method. RESULTS: Alteration in PTEN status was significantly different at protein and gene levels, where the reduced protein expression was observed in 280/608 cases (46.1%) from our group, while genetic aberrations in only 315/4265 (7.4%) cases of the METABRIC and MSK cohorts. PTEN-L tumors were significantly enriched for hormone receptors (HR) and HER2 negativity (n = 48, 17.1%) compared to PTEN-WT tumors (n = 22, 6.7%; p = 0.0008). Lack of HR with or without HER2 overexpression/amplification was significantly associated with worse overall survival (OS) in PTEN-L but not in PTEN-WT breast cancers (p < .0001). Moreover, PTEN-L protein expression but not gene alterations was related to the outcome, in terms of both OS and disease-free survival (p = 0.002). CONCLUSIONS: The combined analysis of PTEN, HER2, and HR status offers relevant information for a more precise risk assessment of patients with breast cancer.

Total neoadjuvant therapy for initially inoperable pancreatic cancer: A systematic review of phase 2-3 studies.

INTRODUCTION: Patients with initially inoperable non-metastatic pancreatic cancer (PC) have a poor prognosis, often similar to those with metastatic disease. Neoadjuvant chemotherapy (CT) plus concomitant or sequential radiotherapy (RT) may cause tumor shrinkage and allow for radical surgery. We pooled data of studies in which patients with locally advanced (unresectable) or borderline resectable PC were treated with a course of induction (or consolidation) CT followed or preceded by neoadjuvant CTRT regimen. MATERIALS AND METHODS: We searched articles, including phase 2 or 3 studies, published in English from 2010 up to December 2020 in PubMed, SCOPUS, the Cochrane Library, and EMBASE. The primary outcomes were the pooled radical and R0 resection rates, median PFS and OS of included patients (those included in the intent to treat analysis). RESULTS: A total of 28 studies were finally considered eligible for inclusion in quantitative analysis for a total of 2446 patients with locally advanced/borderline resectable PC. Overall the pooled rate of resection was 29.7% (95%CI 26.7-32.8%). In patients who completed the CT + CTRT program, the overall resection rate was 31.8% (95% 28.4-35.4%). After exclusion of studies that included resectable PCs, the overall resection rate was 19.9% (95%CI 17.3-22.7%). In studies were all patients had unresectable PC (n = 20 studies), the resection rate was 12.1% (95%CI 10-14.5%). In two studies that enrolled all borderline resectable PCs the resection rate was 59.2% (95%CI 48.9-68.8%). The pooled R0 resection rate was 68.7% (95%CI 64.7-72.3%). The median pooled OS was 15.7 months (95%CI 14-17.2 months) and the median pooled PFS was 10.7 (95%CI 9.3-12.1 months). CONCLUSIONS: Surgery is a treatment option in about one third of patients with initially inoperable PC, following total neoadjuvant therapy. In unresectable cases the resection rate was 12%. Median OS and PFS rates were comparable with historical data of advanced PCs. Optimal integration and sequence of chemo- and radiotherapy in unresectable PC must still be defined.

COVID-19 Vaccination in Patients with Classic Kaposi's Sarcoma.

The novel coronavirus disease 2019 (COVID-19) has represented an overwhelming challenge for worldwide health systems. Patients with cancer are considered at higher risk for severe COVID-19 and increased mortality in case of infection. Although data on the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with cancer are limited, there is enough evidence supporting anti-infective vaccination in general in patients with active cancer, or with history of previous malignancy. Subjects with classic Kaposi's sarcoma (KS) represent a small subset of cancer patients, which should be considered at heightened risk for infections due to several factors including age, and impaired immune function status. Several cases of human herpesviruses reactivation among critically ill COVID-19 patients have been described. Moreover, in case of severe infection and treatment with immunomodulating agents, patients with CKS are exposed at significant risk of viral reactivation and disease progression. Considering the baseline clinical risk factors of patients with CKS, and the complex interplay of the two viral agents, SARS-CoV-2 vaccination should be strongly recommended among patients with KS. KS represents an interesting field to study the interactions among chronic viral infections, SARS-CoV-2 and the host's immune system. Prospective observational studies are needed to provide more insights on vaccine activity and safety among patients with cancer, optimal vaccine schedules, potential interactions with antineoplastic therapies, and other comorbidities including chronic viral infections.

Impact of BMI on Survival Outcomes of Immunotherapy in Solid Tumors: A Systematic Review.

Growing research has focused on obesity as a prognostic factor during therapy with immune-checkpoint inhibitors (ICIs). The role of body-mass index (BMI) in predicting response and toxicity to ICIs is not clear, as studies have shown inconsistent results and significant interpretation biases. We performed a systematic review to evaluate the relationship between BMI and survival outcomes during ICIs, with a side focus on the incidence of immune-related adverse events (irAEs). A total of 17 studies were included in this systematic review. Altogether, the current evidence does not support a clearly positive association of BMI with survival outcomes. Regarding toxicities, available studies confirm a superimposable rate of irAEs among obese and normal weight patients. Intrinsic limitations of the analyzed studies include the retrospective nature, the heterogeneity of patients' cohorts, and differences in BMI categorization for obese patients across different studies. These factors might explain the heterogeneity of available results, and the subsequent absence of a well-established role of baseline BMI on the efficacy of ICIs among cancer patients. Further prospective studies are needed, in order to clarify the role of obesity in cancer patients treated with immunotherapy.

The Appropriateness of Invasive Ventilation in COVID-19 Positive Cancer Patients: Proposal of a New Prognostic Score.

Over the last months, as oncology specialists, we have frequently been contacted for estimating prognosis for cancer patients affected by COVID-19 infection. Until now, there have been no clear markers to guide decision making regarding the appropriateness of invasive ventilation in cancer patients affected by COVID-19 infection. We developed a practical tool encompassing a prognostic score, "The Milano Policlinico ONCOVID-ICU score." The score is composed of three groups of variables: patient's characteristics such as sex, age, BMI, and comorbidities; oncological variables (treatment intent, life expectancy, on or off-treatment status); and clinical parameters in association with laboratory values (the Sequential Organ Failure Assessment (SOFA) score and D-dimer). The SOFA score includes six different clinical parameters and during the first few days of ICU admissions has an important prognostic role. The oncological history should never represent, per se, a contraindication to intensive care and must be considered together with other variables, such as laboratory values, clinical parameters, and patient characteristics, in order to make the hardest but best possible choice. To our knowledge, "The Milano Policlinico ONCOVID-ICU score" is the first prognostic score proposed in this setting of patients and requires further validation. This tool may be useful to assess the prognosis of cancer patients in critical conditions.

Triage process for the assessment of coronavirus disease 2019-positive patients with cancer: The ONCOVID prospective study.

BACKGROUND: Patients with cancer are considered at high risk for the novel respiratory illness coronavirus disease 2019 (COVID-19). General measures to keep COVID-19-free cancer divisions have been adopted worldwide. The objective of this study was to evaluate the efficacy of triage to identify COVID-19 among patients with cancer. METHODS: From March 20 to April 17, 2020, data were collected from patients who were treated or followed at the authors' institution in a prospective clinical trial. The primary endpoint was to estimate the cumulative incidence of COVID-19-positive patients who were identified using a triage process through the aid of medical and patient questionnaires. Based on a diagnostic algorithm, patients with suspect symptoms underwent an infectious disease specialist's evaluation and a COVID-19 swab. Serologic tests were proposed for patients who had symptoms or altered laboratory tests that did not fall into the diagnostic algorithm but were suspicious for COVID-19. RESULTS: Overall, 562 patients were enrolled. Six patients (1%) were diagnosed with COVID-19, of whom 4 (67%) had the disease detected through telehealth triage, and 2 patients (33%) without suspect symptoms at triage had the disease detected later. Seventy-one patients (13%) had suspect symptoms and/or altered laboratory tests that were not included in the diagnostic algorithm and, of these, 47 patients (73%) underwent testing for severe acute respiratory syndrome coronavirus 2 antibody: 6 (13%) were positive for IgG (n = 5) or for both IgM and IgG (n = 1), and antibody tests were negative in the remaining 41 patients. CONCLUSIONS: The triage process had a positive effect on the detection of COVID-19 in patients with cancer. Telehealth triage was helpful in detecting suspect patients and to keep a COVID-19-free cancer center. The overall incidence of COVID-19 diagnosis (1%) and antibody positivity (13%) in patients with suspect symptoms was similar to that observed in the general population.

Coronavirus infection and immune system: An insight of COVID-19 in cancer patients.

The novel coronavirus respiratory illness (COVID-19) is a public health emergency of global concern. Patients with cancer are at high risk of infections, due to an overall immunocompromised status. However, this connection is not straightforward for coronavirus (CoV) infection, in which the host immune response is the main driver of tissue damage. We performed a thorough review of data on CoV pathogenesis and morbidity rate in cancer patients, through the analysis of the previous CoV pandemics. Considering the interaction between CoV and the host immune system, cancer patients receiving immunotherapy might be more at risk for an aberrant immune response in case of infection, and might therefore deserve additional precautions. The limited available data do not allow us to provide practical indications for the management of cancer patients in this critical situation. Efforts should be made to prospectively collect data, to identify effective interventions to guide treatment decision.

Pharmacotherapeutic advances with anaplastic lymphoma kinase inhibitors for the treatment of non-small cell lung cancer.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) inhibitors are potent oral anti-cancer agents acting as tyrosine kinase inhibitors (TKIs), which are approved for the treatment of ALK+ non-small cell lung cancer (NSCLC). Over the last years, several new molecules have been developed and are currently under clinical investigation. AREAS COVERED: In this paper, the authors review the most relevant clinical findings of ALK inhibitors in the treatment of ALK+ NSCLC. The authors discuss differences in the efficacy and treatment-related adverse events (AEs) incidence of distinct ALK inhibitors, molecular mechanisms of acquired resistance, and ongoing clinical studies assessing the use of ALK inhibitors in innovative settings and novel combinations. EXPERT COMMENTARY: ALK inhibitors have dramatically improved the prognosis of patients with ALK+ NSCLC and revolutionized therapy options. Nowadays, several molecules are approved for the treatment of ALK+ NSCLC, either in first or further lines of systemic treatment. Several clinical trials are currently ongoing in order to define a potential role of ALK inhibitors in combination with novel anti-cancer agents, as well as monotherapy in neo- and adjuvant settings.

Integrating Augmented Reality Tools in Breast Cancer Related Lymphedema Prognostication and Diagnosis.

Breast cancer related lymphedema (BCRL) is a detrimental condition characterized by fluid accumulation in the upper limb in breast cancer patients subjected to axillary surgery and/or radiations. Its etiology is multifactorial and include also tumor-specific pathological features, such as lymphovascular invasion (LVI) and extranodal extension (ENE). To date, no widely employed guidelines for the early diagnosis of BCRL are available. Here, we illustrate a protocol for a digitally assisted BCRL assessment using a 3D laser scanner (3DLS) and a tablet computer. It has been specifically optimized in a discovery cohort of high-risk breast cancer patients. This study provides a proof-of-principle that augmented reality tools, such as 3DLS, can be incorporated into the clinical workup of BCRL to allow for a precise, reproducible, reliable, and cheap diagnosis.

PTEN Expression as a Complementary Biomarker for Mismatch Repair Testing in Breast Cancer.

Mismatch repair (MMR) analysis in breast cancer may help to inform immunotherapy decisions but it lacks breast-specific guidelines. Unlike in other neoplasms, MMR protein loss shows intra-tumor heterogeneity and it is not mirrored by microsatellite instability in the breast. Additional biomarkers can improve MMR clinical testing. Phosphatase and tensin homolog (PTEN) inactivation is an early oncogenic event that is associated with MMR deficiency (dMMR) in several tumors. Here, we sought to characterize the diagnostic utility of PTEN expression analysis for MMR status assessment in breast cancer. A total of 608 breast cancers were profiled for their MMR and PTEN status. Proteins expression and distribution were analyzed by immunohistochemistry (IHC) on tissue microarrays and confirmed on full sections; PTEN copy number alterations were detected using a real-time PCR assay. Overall, 78 (12.8%) cases were MMR-heterogeneous (hMMR), while all patterns of PTEN expression showed no intra-tumor heterogeneity. Wild-type PTEN expression was observed in 15 (18.5%) dMMR tumors (p < 0.0001). Survival analyses revealed significant correlations between MMR-proficient (pMMR), PTEN expression, and a better outcome. The positive predictive value of PTEN-retained status for pMMR ranged from 94.6% in estrogen receptor (ER)+/HER2- tumors to 100% in HER2-amplified and ER-/HER2- cases. We propose a novel diagnostic algorithm where PTEN expression analysis can be employed to identify pMMR breast cancers.

Breast Cancer Systemic Treatments and Upper Limb Lymphedema: A Risk-Assessment Platform Encompassing Tumor-Specific Pathological Features Reveals the Potential Role of Trastuzumab.

Breast cancer related lymphedema (BCRL) is frequent but strategies for an individualized risk assessment are lacking. We aimed to define whether tumor-specific pathological features, coupled with clinical and therapeutic data, could help identify patients at risk. Data from 368 patients with node-positive breast cancers were retrospectively collected, including 75 patients with BCRL (0.4⁻25.6 years follow-up). BCRL was assessed during the standard follow-up oncology visits using the circumferential measurement. Clinicopathologic and therapeutic factors associated with BCRL were integrated into a Cox proportional hazards regression model. Lymphovascular invasion (LVI) was more common in BCRL patients (n = 33, 44% vs. n = 85, 29%, p = 0.01), akin extra nodal extension (ENE) of the metastasis (n = 57, 76% vs. n = 180, 61%, p = 0.02). Sentinel lymph node excision without axillary dissection and extra-axillary radiotherapy were BCRL-unrelated. A higher number of BCRL-positive patients were treated with taxane-based chemotherapy with or without trastuzumab, compared to BCRL-negative patients (p < 0.01). Treatment with trastuzumab and/or taxanes, adjusted for systemic infections, laterality, therapy, and pathological features (i.e., LVI and ENE), had a significant impact in BCRL-free survival (p < 0.01). This work offers new insights on BCRL risk stratification, where the integration of clinical, therapeutic, and tumor-specific pathological data suggests a possible role of anti-human epidermal growth factor receptor 2 (HER2) therapy in BCRL pathogenesis.