Impact of BMI on HER2+ metastatic breast cancer patients treated with pertuzumab and/or trastuzumab emtansine. Real-world evidence.

Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting.

We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.

Neoadjuvant Endocrine Therapy in Breast Cancer: Current Knowledge and Future Perspectives.

In locally advanced (LA) breast cancer (BC), neoadjuvant treatments have led to major achievements, which hold particular relevance in HER2-positive and triple-negative BC. Conversely, their role in hormone receptor positive (HR+), hormone epidermal growth factor 2 negative (HER2-) BC is still under debate, mainly due to the generally low rates of pathological complete response (pCR) and lower accuracy of pCR as predictors of long-term outcomes in this patient subset. While administration of neoadjuvant chemotherapy (NCT) in LA, HR+, HER2- BC patients is widely used in clinical practice, neoadjuvant endocrine therapy (NET) still retains an unfulfilled potential in the management of these subgroups, particularly in elderly and unfit patients. In addition, NET has gained a central role as a platform to test new drugs and predictive biomarkers in previously untreated patients. We herein present historical data regarding Tamoxifen and/or Aromatase Inhibitors and a debate on recent evidence regarding agents such as CDK4/6 and PI3K/mTOR inhibitors in the neoadjuvant setting. We also discuss key issues concerning the optimal treatment length, appropriate comparisons with NCT efficacy and use of NET in premenopausal patients.

Early triple negative breast cancer: Are we getting better outcomes? A retrospective analysis from a single institution.

Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10 years OS, DFS, and DRFI were 77% and 65%; 60% and 46%; and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77%; 68% and 54%, 77% both at 5 and 10 years. Prognosis is better than previously described; adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.

Prolactin as a Potential Early Predictive Factor in Metastatic Non-Small Cell Lung Cancer Patients Treated with Nivolumab.

BACKGROUND/AIMS: Prolactin (PRL) is a peptide hormone and several studies have demonstrated its role as a cytokine in human T cell-mediated immunity. We are unaware if PRL is a positive or negative immunomodulator, but its effects on the regulation of T cells could inhibit the antitumor activity elicited by nivolumab (NIVO). We aimed to assess whether the occurrence of hyperprolactinemia in metastatic non-small cell lung cancer (mNSCLC) patients treated with NIVO is associated with poor clinical outcomes. METHODS: We evaluated 26 mNSCLC patients treated with NIVO. Blood samples were collected in every patient to evaluate PRL basal levels before starting the therapy with NIVO and before each following administration of NIVO. All patients underwent a conventional CT to investigate the effect of therapy according to Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST). RESULTS: Twenty patients (77%) developed hyperprolactinemia during the treatment, whereas 6 patients (23%) had stable levels of PRL during the therapy (p = 0.001). A total of 95% of the 20 patients with hyperprolactinemia had progressive disease (PD), according to CT results, whereas only 2 patients (33%) out of 6 with stable PRL levels had PD (p = 0.004). CONCLUSIONS: Hyperprolactinemia in mNSCLC patients treated with NIVO could potentially represent a negative early predictive factor for poor clinical outcomes, thus anticipating PD shown by CT scan.

Sarcopenia in Breast Cancer Patients: A Systematic Review and Meta-Analysis.

(1) Background: We estimated the prevalence and clinical outcomes of sarcopenia among breast cancer patients. (2) Methods: A systematic literature search was carried out for the period between July 2023 and October 2023. Studies with breast cancer patients evaluated for sarcopenia in relation to overall survival (OS), progression-free survival (PFS), relapse of disease (DFS), pathological complete response (pCR), or toxicity to chemotherapy were included. (3) Results: Out of 359 screened studies, 16 were eligible for meta-analysis, including 6130 patients, of whom 5284 with non-MBC. Sarcopenia was evaluated with the computed tomography (CT) scan skeletal muscle index and, in two studies, with the dual-energy x-ray absorptiometry (DEXA) appendicular lean mass index. Using different classifications and cut-off points, overall, there were 2007 sarcopenic patients (33%), of whom 1901 (95%) presented with non-MBC. Sarcopenia was associated with a 33% and 29% higher risk of mortality and progression/relapse of disease, respectively. Sarcopenic patients were more likely to develop grade 3-4 toxicity (OR 3.58, 95% CI 2.11-6.06, p < 0.0001). In the neoadjuvant setting, a higher rate of pCR was observed among sarcopenic patients (49%) (OR 2.74, 95% CI 0.92-8.22). (4) Conclusions: Our meta-analysis confirms the correlation between sarcopenia and negative outcomes, especially in terms of higher toxicity.

Clinical implications of the Drug-Drug Interaction in Cancer Patients treated with innovative oncological treatments.

In the last two-decades, innovative drugs have revolutionized cancer treatments, demonstrating a significant improvement in overall survival. These drugs may present several pharmacokinetics interactions with non-oncological drugs, and vice versa, and, non-oncological drugs can modify oncological treatment outcome both with pharmacokinetic interaction and with an "off-target impact" on the tumor microenvironment or on the peripheral immune response. It's supposed that the presence of a drug-drug interaction (DDI) is associated with an increased risk of reduced anti-tumor effects or severe toxicities. However, clinical evidence that correlate the DDI presence with outcome are few, and results are difficult to compare because of difference in data collection and heterogeneous population. This review reports all the clinical evidence about DDI to provide an easy-to-use guide for DDI management and dose adjustment in solid tumors treated with inhibitors of the cyclin-dependent kinases CDK4-6, Antibody-drug conjugates, Poly ADPribose polymerase inhibitors, androgen-receptor targeted agents, or immunecheckpoints inhibitors.

The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets.

Introduction: Chemokines are small, secreted peptides involved in the mediation of the immune cell recruitment. Chemokines have been implicated in several diseases including autoimmune diseases, viral infections and also played a critical role in the genesis and development of several malignant tumors. CXCL12 is a homeostatic CXC chemokine involved in the process of proliferation, and tumor spread. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, that is still lacking effective therapies and with a dramatically poor prognosis. Method: We conducted a scientific literature search on Pubmed and Google Scholar including retrospective, prospective studies and reviews focused on the current research elucidating the emerging role of CXCL12 and its receptors CXCR4 - CXCR7 in the pathogenesis of pancreatic cancer. Results: Considering the mechanism of immunomodulation of the CXCL12-CXCR4-CXCR7 axis, as well as the potential interaction with the microenvironment in the PDAC, several combined therapeutic approaches have been studied and developed, to overcome the "cold" immunological setting of PDAC, like combining CXCL12 axis inhibitors with anti PD-1/PDL1 drugs. Conclusion: Understanding the role of this chemokine's axis in disease initiation and progression may provide the basis for developing new potential biomarkers as well as therapeutic targets for related pancreatic cancers.

High-grade serous carcinoma of unknown primary origin associated with STIC clinically presented as isolated inguinal lymphadenopathy: a case report.

Serous tubal intraepithelial carcinoma (STIC) is a precancerous lesion of high-grade serous ovarian carcinoma (HGSOC). Usually, it arises from the fimbrial end of the tube, and it is associated with metastatic potential. On average, the time to progress from STIC to HGSOC is 6.5 years. Therefore, whenever a STIC lesion is found, surgical staging and prophylactic salpingectomy are recommended in order to prevent ovarian cancer. We report a rare case of a 45-year-old female patient who clinically presented an isolated right inguinal lymphadenopathy. The remaining clinical examination was normal. Therefore, an excisional biopsy of the lymph node was performed. Pathological analysis revealed a high-grade serous carcinoma, most likely of gynecological origin. Due to histological evidence, a computed tomography (CT) scan was carried out. There was no CT evidence of ovarian disease, pelvic involvement, intra-abdominal lymphadenopathies, metastatic disease, or ascites. All tumor markers were negative. The patient underwent laparoscopic hysterectomy and bilateral salpingo-oophorectomy followed by surgical staging. Surprisingly, pathological examination showed a STIC lesion in the fimbria of the left fallopian tube. We aim to report the potential capability of STIC to spread particularly through lymphatic pathways rather than peritoneal dissemination.

Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab.

Up to 20% of breast cancer overexpress HER2 protein, making it a reliable target for antibody-based treatments. In early HER2-positive breast cancer avoiding anthracycline-based chemotherapy is a challenge. Based on the single-arm phase II APT trial results, adjuvant paclitaxel/trastuzumab is an accepted regimen for patients with stage I HER2-positive disease. In our retrospective study of 240 patients, the median tumor size was 12.0 mm (IQR 9 -15), and 204 (85%) had estrogen receptor-positive disease. After a median follow-up of 4.6 years, 3-year real-world disease-free survival, distant DFS, and overall survival were 98.8% (95% confidence interval (CI), 96.2-99.6), 99.2% (95% CI, 96.7-99.8), and 98.3% (95% CI, 96.2-99.6), respectively. In a real-world setting, an adjuvant paclitaxel/trastuzumab regimen was associated with low recurrence rates among women with stage I, HER2-positive breast cancer. Additionally, we reviewed other treatment optimization strategies attempted or ongoing in HER2-positive breast cancer.

Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs): A Systematic Review and Pooled Analysis.

Background: Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs). Methods: We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs. Results: A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%). Conclusion: This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.

Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives.

Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

PANHER study: a 20-year treatment outcome analysis from a multicentre observational study of HER2-positive advanced breast cancer patients from the real-world setting.

BACKGROUND: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. METHODS: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). RESULTS: Patients who received a first-line pertuzumab-based regimen showed better PFS (p < 0.0001) and OS (p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine (p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine (p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 (p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with 'old' or 'new' drugs (p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. CONCLUSION: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Case report: 5-year progression free survival and complete liver response in a patient with metastatic breast cancer treated with everolimus plus exemestane.

RATIONALE: Within a rapidly expanding therapeutic armamentarium, the combination of everolimus (Eve) plus exemestane (Exe) utility needs to be reinstated in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). PATIENT CONCERNS: We herein report on a patient affected by HR+ HER2- MBC treated with radical surgery after neoadjuvant chemotherapy, who relapsed early on adjuvant tamoxifen, progressed rapidly on first line anastrozole, and failed treatment with third line capecitabine. DIAGNOSES: Metastatic luminal breast cancer progressed under standard endocrine therapy and chemotherapy. INTERVENTIONS: Third line with Eve plus Exe was given after chemotherapy. OUTCOMES: Patient experienced a 5-year progression free interval. LESSONS: Eve plus Exe remains a valid option in HR+HER2- MBC.

Observational Multicenter Study on the Prognostic Relevance of Coagulation Activation in Risk Assessment and Stratification in Locally Advanced Breast Cancer. Outline of the ARIAS Trial.

A hypercoagulable state may either underlie or frankly accompany cancer disease at its onset or emerge in course of cancer development. Whichever the case, hypercoagulation may severely limit administration of cancer therapies, impose integrative supporting treatments and finally have an impact on prognosis. Within a flourishing research pipeline, a recent study of stage I-IIA breast cancer patients has allowed the development of a prognostic model including biomarkers of coagulation activation, which efficiently stratified prognosis of patients in the study cohort. We are now validating our risk assessment tool in an independent cohort of 108 patients with locally advanced breast cancer with indication to neo-adjuvant therapy followed by breast surgery. Within this study population, we will use our tool for risk assessment and stratification in reference to 1. pathologic complete response rate at definitive surgery, intended as our primary endpoint, and 2. rate of thromboembolic events, intended as our secondary endpoint. Patients' screening and enrollment procedures are currently in place. The trial will be shortly enriched by experimental tasks centered on next-generation sequencing techniques for identifying additional molecular targets of treatments which may integrate current standards of therapy in high-risk patients.

Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study.

BACKGROUND: HER2-targeting agents have dramatically changed the therapeutic landscape of HER2+ advanced breast cancer (ABC). Within a short time frame, the rapid introduction of new therapeutics has led to the approval of pertuzumab combined with trastuzumab and a taxane in first-line, and trastuzumab emtansine (T-DM1) in second-line. Thereby, evidence of T-DM1 efficacy following trastuzumab/pertuzumab combination is limited, with data from some retrospective reports suggesting lower activity. The purpose of the present study is to investigate T-DM1 efficacy in pertuzumab-pretreated and pertuzumab naïve HER2 positive ABC patients. We also aimed to provide evidence on the exposure to different drugs sequences including pertuzumab and T-DM1 in HER2 positive cell lines. METHODS: The biology of HER2 was investigated in vitro through sequential exposure of resistant HER2 + breast cancer cell lines to trastuzumab, pertuzumab, and their combination. In vitro experiments were paralleled by the analysis of data from 555 HER2 + ABC patients treated with T-DM1 and evaluation of T-DM1 efficacy in the 371 patients who received it in second line. Survival estimates were graphically displayed in Kaplan Meier curves, compared by log rank test and, when possibile, confirmed in multivariate models. RESULTS: We herein show evidence of lower activity of T-DM1 in two HER2+ breast cancer cell lines resistant to trastuzumab+pertuzumab, as compared to trastuzumab-resistant cells. Lower T-DM1 efficacy was associated with a marked reduction of HER2 expression on the cell membrane and its nuclear translocation. HER2 downregulation at the membrane level was confirmed in biopsies of four trastuzumab/pertuzumab-pretreated patients. Among the 371 patients treated with second-line T-DM1, median overall survival (mOS) from diagnosis of advanced disease and median progression-free survival to second-line treatment (mPFS2) were 52 and 6 months in 177 patients who received trastuzumab/pertuzumab in first-line, and 74 and 10 months in 194 pertuzumab-naïve patients (p = 0.0006 and 0.03 for OS and PFS2, respectively). CONCLUSIONS: Our data support the hypothesis that the addition of pertuzumab to trastuzumab reduces the amount of available plasma membrane HER2 receptor, limiting the binding of T-DM1 in cancer cells. This may help interpret the less favorable outcomes of second-line T-DM1 in trastuzumab/pertuzumab pre-treated patients compared to their pertuzumab-naïve counterpart.

Long-Term Safety and Real-World Effectiveness of Trastuzumab in Breast Cancer.

Trastuzumab is a milestone in the treatment of human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC), in both the early and metastatic settings. Over the last two decades, clinical trials have established the good safety profile of trastuzumab. Cardiotoxicity remains the most frequent adverse event, more commonly exemplified by an asymptomatic decline in the left ventricular ejection fraction rather than congestive heart failure. Results from several long-term (>5 years) safety analyses have been recently published, with the inherent evidence substantially confirming the findings from previous trials. The clinical experience gained over the years in the use of trastuzumab has also fueled a number of observational studies focused on the effectiveness of this drug in the real-world settings. We herein reviewed the evidence available from tree major databases, namely, PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL), to explore and critically discuss key issues related to the long-term safety and effectiveness of trastuzumab in clinical practice.

Highly durable response to capecitabine in patient with metastatic estrogen receptor positive breast cancer: A case report.

RATIONALE: In estrogen receptor-positive HER2-negative (ER+HER2-) metastatic breast cancer, chemotherapy should be offered only to patients who develop endocrine resistance or have a rapid disease progression. However, the correct sequence of chemotherapy administration is still debated. PATIENT CONCERNS: We report the case of a 49-year-old woman with ER+ HER2- metastatic breast cancer who experienced an exceptionally long response to capecitabine administered as second-line therapy following a first-line anthracycline-based chemotherapy. DIAGNOSES: The patient was diagnosed with ER+ HER2- metastatic breast cancer with massive liver involvement and mediastinal lymph nodes metastasis. INTERVENTIONS: This patient was treated with capecitabine 1000 mg/mq bid given intermittently for 14 days within a 21-day cycle as a second-line therapy following a rapid progression on letrozole treatment given as a maintenance therapy. OUTCOMES: Our patient experienced a progression-free survival (PFS) >3 years with an exceptionally good quality of life (QoL). LESSONS: In ER+HER2- metastatic breast cancer patients, capecitabine monochemotherapy in second line may be associated with a particularly satisfactory PFS and no impact in terms of QoL. Future studies focused on biomarkers with predictive ability may help select patients who represent the best candidates to this treatment.

Eribulin in Triple Negative Metastatic Breast Cancer: Critic Interpretation of Current Evidence and Projection for Future Scenarios.

Triple negative breast cancer (TNBC) is characterized by distinctive biological features that confer an aggressive clinical behavior. In TNBC patients, the absence of well-defined driver pathways such as hormonal receptor expression or hyperactivation of the human epidermal growth factor receptor 2 (HER2) significantly reduce the spectrum of therapeutic options, which are currently mainly confined to chemotherapy. Thus far, median overall survival for patients with metastatic TNBC is about 9-12 months with conventional cytotoxic agents. However, the heterogeneity recently revealed at a gene expression level inside the TNBC family may help inform therapeutic decisions concerning the use of chemotherapy and hopefully lead the way to novel targeted options that include immunotherapy. Eribulin, a halichondrin class antineoplastic drug, is currently recommended for treatment of HER2 negative metastatic or recurrent breast cancer (BC) previously exposed to anthracyclines and taxanes, also for patients with a TNBC. It is currently indicated from the second line of treatment. In this review, we aim to analyze a wide range of cumulated evidence on eribulin use in TNBC including preclinical studies, intervention and observational clinical trials. Data from the real-world setting and the emerging evidence increasingly substantiating the rationale for combinations with new generation treatment strategies, e.g., PARP-inhibitors, immune checkpoint inhibitors, will be also discussed.

Mutations in the KEAP1-NFE2L2 Pathway Define a Molecular Subset of Rapidly Progressing Lung Adenocarcinoma.

INTRODUCTION: Molecular characterization studies revealed recurrent kelch like ECH associated protein 1 gene (KEAP1)/nuclear factor, erythroid 2 like 2 gene (NFE2L2) alterations in NSCLC. These genes encode two interacting proteins (a stress response pathway [SRP]) that mediate a cytoprotective response to oxidative stress and xenobiotics. Nevertheless, whether KEAP1/NFE2L2 mutations have an impact on clinical outcomes is unclear. METHODS: We performed amplicon-based next-generation sequencing to characterize the SRP in patients with metastatic NSCLC (Regina Elena National Cancer Institute cohort [n = 88]) treated with first-line chemotherapy. Mutations in the DNA damage response (tumor protein p53 gene [TP53], ATM serine/threonine kinase gene [ATM], and ATR serine/threonine kinase gene [ATR]) were concomitantly analyzed. In lung adenocarcinoma (LAC), we also determined the expression of phosphorylated ataxia telangiectasia mutated kinase and ataxia telangiectasia and Rad3-related protein. Two independent cohorts (the Memorial Sloan Kettering Cancer Center cohort and The Cancer Genome Atlas cohort) with data from approximately 1400 patients with advanced LAC were used to assess the reproducibility of the results. RESULTS: In the Regina Elena National Cancer Institute cohort, patients whose tumors carried mutations in the KEAP1/NFE2L2 pathway had significantly shorter progression-free survival and overall survival than their wild-type counterparts did (log-rank p = 0.006 and p = 0.018, respectively). This association was driven by LAC in which KEAP1/NFE2L2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression and death. LACs carrying KEAP1/NFE2L2 mutations were characterized by elevated expression of phosphorylated ataxia telangiectasia mutated (pATM) kinase and ataxia telangiectasia and Rad3-related (pATR) protein in association with a pattern of mutual exclusivity with TP53 alterations. The relationship between KEAP1/NFE2L2 mutations and shorter survival was validated in the Memorial Sloan Kettering Cancer Center cohort (n = 1256) (log-rank p < 0.001) and in The Cancer Genome Atlas cohort (n = 162) (log-rank p = 0.039). CONCLUSION: These findings suggest that a mutant SRP represents a negative prognostic/predictive factor in metastatic LAC and that KEAP1/NFE2L2 mutations may define a molecular subtype of chemotherapy-resistant and rapidly progressing LAC.