T-cell-based breast cancer immunotherapy.

Cancer immunotherapy has witnessed a new renaissance with the advent of immune checkpoint inhibitors, which reactivate T cells and foster endogenous anti-tumor responses. The excellent results of immunotherapy in the field of melanoma, renal cancer, lung cancer, and other cancer types that have traditionally been known to be immunogenic, rekindled the interest of the oncology community in extending the benefits to all cancers including breast cancer (BC). In this review, we highlight the current state of using T cells as both markers for clinical practice and therapeutic options for BC.

Highly specialized Breast Centers did not experience delay of care during COVID-19 pandemic in Italy: the Senonetwork experience.

AIM OF THE STUDY: The study aims to evaluate the performance of selected, high-volume, highly specialized, Italian Breast Centers at the time of COVID-19 pandemic (year 2020), compared to pre-pandemic time (year 2019), highlighting differences in terms of clinical presentation of breast cancer (BC) and therapeutic strategies. METHODS: Patients' data were provided by the Senonetwork data warehouse Senonet. In order to examine changes in the surgical and oncological management of BC patients during different phases of COVID-19 pandemic, we took advantage of a selection quality indicators (QIs). We performed the analyses in two time-frames, from July to September (Jul-Sep) (2019 versus 2020) and from October to December (Oct-Dec) (2019 versus 2020). RESULTS: Our analysis did not show any statistically significant difference in terms of diagnosis, surgical, oncological and radiation therapy procedures between the two trimesters 2019 and 2020. Nevertheless, we observed statistically significant differences, favoring 2020, when analyzing time-to surgery and time-to radiotherapy. On the other hand, we observed a significant reduction of neoadjuvant chemotherapy and we did not recollect any data on a major use of neoadjuvant endocrine therapy. CONCLUSIONS: In Italian Breast Centers, partners of Senonetwork, we could not observe any treatment delay or change in standard clinical practice for BC care during the 2020 pandemic year, compared to 2019 pre-pandemic year. This finding is in contrast with the globally reported decrease in the performance of the Italian Breast Centers due to the COVID-19 pandemic, and has to be linked to the sharp selection of Senonetwork Breast Centers.

Safety of autologous fat grafting in breast cancer: a multicenter Italian study among 17 senonetwork breast units autologous fat grafting safety: a multicenter Italian retrospective study.

BACKGROUND: Autologous fat grafting (AFG), defined as the re-implant to the breast of fat tissue from different body areas, has been firstly applied to esthetic plastic surgery and then has moved to reconstructive surgery, mainly used for scar correction and opposite breast altering. Nevertheless, due to the potentially unsafe stem-like properties of adipocytes at the tumoral bed level, no clear evidence of the procedure's oncological safety has been clearly documented at present. PATIENTS AND METHODS: We retrospectively collected data of early breast cancer (BC) patients from 17 Italian Breast Units and assessed differences in terms of locoregional recurrence rate (LRR) and locoregional recurrence-free survival (LRFS) between patients who underwent AFG and patients who did not. Differences were analyzed in the entire cohort of invasive tumors and in different subgroups, according to prognostic biological subtypes. RESULTS: With a median follow-up time of 60 months, LRR was 5.3% (n = 71) in the matched population, 3.9% (n = 18) in the AFG group, and 6.1% (n = 53) in the non-AFG group, suggesting non-inferiority of AFG (p = 0.084). Building Kaplan-Meier curves confirmed non-inferiority of the AFG procedure for LRFS (aHR 0.73, 95% CI 0.41-1.30, p = 0.291). The same effect, in terms of LRFS, was also documented among different biological subtypes (luminal-like group, aHR 0.76, 95% CI 0.34-1.68, p = 0.493; HER2 enriched-like, aHR 0.89, 95% CI 0.19-4.22, p = 0.882; and TNBC, aHR 0.61, 95% CI 0.12-2.98, p = 0.543). CONCLUSIONS: Our study confirms in a very large, multicenter cohort of early BC patients that, aside the well-known benefits on the esthetic result, AFG do not interfere negatively with cancer prognosis.

Prognostic factors and outcome of HER2+ breast cancer with CNS metastases.

Aim: Trastuzumab prolongs progression-free and overall survival in HER2+ breast cancer (BC), but these are associated with increased distant recurrences and central nervous system metastases (CNSm). We retrospectively evaluated outcome and prognostic factors in CNSm and non-CNSm patients. Methods: Records of HER2+ BC treated in 2000-2017 were reviewed. Results: 283/1171 (24%) HER2+ BC patients developed metastatic disease. 109/283 patients (39%) have CNSm associated with worse prognosis and increased risk of death (hazard ratio: 4.7; 95% CI: 3.5-6.4). Prognostic factors were: number of CNSm (single vs multiple lesions; 3-year overall survival 39 vs 18%; p = 0.003); brain radiation (30 vs 14%; p < 0.001); new HER2-targeting therapies (30.6 vs 22.5%; p = 0.025). Conclusion: Prognosis of BC patients with CNSm has improved using HER2-targeting therapies but remains poor.

Predictive Factors of Eribulin Activity in Metastatic Breast Cancer Patients.

OBJECTIVES: Predictive factors of response to eribulin are lacking. We aimed to investigate the activity and safety of eribulin in a real-world population of metastatic breast cancer (MBC) patients and to identify possible predictive factors of progression-free survival (PFS) and objective response. METHODS: We retrospectively analyzed 71 eribulin-treated MBC patients. Best response rate, PFS, and adverse events (AEs) were evaluated. The impact of different clinical-pathological factors on PFS was evaluated using the Cox proportional hazards model. Predictive factors of response were identified by discriminant function analysis (DFA). RESULTS: Median PFS was 3.75 months (95% CI, 2.39-4.48); 12 patients (16.90%) achieved partial response (PR), 27 (38.03%) stable disease. The most common AEs were fatigue (25.83%), neutropenia (16.56%), and peripheral neuropathy (13.91%). A worse performance status (p = 0.025) and a higher number of metastatic organ sites (p = 0.011) were associated with a worse PFS under eribulin. Overall, in the DFA-predictive model, neutrophil-to-lymphocyte ratio at baseline, estrogen receptor, Ki67, histology, and age were predictive of PR with 100% accuracy. CONCLUSIONS: Activity and safety profiles of eribulin were consistent with literature data. Performance status and number of metastatic sites were predictive factors of PFS. DFA could be a promising tool to discriminate responses to eribulin among MBC patients.

An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) are a robust prognostic factor in triple-negative breast cancer (TNBC). However, the clinical significance of TILs may be influenced by the complex landscape of the tumor immune microenvironment. In this study, we aimed to evaluate the composition and the functionality of lymphocytic infiltration and checkpoint receptors in TNBC. METHODS: Formalin-fixed, paraffin-embedded tissues were retrospectively collected from a cohort of patients with early-stage TNBC treated with adjuvant anthracycline-based chemotherapy (n = 259). Results were validated in an independent cohort of patients with TNBC (n = 104). Stromal TILs were evaluated on hematoxylin-and-eosin-stained sections. The density of CD4+, CD8+, and FOXP3+ lymphocytes, and the expression of the immune checkpoints PD-1 and LAG-3, were assessed by immunohistochemical analysis. RESULTS: The presence of elevated TILs positively correlated with the density of all T cell subtypes, especially cytotoxic CD8+ lymphocytes. We showed that increasing stromal TILs assessed as a continuous variable is an independent prognostic marker of prolonged relapse-free survival and overall survival in TNBC. Among immune subpopulations, CD8+ lymphocytes are the main effectors of anti-tumor immune responses. In two independent cohorts, we found that PD-1 and LAG-3 were concurrently expressed in approximately 15% of patients with TNBC. The expression of both checkpoint receptors positively correlated with the presence of TILs, but was not significantly associated with patient outcome. CONCLUSIONS: Overall, our data indicate that the evaluation of stromal TILs remains the most reliable immune prognostic marker in TNBC, and support the clinical evaluation of anti-PD-1/PD-L1 and anti-LAG-3 in a subset of patients with TNBC who have concurrent expression of both checkpoint receptors.

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series.

BACKGROUND: Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC). METHODS: We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013. RESULTS: From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia. CONCLUSION: Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS. IMPLICATIONS FOR PRACTICE: There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.

T Cell Features in Glioblastoma May Guide Therapeutic Strategies to Overcome Microenvironment Immunosuppression.

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor, bearing a survival estimate below 10% at five years, despite standard chemoradiation treatment. At recurrence, systemic treatment options are limited and the standard of care is not well defined, with inclusion in clinical trials being highly encouraged. So far, the use of immunotherapeutic strategies in GBM has not proved to significantly improve patients' prognosis in the treatment of newly diagnosed GBM, nor in the recurrent setting. Probably this has to do with the unique immune environment of the central nervous system, which harbors several immunosuppressive/pro-tumorigenic factors, both soluble (e.g., TGF-ß, IL-10, STAT3, prostaglandin E2, and VEGF) and cellular (e.g., Tregs, M2 phenotype TAMs, and MDSC). Here we review the immune composition of the GBMs microenvironment, specifically focusing on the phenotype and function of the T cell compartment. Moreover, we give hints on the therapeutic strategies, such as immune checkpoint blockade, vaccinations, and adoptive cell therapy, that, interacting with tumor-infiltrating lymphocytes, might both target in different ways the tumor microenvironment and potentiate the activity of standard therapies. The path to be followed in advancing clinical research on immunotherapy for GBM treatment relies on a twofold strategy: testing combinatorial treatments, aiming to restore active immune anti-tumor responses, tackling immunosuppression, and additionally, designing more phase 0 and window opportunity trials with solid translational analyses to gain deeper insight into the on-treatment shaping of the GBM microenvironment.

Brain metastases and next-generation anticancer therapies: a survival guide for clinicians.

Historically, patients with brain metastases (BMs) have been characterized by few systemic treatment options and poor prognosis. The recent introduction of next-generation anticancer therapies such as molecular targeted agents and immunotherapy have revolutionized the clinical decision-making process of this sub-population, posing new challenges to physicians. In this review, current evidence for the use of checkpoint inhibitors and targeted therapies in patients with BMs are discussed, with a focus on lung cancer, breast cancer, melanoma and renal cell carcinoma, providing suggestions and potential workflows for daily clinical practice. Several other on-going and future challenges, such as clinical trials design, ways to improve CNS penetration of novel drugs and unique molecular characteristics of BMs, are also discussed. The aim is producing an updated and easy-to-read guide for physicians, to improve decision-making in clinical practice.

Refining patient selection for next-generation immunotherapeutic early-phase clinical trials with a novel and externally validated prognostic nomogram.

Introduction: Identifying which patient may benefit from immunotherapeutic early-phase clinical trials is an unmet need in drug development. Among several proposed prognostic scores, none has been validated in patients receiving immunomodulating agents (IMAs)-based combinations. Patients and methods: We retrospectively collected data of 208 patients enrolled in early-phase clinical trials investigating IMAs at our Institution, correlating clinical and blood-based variables with overall survival (OS). A retrospective cohort of 50 patients treated with IMAs at Imperial College (Hammersmith Hospital, London, UK) was used for validation. Results: A total of 173 subjects were selected for analyses. Most frequent cancers included non-small cell lung cancer (26%), hepatocellular carcinoma (21.5%) and glioblastoma (13%). Multivariate analysis (MVA) revealed 3 factors to be independently associated with OS: line of treatment (second and third vs subsequent, HR 0.61, 95% CI 0.40-0.93, p 0.02), serum albumin as continuous variable (HR 0.57, 95% CI 0.36-0.91, p 0.02) and number of metastatic sites (<3 vs ≥3, HR 0.68, 95% CI 0.48-0.98, p 0.04). After splitting albumin value at the median (3.84 g/dL), a score system was capable of stratifying patients in 3 groups with significantly different OS (p<0.0001). Relationship with OS reproduced in the external cohort (p=0.008). Then, from these factors we built a nomogram. Conclusions: Prior treatment, serum albumin and number of metastatic sites are readily available prognostic traits in patients with advanced malignancies participating into immunotherapy early-phase trials. Combination of these factors can optimize patient selection at study enrollment, maximizing therapeutic intent.

Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation.

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Breast conserving surgery versus salvage mastectomy for ipsilateral breast cancer recurrence: a propensity score matching analysis.

Salvage mastectomy is regarded as the treatment of first choice for ipsilateral breast cancer recurrence (IBCR), even if a second breast conserving surgery (BCS) is feasible. The purpose of this study was to compare the long-term oncological outcomes of IBCR patients who had undergone either mastectomy or second BCS, performing a propensity score matching (PSM) analysis to reduce the selection bias. All the consecutive patients with IBCR were retrospectively reviewed and divided into two different groups of treatment: repeat BCS versus salvage mastectomy. The propensity score predicting the probability of surgical treatment was determined for each patient and a 1:1 matching was performed. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. A total of 309 patients underwent surgical treatment for IBCR. After PSM, 108 patients treated with repeat BCS and 108 patients treated with salvage mastectomy were included in the analysis. There was no significant difference in terms of DFS between patients with IBCR receiving repeat BCS or salvage mastectomy (p = 0.167). However, patients with IBCR undergoing second BCS had significantly better DDFS, OS, and BCSS compared to salvage mastectomy (p < 0.001). Salvage mastectomy should not be considered the optimal treatment for IBCR and it does not seem to improve prognosis compared to repeat conserving surgery. Second BCS for IBCR is a safe option with encouraging long-term oncological outcomes and should be proposed to all patients, when technically feasible.

Surgical management of BRCA-mutation carriers: A single institution experience.

INTRODUCTION: The optimal surgical management of BRCA-mutation carriers remains a subject of debate. To evaluate the appropriateness of breast cancer (BC) treatment, the oncological outcomes of BRCA-mutation carriers treated either with breast-conserving therapy (BCT) or mastectomy were compared. Additionally, the role of bilateral salpingo-oophorectomy (BSO) and potential independent predictive factors for BC treatment were analyzed. MATERIALS AND METHODS: We retrospectively reviewed all the consecutive patients with a pathogenic germline mutation in the BRCA1/2 genes tested at our Institution between July 2008 and October 2018. Primary end-points were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: The characteristics and outcomes of 124 BRCA-associated BC patients were analyzed. Overall, 69 (55.7%) and 55 (44.3%) patients underwent BCT and mastectomy, respectively; 72 (58.1%) patients underwent BSO. After a median interval of 13.3 months, 24 patients underwent mastectomy after primary BCT. There was no significant difference in terms of DFS, DDFS, and OS between patients treated with BCT or mastectomy (p = 0.39,p = 0.27,p = 0.265, respectively). Patients treated with BSO had significantly better DDFS and OS compared to ovarian conservation (p = 0.033,p = 0.040, respectively). Three independent predictive factors for BCT were identified: age ≤41 years, genetic testing performed post-operatively, and breast tumors ≤21 mm. CONCLUSIONS: Our data suggest that BRCA-mutation carriers treated with BCT present similar oncological outcomes compared to mastectomy. Ovarian preservation decreases survival. Young BRCA-mutated patients with small BCs may not need up-front mastectomy, and BSO might be performed when ovarian cancer risk epidemiologically rises and potential reproductive desire is fulfilled.

Progress and pitfalls in the use of immunotherapy for patients with triple negative breast cancer.

INTRODUCTION: Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a 'cold' tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression, and tumor mutational burden compared to other breast cancer subtypes. AREAS COVERED: This review examines the available evidence on the use of immunotherapeutic strategies in early and advanced TNBC, discusses the pitfalls and limitations often encountered in clinical research, and summarizes data on novel promising immunomodulatory approaches that have been explored in early-phase trials. EXPERT OPINION: PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution towards a more personalized approach, and extended clinical benefit in TNBC.Abbreviations:Triple-negative breast cancer (TNBC); breast cancers (BCs); estrogen receptor (ER); progesterone receptor (PgR); human epidermal growth factor-2 (HER-2); basal-like 1 (BL1), basal-like 2 (BL2); mesenchymal (MES); mesenchymal stem-like (MSL); immunomodulatory (IM); luminal androgen receptor (LAR); basal-like immunosuppressed (BLIS); basal-like immune-activated (BLIA); tumor-infiltrating lymphocytes (TILs); tumor mutational burden (TMB); immune cells (ICs); immunohistochemistry (IHC); overall response rate (ORR); overall survival (OS); progression-free survival (PFS); intention-to-treat (ITT); hazard ratio (HR); confidence interval (CI); Food and Drug Administration (FDA); European Medicines Agency (EMA); immune checkpoint inhibitors (ICI); Combined Positive Score (CPS); disease control rate (DCR); neoadjuvant chemotherapy (NACT); pathological complete response (pCR); event-free survival (EFS); disease-free survival (DFS); residual cancer burden (RCB); San Antonio Breast Cancer Symposium (SABCS); antibody-drug conjugates (ADCs); PARP inhibitors (PARPi); clinical benefit rate (CBR); Histone deacetylase inhibitors (HDACi); Dendritic cell (DC); talimogene laherparepvec (TVEC); granulocyte-macrophage colony-stimulating factor (GM-CSF); mismatch repair deficiency (dMMR).

Precision Oncology in Lower-Grade Gliomas: Promises and Pitfalls of Therapeutic Strategies Targeting IDH-Mutations.

Mutations in isocitrate dehydrogenase (IDH)1 and its homolog IDH2 are considered an earliest "driver" genetic event during gliomagenesis, representing now the molecular hallmark of lower-grade gliomas (LGGs). IDH-mutated genes encode for a neomorphic enzyme that converts α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG), which accumulates to high concentrations and alters cellular epigenetics and metabolism. Targeting IDH mutations is the first attempt to apply "precision oncology" in LGGs. Two distinct strategies have been proposed so far and are under intense clinical investigation: (i) reducing the amount of intratumoral 2-HG by directly blocking the function of mutant IDH enzyme; (ii) exploiting the selective epigenetic and metabolic cellular vulnerabilities as a consequence of 2-HG accumulation. The present review describes the physiopathological mechanisms by which IDH mutations lead to tumorigenesis, discussing their prognostic significance and pivotal role in the gliomas diagnostic classification system. We critically review preclinical evidence and available clinical data of first-generation mutant-selective IDH inhibitors and novel IDH-targeted vaccines. Finally, as an alternative and attractive approach, we present the rationale to take advantage of selective 2-HG related epigenetic and metabolic weaknesses. The results of ongoing clinical trials will help us clarify the complex scenario of IDH-targeted therapeutic approaches in gliomas.

Neo-Adjuvant Chemotherapy in Luminal, Node Positive Breast Cancer: Characteristics, Treatment and Oncological Outcomes: A Single Center's Experience.

OBJECTIVE: Neo-adjuvant chemotherapy (NAC) is the treatment of choice for patients with locally advanced breast cancer (BC). In luminal-like BC, the decision to administer NAC remains controversial. The purpose of this study was to describe the clinical characteristics, treatment, and oncological outcomes of luminal-like, node positive, BC patients treated with NAC, and to identify independent predictive factors for treatment. MATERIALS AND METHODS: All consecutive patients with luminal-like, node positive BC who underwent NAC were retrospectively reviewed. Pathologic complete response (pCR) was defined as no invasive or in situ residual tumor in both breast and axillary nodes (ypT0N0). RESULTS: A total of 205 luminal-like, node positive BC patients underwent NAC. Overall, 34 (16.6%) patients showed pCR, 86 (42.0%) patients underwent breast-conserving surgery (BCS), 119 (58.0%) patients underwent mastectomy, 130 (63.4%) patients underwent axillary lymph node dissection (ALND) without prior sentinel lymph node biopsy (SLNB), and 75 (36.6%) patients underwent breast surgery plus SLNB. Pathologic CR to NAC (29.1% vs 7.6% if no pCR, odds ratio = 2.866, 95% confidence interval = 1.296-6.341, p = 0.009) was found to significantly increase the probability to receive BCS. There was no significant difference in terms of disease-free and overall survival between patients with luminal-like, node positive BC receiving BCS or mastectomy (p = 0.596, p = 0.134, respectively), and ALND or SLNB only (p = 0.661, p = 0.856, respectively). CONCLUSION: Luminal-like, node positive BC presents low pCR rates after NAC. Pre-operative chemotherapy increases the rate of BCS. Pathologic CR has emerged as an independent predictive factor for BCS. In patients with axillary pCR, SLNB is an acceptable procedure not associated with worse oncological outcomes.

Neoadjuvant chemotherapy in hormone receptor-positive/HER2-negative early breast cancer: When, why and what?

Indication for neoadjuvant chemotherapy (NACT) in HR+/HER2-negative tumors is controversial. Pathological complete response (pCR) rates range from 0 to 18 % while breast-conserving surgery (BCS) is achievable in up to 60 % of tumors. No pathological feature definitely predicts pCR; lobular and molecular luminal A tumors are less likely to achieve pCR although experiencing better outcomes. Luminal B subtype, high proliferation, lack of progesterone receptor, high tumor-infiltrating lymphocytes are positively associated with increased pCR rates but worse outcomes and the prognostic role of pCR is inconsistent across studies. Molecular intrinsic subtyping and genomic signatures appear as more accurate predictors of benefit from NACT, but larger studies are needed. Anthracycline and taxane-based chemotherapy remains the standard NACT; however, CDK 4/6 inhibitors and immune checkpoint inhibitors are under evaluation. In conclusion, NACT may be proposed for luminal tumors requiring downsizing for BCS after multidisciplinary evaluation, provided that other contraindications to BCS are excluded.

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab.

BACKGROUND: Few data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors. PATIENTS AND METHODS: We retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity. RESULTS: Within 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups. CONCLUSION: Our study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.