Fasting-mimicking diet: a metabolic approach for the treatment of breast cancer.

PURPOSE OF REVIEW: Metabolic reprogramming is a new and potentially targetable hallmark of cancer. In recent years, fasting and fasting-mimicking diets (FMDs) have been tested as anticancer strategies both in preclinical experiments and in clinical trials. In this review, we aim at summarizing the available evidence about the antitumour activity of these approaches in preclinical breast cancer models, as well as results from clinical trials investigating fasting/FMD in breast cancer patients. RECENT FINDINGS: Preclinical evidence demonstrated that nutrient deprivation boosts the antitumor activity of chemotherapy, immunotherapy or targeted therapies in triple-negative breast cancer (TNBC) and HR+/HER2 models through both cell-autonomous antitumour effects in cancer cells and favourable modifications in intratumor immune cells. Several clinical experiences demonstrated that fasting/FMD is feasible and well tolerated in combination with standard treatments in BC patients, and that it could reduce chemotherapy-related toxicities. Finally, despite the absence of randomized trials demonstrating the antitumor activity of fasting/FMD in breast cancer patients, preliminary clinical reports suggest that this experimental nutritional strategy may enhance chemotherapy activity. Randomized clinical trials are ongoing to validate these results at a larger scale. SUMMARY: Fasting/FMD is a promising therapeutic approach in patients with breast cancer; ongoing and future trials will confirm their role in improving breast cancer care.

Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications.

BACKGROUND: The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2- mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2- mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2- mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2- BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. CONCLUSIONS: Based on the available efficacy and safety data, the "new" alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the "old" everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2- mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.

Cyclic Fasting-Mimicking Diet Plus Bortezomib and Rituximab Is an Effective Treatment for Chronic Lymphocytic Leukemia.

Cyclic fasting-mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two patients with chronic lymphocytic leukemia (CLL) and investigated the effects of fasting and FMD cycles in preclinical CLL models. Fasting-mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacologic inhibition of this escape mechanism with the proteasome inhibitor bortezomib resulted in a strong enhancement of the proapoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with bortezomib and rituximab, an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials. SIGNIFICANCE: Chronic lymphocytic leukemia cells resist fasting-mimicking diet by inducing proteasome activation to escape starvation, which can be targeted using proteasome inhibition by bortezomib treatment to impede leukemia progression and prolong survival.

Breast cancers arising in subjects with germline BRCA1 or BRCA2 mutations: Different biological and clinical entities with potentially diverse therapeutic opportunities.

Breast cancers (BCs) arising in carriers of germline BRCA1 and BRCA2 pathogenic variants (PVs) have long been considered as indistinguishable biological and clinical entities. However, the loss of function of BRCA1 or BRCA2 proteins has different consequences in terms of tumor cell reliance on estrogen receptor signaling and tumor microenvironment composition. Here, we review accumulating preclinical and clinical data indicating that BRCA1 or BRCA2 inactivation may differentially affect BC sensitivity to standard systemic therapies. Based on a different crosstalk between BRCA1 or BRCA2 and the ER pathway, BRCA2-mutated Hormone Receptor-positive, HER2-negative advanced BC may be less sensitive to endocrine therapy (ET) plus CDK 4/6 inhibitors (CDK 4/6i), whereas BRCA2-mutated triple-negative breast cancer (TNBC) may be especially sensitive to immune checkpoint inhibitors. If validated in future prospective studies, these data may have relevant clinical implications, thus establishing different treatment paths in patients with BRCA1 or BRCA2 PVs.

Efficacy and Safety of First-line Carboplatin-paclitaxel and Carboplatin-gemcitabine in Patients With Advanced Triple-negative Breast Cancer: A Monocentric, Retrospective Comparison.

BACKGROUND: Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear. MATERIALS AND METHODS: We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates. RESULTS: Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009). CONCLUSION: CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile.

The pan-immune-inflammation value is associated with clinical outcomes in patients with advanced TNBC treated with first-line, platinum-based chemotherapy: an institutional retrospective analysis.

Background: Advanced triple-negative breast cancer (aTNBC) has a poor prognosis; thus, there is a need to identify novel biomarkers to guide future research and improve clinical outcomes. Objectives: We tested the prognostic ability of an emerging, complete blood count (CBC)-based inflammatory biomarker, the pan-immune-inflammation value (PIV), in patients with aTNBC treated with first-line, platinum-based chemotherapy. Design: This was a retrospective, monocentric, observational study. Methods: We included consecutive aTNBC patients treated with platinum-based, first-line chemotherapy at our Institution, and for whom baseline (C1) CBC data were available. We collected CBC data early on-treatment, when available. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) were included in a control, non-TNBC cohort. Results: A total of 78 aTNBC patients were included. When evaluated as a continuous variable, PIV-C1 was associated with worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). On the other hand, when PIV-C1 was assessed on the basis of its quantile distribution, patients with 'high PIV-C1' experienced worse OS [adjusted hazard ratio (HR): 4.46, 95% confidence interval (CI): 2.22-8.99; adjusted p < 0.001] and PFS (adjusted HR: 2.03, 95% CI: 1.08-3.80; adjusted p = 0.027) when compared to patients with 'low PIV-C1'. Higher PIV-C1 was also associated with primary resistance to chemotherapy. Similarly, a higher PIV calculated from CBC at C2D1 (PIV-C2) was associated with worse survival outcomes. We also created a PIV-based score combining information about both PIV-C1 and PIV-C2 and allowing the stratification of patients at low, intermediate, and high risk of death. No association was observed between PIV-C1 and clinical outcomes of HR+/HER2- aBC patients. Conclusion: PIV has a promising prognostic discrimination ability in aTNBC patients treated with first-line, platinum-based chemotherapy. Both baseline and early on-treatment PIV are associated with clinical outcomes and may be exploited for creating PIV-based risk classifiers if further validated.

Guideline-Based Follow-Up Outcomes in Patients With Gastrointestinal Stromal Tumor With Low Risk of Recurrence: A Report From the Italian Sarcoma Group.

Importance: Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure. Objective: To evaluate the outcomes of guideline-based follow-up in low-risk GIST. Design, Setting, and Participants: This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up. Exposures: All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines. Main Outcomes and Measures: The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed. Results: A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients. Conclusions and Relevance: In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy.

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.

Prognostic impact of body mass index (BMI) in HER2+ breast cancer treated with anti-HER2 therapies: from preclinical rationale to clinical implications.

Human Epidermal growth factor Receptor 2 (HER2) overexpression or HER2 gene amplification defines a subset of breast cancers (BCs) characterized by higher biological and clinical aggressiveness. The introduction of anti-HER2 drugs has remarkably improved clinical outcomes in patients with both early-stage and advanced HER2+ BC. However, some HER2+ BC patients still have unfavorable outcomes despite optimal anti-HER2 therapies. Retrospective clinical analyses indicate that overweight and obesity can negatively affect the prognosis of patients with early-stage HER2+ BC. This association could be mediated by the interplay between overweight/obesity, alterations in systemic glucose and lipid metabolism, increased systemic inflammatory status, and the stimulation of proliferation pathways resulting in the stimulation of HER2+ BC cell growth and resistance to anti-HER2 therapies. By contrast, in the context of advanced disease, a few high-quality studies, which were included in a meta-analysis, showed an association between high body mass index (BMI) and better clinical outcomes, possibly reflecting the negative prognostic role of malnourishment and cachexia in this setting. Of note, overweight and obesity are modifiable factors. Therefore, uncovering their prognostic role in patients with early-stage or advanced HER2+ BC could have clinical relevance in terms of defining subsets of patients requiring more or less aggressive pharmacological treatments, as well as of designing clinical trials to investigate the therapeutic impact of lifestyle interventions aimed at modifying body weight and composition. In this review, we summarize and discuss the available preclinical evidence supporting the role of adiposity in modulating HER2+ BC aggressiveness and resistance to therapies, as well as clinical studies reporting on the prognostic role of BMI in patients with early-stage or advanced HER2+ BC.

Exceptional tumour responses to fasting-mimicking diet combined with standard anticancer therapies: A sub-analysis of the NCT03340935 trial.

BACKGROUND: Cyclic fasting or calorie-restricted, low-carbohydrate, low-protein diets, collectively referred to as fasting-mimicking diets (FMDs), demonstrated additive or synergistic antitumour effects when combined with chemotherapy, targeted therapies, or immunotherapy in several preclinical in vivo models, including murine models of breast cancer, lung cancer, and colorectal cancer. However, no data on the antitumour efficacy of cyclic FMD in patients with cancer have been published so far. Here, we aim at reporting on patients with advanced cancer achieving complete and long-lasting tumour remissions with cyclic FMD in combination with standard anticancer therapies in the context of the phase Ib NCT03340935 trial. PATIENTS AND METHODS: The NCT03340935 trial enrolled 101 patients with different tumour types, and it showed that a severely calorie-restricted FMD regimen is safe and feasible in patients with cancer receiving concomitant standard-of-care antineoplastic therapies. In addition, cyclic FMD resulted in positive metabolic and immunologic modifications, thus recapitulating the biological effects that in preclinical models were found to mediate the antitumour effects of fasting/FMD. RESULTS: Of the 101 patients enrolled in the NCT03340935 trial, we identified five patients with advanced, poor prognosis solid neoplasms (n = 1: extensive stage small cell lung cancer; n = 1: metastatic pancreatic adenocarcinoma; n = 1: metastatic colorectal cancer; n = 2: metastatic triple-negative breast cancer), who achieved complete and long-lasting tumour responses when treated with a combination of cyclic FMD and standard systemic treatments in the context of the NCT03340935 trial. CONCLUSION: These excellent responses prompt the initiation of clinical trials to investigate cyclic FMD in combination with standard antitumour therapies in specific clinical contexts.

Case Report: Prolonged clinical benefit with sequential trastuzumab-containing treatments in a patient with advanced extramammary Paget disease of the groin.

Extramammary Paget disease (EMPD) is a rare form of cutaneous, intraepithelial adenocarcinoma, which typically presents itself as an erythematous plaque originating from apocrine-gland rich regions, such as the vulva, the perianal region, the scrotum, the penis, or the axilla. EMPD patients typically have a good prognosis, with expected 5-year survival of 60%-92%, but it is estimated that about one-third of EMPD patients will develop lymph node or distant metastases. Treatment approaches for EMPD include locoregional therapies such as broad surgical resection, radiotherapy, or topical imiquimod, when the disease is localized, and chemotherapy and biological agents for advanced EMPD. We report the case of a 58-year-old man diagnosed with locally advanced, symptomatic HER2-overexpressing, AR-positive EMPD, who achieved long-term tumor control with a sequence of several trastuzumab-based treatments (more than 30 months with second-line carboplatin plus paclitaxel plus trastuzumab followed by trastuzumab maintenance; 9 months for third-line vinorelbine plus trastuzumab). Even if it is reported that AR expression occurs concomitantly with HER2 overexpression in more than half of the cases of EMPD, to the best of our knowledge, this is the first case report describing androgen receptor blockade therapy in combination with an anti-HER2 agent. Our patient did not benefit from androgen receptor blockade in combination with trastuzumab, thus suggesting that AR expression may simply reflect an intrinsic characteristic of the EMPD cell of origin, rather than tumor dependence upon AR signaling. Given the reported sensibility to anti-HER2 therapy, also new antibody drug conjugates targeting HER2 are worth exploring in the management of advanced EMPD.

Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab.

BACKGROUND: Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. METHODS: Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. RESULTS: In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). CONCLUSIONS: High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.

Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer.

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMD) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments. Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments. SIGNIFICANCE: Cyclic FMD is well tolerated and causes remarkable systemic metabolic changes in patients with different tumor types and treated with concomitant antitumor therapies. In addition, the FMD reshapes systemic and intratumor immunity, finally activating several antitumor immune programs. Phase II/III clinical trials are needed to investigate FMD antitumor activity/efficacy.This article is highlighted in the In This Issue feature, p. 1.

HER2 Signaling and Breast Cancer Stem Cells: The Bridge behind HER2-Positive Breast Cancer Aggressiveness and Therapy Refractoriness.

HER2 overexpression/amplification occurs in 15-20% of breast cancers (BCs) and identifies a highly aggressive BC subtype. Recent clinical progress has increased the cure rates of limited-stage HER2-positive BC and significantly prolonged overall survival in patients with advanced disease; however, drug resistance and tumor recurrence remain major concerns. Therefore, there is an urgent need to increase knowledge regarding HER2 biology and implement available treatments. Cancer stem cells (CSCs) represent a subset of malignant cells capable of unlimited self-renewal and differentiation and are mainly considered to contribute to tumor onset, aggressiveness, metastasis, and treatment resistance. Seminal studies have highlighted the key role of altered HER2 signaling in the maintenance/enrichment of breast CSCs (BCSCs) and elucidated its bidirectional communication with stemness-related pathways, such as the Notch and Wingless/ß-catenin cascades. d16HER2, a splice variant of full-length HER2 mRNA, has been identified as one of the most oncogenic HER2 isoform significantly implicated in tumorigenesis, epithelial-mesenchymal transition (EMT)/stemness and the response to targeted therapy. In addition, expression of a heterogeneous collection of HER2 truncated carboxy-terminal fragments (CTFs), collectively known as p95HER2, identifies a peculiar subgroup of HER2-positive BC with poor prognosis, with the p95HER2 variants being able to regulate CSC features. This review provides a comprehensive overview of the current evidence regarding HER2-/d16HER2-/p95HER2-positive BCSCs in the context of the signaling pathways governing their properties and describes the future prospects for targeting these components to achieve long-lasting tumor control.

Prolonged benefit from palbociclib plus letrozole in heavily pretreated advanced male breast cancer: case report.

INTRODUCTION: Breast cancer in men is less common than in women and treatment recommendations are often derived from clinical trials exclusively involving women. Data on efficacy of CDK 4/6 inhibitors, which are the mainstay of treatment for hormone receptor-positive/HER2-negative advanced breast cancer, are lacking in male patients. CASE REPORT: We present a clinical case of prolonged benefit from palbociclib in combination with letrozole and LHRH analogue in a man who had previously been treated with six lines of endocrine therapies and chemotherapy regimens but was still in excellent clinical condition. CONCLUSIONS: This clinical case demonstrates that male breast cancer stands out as an endocrine-sensitive disease, which could potentially benefit from CDK 4/6 inhibitors in combination with endocrine agents even in very heavily pretreated settings of disease, underscoring both the importance of an accurate selection of patients for later treatment lines, taking into account disease history and previous treatment responses, and the peculiarity of breast cancer in men, which deserves dedicated clinical trials to tailor future recommendations.

Risk assessment of thromboembolic events in hospitalized cancer patients.

Hospitalized cancer patients are at increased risk for Thromboembolic Events (TEs). As untailored thromboprophylaxis is associated with hemorrhagic complications, the definition of a risk-assessment model (RAM) in this population is needed. INDICATE was a prospective observational study enrolling hospitalized cancer patients, with the primary objective of assessing the Negative Predictive Value (NPV) for TEs during hospitalization and within 45 days from discharge of low-grade Khorana Score (KS = 0). Secondary objectives were to assess KS Positive Predictive Value (PPV), the impact of TEs on survival and the development of a new RAM. Assuming 7% of TEs in KS = 0 patients as unsatisfactory percentage and 3% of as satisfactory, 149 patients were needed to detect the favorable NPV with one-sided α = 0.10 and power = 0.80. Stepwise logistic regression was adopted to identify variables included in a new RAM. Among 535 enrolled patients, 153 (28.6%) had a KS = 0. The primary study objective was met: 29 (5.4%) TEs were diagnosed, with 7 (4.6%) cases in the KS = 0 group (NPV = 95.4%, 95% CI 90.8-98.1%; one-sided p = 0.084). However, the PPV was low (5.7%, 95% CI 1.9-12.8%); a new RAM based on albumin (OR 0.34, p = 0.003), log(LDH) (OR 1.89, p = 0.023) and presence of vascular compression (OR 5.32, p < 0.001) was developed and internally validated. Also, TEs were associated with poorer OS (median, 5.7 vs 24.8 months, p < 0.001). INDICATE showed that the KS has a good NPV but poor PPV for TEs in hospitalized cancer patients. A new RAM was developed, and deserves further assessment in external cohorts.

Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin.

BACKGROUND: We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. PATIENTS: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). RESULTS: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22-0.94; adjusted p = 0.035). CONCLUSIONS: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.

Hormone receptor status influences the impact of body mass index and hyperglycemia on the risk of tumor relapse in early-stage HER2-positive breast cancer patients.

BACKGROUND: High body mass index (BMI) has been associated with worse clinical outcomes in patients with early-stage breast cancer (BC), and its negative effects could be mediated by hyperglycemia/diabetes. However, the prognostic impact of high BMI in early-stage HER2-positive (HER2+) BC patients remains controversial. METHODS: We conducted a retrospective study to investigate the impact of baseline BMI or glycemia on relapse-free survival (RFS) and overall survival (OS) in patients with surgically resected, stage I-III HER2+ BC treated with standard-of-care, trastuzumab-containing adjuvant biochemotherapy. The optimal BMI and glycemia cut-off values for RFS were identified through maximally selected rank statistics. Cox regression models were used to assess the impact of BMI, glycemia and other relevant variables on clinical outcomes. RESULTS: Among 505 patients included in the study, a BMI cut-off of 27.77 kg/m2 was identified as the best threshold to discriminate between patients with low BMI (n = 390; 77.2%) or high BMI (n = 115; 22.8%). At multivariable analysis, higher BMI was associated with significantly worse RFS [hazard ratio 2.26; 95% confidence interval (CI): 1.08-4.74, p = 0.031] and worse OS (hazard ratio 2.25, 95% CI 1.03-4.94, p = 0.043) in the whole patient population. The negative impact of high BMI was only observed in patients with hormone receptor (HR)-negative/HER2+ BC (hazard ratio 2.29; 95% CI: 1.01-5.20; p = 0.047), but not in patients with HR-positive (HR+)/HER2+ BC (hazard ratio 1.36; 95% CI: 0.61-3.07, p = 0.452). By contrast, hyperglycemia (⩾109 mg/dl) at baseline was associated with a trend toward significantly worse RFS at multivariable analysis only in patients with HR+/HER2+ BC (hazard ratio 2.52; 95% CI: 0.89-7.1; p = 0.080). CONCLUSIONS: High BMI is associated with worse clinical outcomes in early-stage HR-/HER2+ BC patients treated with trastuzumab-containing adjuvant biochemotherapy, while baseline hyperglycemia could be a predictor of worse RFS in HR+/HER2+ BC patients. Prospective studies are needed to investigate if modifying patient BMI/glycemia during treatment can improve clinical outcomes.

Targeting lipid metabolism is an emerging strategy to enhance the efficacy of anti-HER2 therapies in HER2-positive breast cancer.

De novo or acquired resistance of cancer cells to currently available Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors represents a clinical challenge. Several resistance mechanisms have been identified in recent years, with lipid metabolism reprogramming, a well-established hallmark of cancer, representing the last frontier of preclinical and clinical research in this field. Fatty Acid Synthase (FASN), the key enzyme required for fatty acids (FAs) biosynthesis, is frequently overexpressed/activated in HER2-positive (HER2+) breast cancer (BC), and it crucially sustains HER2+ BC cell growth, proliferation and survival. After the synthesis of new, selective and well tolerated FASN inhibitors, clinical trials have been initiated to test if these compounds are able to re-sensitize cancer cells with acquired resistance to HER2 inhibition. More recently, the upregulation of FA uptake by cancer cells has emerged as a potentially new and targetable mechanism of resistance to anti-HER2 therapies in HER2+ BC, thus opening a new era in the field of targeting metabolic reprogramming in clinical setting. Here, we review the available preclinical and clinical evidence supporting the inhibition of FA biosynthesis and uptake in combination with anti-HER2 therapies in patients with HER2+ BC, and we discuss ongoing clinical trials that are investigating these combination approaches.