Oligometastatic breast cancer and metastasis-directed treatment: an aggressive multimodal approach to reach the cure.

Metastatic breast cancer (BC) is considered an incurable disease and is usually treated with palliative intent. However, about 50% of metastatic BCs present with only a few metastatic lesions and are characterized by longer overall survival. These patients, defined as oligometastatic, could benefit from a multimodal approach, which combines systemic therapy with metastasis-directed treatment (stereotactic ablative therapy or surgery). The current definition of oligometastatic seems incomplete since it is based only on imaging findings and does not include biological features, and the majority of relevant data supporting this strategy comes from retrospective or non-randomized studies. However, the chance of reaching long-term complete remission or even a cure has led to the development of randomized trials investigating the impact of combined treatment in oligometastatic BC (OMBC). The SABR-COMET trial, the first randomized study to include BC patients, showed promising results from a combination of stereotactic ablative radiotherapy and systemic therapy. Considering the randomized trial's results, multidisciplinary teams should be set up to select OMBC patients who could achieve long-term survival with aggressive multimodal treatment.

Locoregional treatment of de novo stage IV breast cancer in the era of modern oncology.

Approximately 6% of metastatic breast cancers arise de novo. While systemic therapy (ST) remains the treatment backbone as for patients with metachronous metastases, locoregional treatment (LRT) of the primary tumor remains a controversial method. The removal of the primary has an established role for palliative purposes, but it is unclear if it could also determine a survival benefit. Retrospective evidence and pre-clinical studies seem to support the removal of the primary as an effective approach to improve survival. On the other hand, most randomized evidence suggests avoiding LRT. Both retrospective and prospective studies suffer several limitations, ranging from selection bias and outdated ST to a small sample of patients. In this review we discuss available data and try to identify subgroups of patients which could benefit the most from LRT of the primary, to facilitate clinical practice decisions, and to hypothesize future studies design on this topic.

Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy.

The phosphoinositide 3 kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of the rapamycin (mTOR) axis is a key signal transduction system that links oncogenes and multiple receptor classes which are involved in many essential cellular functions. Aberrant PI3K signalling is one of the most commonly mutated pathways in cancer. Consequently, more than 40 compounds targeting key components of this signalling network have been tested in clinical trials among various types of cancer. As the oncogenic activation of the PI3K/AKT/mTOR pathway often occurs alongside mutations in other signalling networks, combination therapy should be considered. In this review, we highlight recent advances in the knowledge of the PI3K pathway and discuss the current state and future challenges of targeting this pathway in clinical practice.

Neoadjuvant endocrine therapy for luminal breast tumors: State of the art, challenges and future perspectives.

Neoadjuvant endocrine treatment (NET) associates to satisfactory rates of breast conservative surgery and conversions from inoperable to operable hormone receptor-positive (HR+)/HER2-negative breast cancer (BC), with less toxicities than neoadjuvant chemotherapy (NACT) and similar outcomes. Hence, it has been proposed as a logical alternative to NACT in patients with HR+/HER2- BC candidate to a neoadjuvant approach. Nevertheless, potential barriers to the widespread use of NET include the heterogeneous nature of patient response coupled with the long duration needed to achieve a clinical response. However, interest in NET has significantly increased in the last decade, owing to more in-depth investigation of several biomarkers for a more adequate patient selection and on-treatment benefit monitoring, such as PEPI score, Ki67 and genomic assays. This review is intended to describe the state-of-the-art regarding NET, its future perspectives and potential integration with molecular biomarkers for the optimal selection of patients, regimen and duration of (neo)adjuvant treatments.

Cell-Free DNA Fragmentomics: A Promising Biomarker for Diagnosis, Prognosis and Prediction of Response in Breast Cancer.

Identifying novel circulating biomarkers predictive of response and informative about the mechanisms of resistance, is the new challenge for breast cancer (BC) management. The integration of omics information will gradually revolutionize the clinical approach. Liquid biopsy is being incorporated into the diagnostic and decision-making process for the treatment of BC, in particular with the analysis of circulating tumor DNA, although with some relevant limitations, including costs. Circulating cell-free DNA (cfDNA) fragmentomics and its integrity index may become a cheaper, noninvasive biomarker that could provide significant additional information for monitoring response to systemic treatments in BC. The purpose of our review is to focus on the available research on cfDNA integrity and its features as a biomarker of diagnosis, prognosis and response to treatments in BC, highlighting new perspectives and critical issues for future applications.

Circulating inflammatory cells in patients with metastatic breast cancer: Implications for treatment.

Adaptive and innate immune cells play a crucial role as regulators of cancer development. Inflammatory cells in blood flow seem to be involved in pro-tumor activities and contribute to breast cancer progression. Circulating lymphocyte ratios such as the platelet-lymphocytes ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the neutrophil-lymphocyte ratio (NLR) are new reproducible, routinely feasible and cheap biomarkers of immune response. These indexes have been correlated to prognosis in many solid tumors and there is growing evidence on their clinical applicability as independent prognostic markers also for breast cancer. In this review we give an overview of the possible value of lymphocytic indexes in advanced breast cancer prognosis and prediction of outcome. Furthermore, targeting the immune system appear to be a promising therapeutic strategy for breast cancer, especially macrophage-targeted therapies. Herein we present an overview of the ongoing clinical trials testing systemic inflammatory cells as therapeutic targets in breast cancer.

Cancer patient perspective in the arena of COVID-19 pandemic.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) outbreak has been declared a global pandemic of unprecedented proportions. Italy is a country which has been heavily affected. Cancer patients are at a higher risk owing to their intrinsic fragility related to their underlying disease and oncologic treatment. Against this backdrop, we conducted a survey to investigate how patients perceived their condition, clinical management and availability of information during the pandemic. METHODS: Between 15 April and 1 May 2020 a survey was submitted to cancer patients at oncology departments in the Marche region. Questions regarding the perception of personal safety, continuity of cancer care, information quality and psychological distress. RESULTS: Seven hundred patients participated in the survey; 59% were female and 40% were aged between 46 and 65. The majority of the participants perceived compliance with appropriate safety standards by cancer care providers and 80% were reassured about their concerns during the medical interview. 40% were worried of being at a higher risk of infection and 71% felt they were at a greater risk because of chemotherapy. 55% felt that postponing cancer treatment could reduce its efficacy, however 76% declared they did not feel abandoned at the time of treatment postponement. Patients between 46 and 65 years declared a significant reduction in sleep (p < 0.01) and in concentration (p = 0.03). CONCLUSIONS: The emergency care offered to cancer patients has been deemed satisfactory in terms of both safety standards and care management. However, the majority of participants perceived the mutual negative influence between their oncologic disease and the risk of infection highlighting the need for special measures to ensure safe continuity of care.

Potential Impact of Preoperative Circulating Biomarkers on Individual Escalating/de-Escalating Strategies in Early Breast Cancer.

The research on non-invasive circulating biomarkers to guide clinical decision is in wide expansion, including the earliest disease settings. Several new intensification/de-intensification strategies are approaching clinical practice, personalizing the treatment for each patient. Moreover, liquid biopsy is revealing its potential with multiple techniques and studies available on circulating biomarkers in the preoperative phase. Inflammatory circulating cells, circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and other biological biomarkers are improving the armamentarium for treatment selection. Defining the escalation and de-escalation of treatments is a mainstay of personalized medicine in early breast cancer. In this review, we delineate the studies investigating the possible application of these non-invasive tools to give a more enlightened approach to escalating/de-escalating strategies in early breast cancer.

The Impact of Lifestyle Interventions in High-Risk Early Breast Cancer Patients: A Modeling Approach from a Single Institution Experience.

A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

Prognostic Impact of Ki-67 Change in Locally Advanced and Early Breast Cancer after Neoadjuvant Chemotherapy: A Single Institution Experience.

Systemic neoadjuvant chemotherapy (NCT) is a standard treatment for locally advanced breast cancer (LABC) and for selected early breast cancer (EBC). In these settings, the prognostic and predictive role of Ki-67 before and after NCT is unclear. The aim of our study was to investigate the prognostic role of Ki-67 change in patients not achieving pathological complete response (pCR). We retrospectively analyzed data of patients who did not achieve pCR assessing Ki-67 expression pre- and post-NCT. We stratified three groups: high reduction (>20%), low reduction (1-20%), and no reduction in Ki-67. These groups were correlated with clinical and pathological data by χ2 test. We estimated disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier method, and we adopted univariate and multivariate Cox proportional hazard models. We selected 82 patients from a database of 143 patients, excluding those who were metastatic at diagnosis, achieved pCR, or lack data regarding Ki-67. Median age at diagnosis was 54 years (range 30-75); 51 patients were Luminal B, 10 human epidermal growth factor receptor 2 (HER-2) enriched, and 21 triple negative. A significant correlation between high Ki-67 reduction and luminal B HER-2-negative subtype was observed (p = 0,0035). The change in Ki-67 was significantly associated with DFS (p = 0,0596) and OS (p = 0,0120), also at multivariate analysis (p = 0,0256 for DFS; p = 0,0093 for OS). In particular, as compared to patients with low/no reduction of Ki-67, those with high Ki-67 reduction (>20%) after NCT showed better survival (60% vs. 56% vs. 83% after 5 years from diagnosis, respectively; p = 0.01). In conclusion, in our study, Ki-67 change showed a significant prognostic role in breast cancer patients treated with NCT who did not achieve pCR. Crucially, Ki-67 < 20% identifies a high-risk population that may be eligible for clinical trials with novel therapeutic interventions in adjuvant setting.

Old but gold: the role of drug combinations in improving response to immune check-point inhibitors in thoracic malignancies beyond NSCLC.

The introduction of immune checkpoint inhibitors (ICIs) in non-oncogene addicted non-small cell lung cancer (NSCLC) has revolutionized the treatment scenario and led to a meaningful improvement in patient prognosis. Disappointingly, the success of ICI therapy in NSCLC has not been fully replicated in other thoracic malignancies as small cell lung cancer (SCLC), malignant pleural mesothelioma (MPM), and thymic epithelial tumors (TETs), due to the peculiar biological features of these disease and to the difficulties in the conduction of well-designed, biomarker-driven clinical trials. Therefore, combination strategies of ICIs plus conventional therapies (either chemotherapy, alternative ICIs or targeted agents) have been implemented. Although first approvals of ICI therapy have been recently granted in SCLC and MPM (in combination with chemotherapy and different ICIs), results remain somewhat modest and limited to a small proportion of patients. This work reviews the trial results of ICI therapy in mesothelioma, SCLC, and TETs and discusses the potential of combining ICIs with old drugs.

Scientia Potentia Est: How the Italian World of Oncology Changes in the COVID-19 Pandemic.

PURPOSE: After coronavirus disease 2019 (COVID-19) was declared a pandemic by the WHO, a response from the Italian Health System to react to an unprecedented condition became necessary and sudden. The COVID-19 pandemic has required oncologists to redefine clinical organization and patient management. The purpose of our study was to document the difficulties emerging during the SARS-CoV-2 pandemic in Italian oncology. METHODS: We broadcasted an electronic survey to oncologic health care professionals. It consisted of 45 questions ranging from individual perception of pandemic management by hospital centers to physicians' and nurses' psychological distress and patient care. RESULTS: A total of 383 oncology health workers participated in the survey. The majority were female (71.8%) and from central Italy (46.2%). Impressively, a total of 357 (93%) participants declared the oncologic department reorganized routine clinical activity, but only 40.5% were adequately trained about the required procedures; 20% of the survey respondents think they have not received adequate and timely protective devices. CONCLUSION: Our survey demonstrated the flexibility of oncologic teams. However, the emergency response quality has been heterogeneous, and several drawbacks have emerged from the first analyses investigating how the world of oncology changes in the COVID-19 pandemic. Information, protection, testing, and training of health care professionals are key words that should be kept in mind to encourage recovery after this tragedy and to be ready to face a similar emergency in the future.

Evaluation of Second-line Anti-VEGF after First-line Anti-EGFR Based Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Multicenter "SLAVE" Study.

: Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. METHODS: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. RESULTS: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7-34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95-1.89); p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3-18.1) and 12.7 (95%CI: 8.8-17.5) months, respectively (HR= 1.31 (95%CI: 0.89-1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02-2.03); p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99-2.17); p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). CONCLUSION: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.

Electrolyte disorders in advanced non-small cell lung cancer patients treated with immune check-point inhibitors: A systematic review and meta-analysis.

BACKGROUND: Aim of this meta-analysis was to determine the relative risk (RR) of electrolyte disorders (EDs) in advanced non-small cell lung cancer (aNSCLC) patients treated with immune check-point inhibitors (ICIs). METHODS: We searched for phase II/III randomized controlled trials (RCTs) comparing ICIs (alone or combined with chemotherapy) with standard chemotherapy in aNSCLC. Summary incidence and RR were calculated. RESULTS: Six RCTs with data on all-grade hyponatremia were identified (n = 3257). The incidence was 8.7 % in the study group and 4.9 % in the control group (RR 1.78, 95 %CI 1.12-2.80). Looking at all-grade hypokalemia, 7 RCTs were included (n = 4119). Incidence was 10.4 % in ICIs-treated patients and 5.9 % in the control arms (RR 1.62, 95 % CI 1.30-2.02). CONCLUSIONS: Treatment with ICIs in aNSCLC is associated with a significant increased risk of hyponatremia and hypokalemia compared to chemotherapy. Monitoring of electrolyte levels should be emphasized in this setting.

Body Mass Index and Hormone Receptor Status Influence Recurrence Risk in HER2-Positive Early Breast Cancer Patients.

INTRODUCTION: A reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting. PATIENTS AND METHODS: We retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test. RESULTS: The early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR- patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR- tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03). CONCLUSION: Our real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR- and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase.

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.

Long-responders to anti-HER2 therapies: A case report and review of the literature.

Since the introduction of targeted therapies, prognosis in human epidermal growth factor receptor (HER) 2-positive metastatic breast cancer (MBC) has radically changed. The addition of Pertuzumab to Trastuzumab and standard chemotherapy has further increased patients' overall survival (OS). However, there is no agreement regarding the optimal duration of trastuzumab therapy in selected patients achieving long-term complete remission. In addition, no potential factors of long-term benefit have been identified yet. In the present study, we report the case of a MBC woman who was successfully treated with trastuzumab for over 10 years. At the time of diagnosis (February 2005), she revealed lung, nodal and bone metastases. Therefore, a first-line chemotherapy with Epirubicine and Docetaxel was administered for 6 cycles and then the patient started Trastuzumab plus hormonal therapy until reaching a sensible reduction of mammary lump and disappearance of distant metastases. Following a multidisciplinary evaluation, in November 2006, the patient underwent radical mastectomy and axillary dissection, achieving a complete remission. She continued Trastuzumab until September 2015 (for a total of 156 cycles) when a pleural diffusion was demonstrated. Long-term survival during anti-HER2 treatment remains a rare and optimal situation. Currently, no data exist to support trastuzumab interruption in this setting and collaborative efforts to better analyze the characteristics of long-responder patients are needed. Data regarding prognostic factors in this setting are relatively confusing. Our review reveals that hormonal receptor (HR)-positive disease is associated with a better prognosis, whereas the role of visceral spread differs by single or dual target anti HER2-inhibition. The introduction of Pertuzumab is raising concerns in terms of toxicity and its cost effectiveness. While waiting for novel molecular data and randomized trials, available evidence advocates continuous use of anti-HER2 therapies until disease progression or development of side effects.