Host-Related Factors in the Interplay among Inflammation, Immunity and Dormancy in Breast Cancer Recurrence and Prognosis: An Overview for Clinicians.

A significant proportion of patients treated for early breast cancer develop medium-term and late distant recurrence. The delayed manifestation of metastatic disease is defined as "dormancy". This model describes the aspects of the clinical latency of isolated metastatic cancer cells. Dormancy is regulated by extremely complex interactions between disseminated cancer cells and the microenvironment where they reside, the latter in turn influenced directly by the host. Among these entangled mechanisms, inflammation and immunity may play leading roles. This review is divided into two parts: the first describes the biological underpinnings of cancer dormancy and the role of the immune response, in particular, for breast cancer; the second provides an overview of the host-related factors that may influence systemic inflammation and immune response, subsequently impacting the dynamics of breast cancer dormancy. The aim of this review is to provide physicians and medical oncologists a useful tool to understand the clinical implications of this relevant topic.

Fight against cancer in Italy: What patients, caregivers and healthy citizens think about care delivery from National Health System.

OBJECTIVE: This survey aimed to analyse healthy citizens (HC), cancer patients and their caregivers (CP&CG) perception about cancer care among six different Italian regions. METHODS: The survey for HC was conducted by a multinational market research institute (IPSOS) through a computer-assisted web interviewing system, using a dataset of people who had consented to be interviewed for previous studies. CP&CG were interviewed by patient advocates using paper questionnaires. RESULTS: HC completed 1831 questionnaires between May and June 2019; CP&CG filled 1779 questionnaires between May and October 2019. 55% of all interviewees felt they were adequately informed about cancer, with no disparities between regions. Overall, population was satisfied with the National Health Care System (HCS), CP&CG more than HC, probably for their personal positive experience. There were different satisfaction levels between regions regarding components of the pathway of care, but agreement about health workers' 'human component'. Forty-three per cent of the interviewed were informed about genetic tests, 47% about innovative drugs. The percentage was greater among CP&CG (51% and 61% respectively). CONCLUSIONS: Italian people were overall satisfied with HCS although with significant different perceptions between regions. Moreover, some critical issues were highlighted as low adherence at screening invitation and genetic tests. Understanding people's perception regarding HCS is crucial to support health policies and to improve the performance of HCS.

The emotional impact of the COVID-19 outbreak on cancer outpatients and their caregivers: results of a survey conducted in the midst of the Italian pandemic.

INTRODUCTION: The study investigates the emotional discomfort of cancer patients and their caregivers, who need to access the oncology day hospital to receive treatment during the COVID-19 pandemic in Italy. METHODS: This is a single-institution, prospective, cross-sectional study. From May to June 2020, the points of view of both patients and caregivers were compared through 2 different multiple-choice questionnaires, enquiring demographic characteristics, changes in emotional status, interpersonal relationships with health professionals (HCPs) and self-perception of treatment outcomes. RESULTS: Six hundred twenty-five patients and 254 caregivers were enrolled. Females were prevalent and patients were generally older than caregivers. Forty percent of patients and 25.6% of caregivers thought they were at a greater risk of contagion because lived together with a cancer patient or accessed the hospital. Both patients (86.3%) and caregivers (85.4%) considered containment measures a valid support to avoid the spread of infection. People with a lower education level were less worried about being infected with SARS-COV-2. Waiting and performing visits/treatments without caregivers had no impact on the emotional status of patients (64.4%), but generated in caregivers greater anxiety (58.8%) and fear (19.8%) of not properly managing patients at home. The majority of patients (54%) and caregivers (39.4%) thought the pandemic does not influence treatment outcomes. The relationship with HCPs was not negatively impacted for majority of patients and caregivers. CONCLUSIONS: Starting from these data, we can better understand the current psychological distress of patients and their families in order to develop potential strategies to support them in this strenuous period of crisis.

Pegylated liposomal doxorubicin as first line treatment in aids-related Kaposi's sarcoma: a real-life study.

Despite the introduction of effective combination antiretroviral therapy (cART) AIDS-related Kaposi Sarcoma (AIDS-KS) remains the most common malignancy in HIV positive patients. In advanced stage or progressive forms, chemotherapy (CT) in combination with cART is the treatment of choice. The aim of the study is to evaluate efficacy and tolerability of Pegylated Liposomal Doxorubicin (PLD) as first line CT in AIDS-KS. In this single institution retrospective study PLD (20 mg/m2 IV every 2 weeks for 6 or 12 cycles) in combination with cART was administered in poor risk and some cases of good prognosis or limited cutaneous disease. Response rate and adverse events to treatment was evaluated. We enrolled 33 patients with AIDS-KS: median age 44ys, male 90.9%, Caucasian 72.7%, cART-naïve (simultaneous diagnosis of HIV infection and KS) 84.4%, median lymphocyte CD4+ count 134cells, median HIV viral load 4.9 log10 copies/ml. 32 patients were assigned to a Poor Risk KS stage. Grade 3-4 toxicity was reported in 9 patients. No cardiovascular events or severe sepsis were described. Complete response was reported in 25 of 31 patients evaluable for efficacy. After a median follow-up of 52 months the 3-years PFS was 68.6%. PLD associated with cART is an effective, feasible and well tolerated first-line CT in advanced AIDS-KS.

PD-1 Inhibitors-Related Neurological Toxicities in Patients with Non-Small-Cell Lung Cancer: A Literature Review.

The advent of immune checkpoint inhibitors gave rise to a new era in oncology and general medicine. The increasing use of programmed death-1 (PD-1) inhibitors in non-small cell lung cancer and in other malignancies means clinicians have to face up to new challenges in managing immune-related adverse events (irAEs), which often resemble autoimmune diseases. Neurological irAEs represent an emerging toxicity related to immunotherapy, and it is mandatory to know how to monitor, recognize, and manage them, since they can rapidly lead to patient death if untreated. Guidelines for the diagnosis and treatment of these irAEs have been recently published but sharing some of the most unusual clinical cases is crucial, in our opinion, to improve awareness and to optimize the approach for these patients. A literature review on the diagnosis and treatment of immune-related neurotoxicity's has been conducted starting from the report of four cases of neurological irAEs regarding cases of polyneuropathy, myasthenia gravis, Bell's palsy, and encephalopathy, all of which occurred in oncological patients receiving PD-1 inhibitors (pembrolizumab and nivolumab) for the treatment of non-oncogene addicted advanced non-small cell lung cancer. The exclusion of other differential diagnoses and the correlation between the suspension of immunotherapy and improvement of symptoms suggest that immunotherapy could be the cause of the neurological disorders reported.

The prognostic role of tumor size in early breast cancer in the era of molecular biology.

BACKGROUND: The prognosis of early breast cancer (EBC) depends on patient and tumor characteristics. The association between tumor size, the largest diameter in TNM staging, and prognosis is well recognized. According to TNM, tumors classified as T2, could have very different volumes; e.g. a tumor of 2.1 cm has a volume of 4500 mm3, while a tumor of 4.9 cm has a volume of 60.000 mm3 even belonging to the same class. The aim of the study is to establish if the prognostic role of tumor size, expressed as diameter and volume, has been overshadowed by other factors. METHODS: The primary objective is to evaluate the association between tumor dimensions and overall survival (OS) / disease free survival (DFS), in our institution from January 1st 2005 to September 30th 2013 in a surgical T1-T2 population. Volume was evaluated with the measurement of three half-diameters of the tumor (a, b and c), and calculated using the following formula: 4/3π x a x b x c. RESULTS: 341 patients with T1-T2 EBC were included. 86.5% were treated with conservative surgery. 85.1% had a Luminal subtype, 9.1% were Triple negative and 7.4% were HER2 positive. Median volume was 942 mm3 (range 0.52-31.651.2). 44 patients (12.9%) relapsed and 23 patients died. With a median follow-up of 6.5 years, the univariate analysis for DFS showed an association between age, tumor size, volume, histological grading and molecular subtype. The multivariate analysis confirmed the statistically significant association only for molecular subtype (p 0.005), with a worse prognosis for Triple negative and HER2 positive subtypes compared with Luminal (HR: 2.65; 95%CI: 1.34-5.22). Likewise for OS, an association was shown by the multivariate analysis solely for molecular subtype (HER2 and Triple negative vs. Luminal. HR: 2.83; 95% CI:1.46-5.49; p 0.002). CONCLUSIONS: In our study, the only parameter that strongly influences survival is molecular subtype. These findings encourage clinicians to choose adjuvant treatment not based on dimensional criteria but on biological features.

The 5'UTR variant of ERCC5 fails to influence outcomes in ovarian and lung cancer patients undergoing treatment with platinum-based drugs.

The common polymorphic variant in the 5' untranslated region of the excision repair cross-complementation group 5 (ERCC5) gene was described to generate an upstream open reading frame that regulates both the basal ERCC5 expression and its ability to be synthesized following DNA damage. This variant was reported to affect response to platinum therapy in a cohort of patients with pediatric ependymoma. The role of this variant was investigated in two cohorts of cancer patients, specifically in non-small-cell lung cancer (NSCLC) patients (N = 137) and in epithelial ovarian carcinoma (EOC) patients (N = 240), treated in first-line with platinum-based compounds. Differently from what reported for pediatric ependymoma, the analysis of the polymorphism in NSCLC patients cohort was not able to detect any difference among patients harboring different genotypes both in progression free survival (HR = 0.93; 95%CI 0.64-1.33; p-value = 0.678) and overall survival (HR = 0.90; 95%CI 0.62-1.33; p-value = 0.625). These data were corroborated in a EOC patients cohort, where similar progression free survival (HR = 0.91; 95% CI 0.67-1.24; p-value = 0.561) and overall survival (HR = 0.98; 95% CI 0.71-1.35; p-value = 0.912) were found for the different genotypes. These data, obtained in appropriately sized populations, indicate that the effect of this ERCC5 polymorphism is likely to be relevant only in specific tumors.

DNA repair gene polymorphisms in non-small-cell lung cancer patients treated with first-line platinum-containing chemotherapy.

PURPOSE: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are believed to contribute to the clinical outcome of patients receiving platinum-based chemotherapy. We investigated the impact of 2 SNPs of excision repair cross-complementation group 1 and 2 of xeroderma pigmentosum complementation group G on the outcome in patients with non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. METHODS: Between October 2007 and March 2012, we collected 374 blood samples from consecutive patients registered in the TAILOR trial. Four SNPs (rs11615, rs3212986, rs17655, rs1047768) were genotyped using real-time polymerase chain reaction. RESULTS: The rs11615 polymorphism was associated with histotype (p = 0.0123). No other correlations were found with clinical variables or with EGFR or KRAS mutational status. None of the SNPs had any impact on overall survival or progression-free survival. CONCLUSIONS: The findings suggest that the investigated SNPs do not make any significant contribution to the outcome of NSCLC.

Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient's baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15-0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52-1.01, p = 0.056) in terms of PFS.

KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy.

UNLABELLED: KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status.Of these, 247 patients were eligible and included in the present study. The primary endpoint was overall survival (OS) according to KRAS mutational status in patients harboring EGFR wild-type.Sixty (24.3%) out of 247 patients harbored KRAS mutations. Median OS was 14.3 months and 10.6 months in wild-type and mutated KRAS patients, respectively (unadjusted Hazard Ratio [HR]=1.41, 95%Confidence Interval [CI]: 1.03-1.94 P = 0.032; adjusted HR=1.39, 95%CI: 1.00-1.94 P = 0.050). This study, with all consecutive patients genotyped, indicates that the presence of KRAS mutations has a mild negative impact on OS in advanced NSCLC patient treated with a first-line platinum-containing regimen. TRIAL REGISTRATION: clinicaltrials.gov identifierNCT00637910.

Prospective, mono-institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates for bone metastases.

The aim of our study was to investigate the occurrence of osteonecrosis of the jaw (ONJ) after implementation of dental preventive measures before starting bisphosphonates (BPs) therapy and during treatment. All consecutive patients with bone lesions eligible for BPs treatment were prospectively evaluated. Before starting BPs, each patient underwent a strict dental preventive program with a specialized odontoiatric team. The odontoiatric evaluation identified patients with oral pathologies or inadequate oral hygiene and provided a dental preventive treatment. From April 2007 to April 2012, 254 patients were enrolled. After excluding patients due to previous BPs treatment, 212 patients with a mean age of 74 years (range 37-95) were included. On average, patients received 9.7 treatment cycles (range 1-48). No ONJ was recorded (0.0 %; 95 % confidence interval [CI] 0.0-1.4). Comparing this risk with that observed in a previous cohort who did not receive dental prevention (16/186, 8.6 %; 95 % CI 4.2-15.3 %), we observed clear efficacy in preventing ONJ (relative risk reduction: 100 %, 95 % CI 86-100 %, P < 0.0001). We developed a strict three-step prevention program that is able to decrease ONJ incidence and the need for destructive surgery with permanent sequelae. We demonstrated that ONJ could be effectively prevented. We recommend a mandatory preventive program involving a multidisciplinary team for all patients starting BPs.

Efficacy of biological agents in metastatic triple-negative breast cancer.

Metastatic triple-negative breast cancer (mTNBC) represents 15% of invasive breast cancers. Prognosis is poor, and there is no specific target therapy but biological agents combined with chemotherapy may be effective. To assess the role of biological agents in metastatic triple-negative breast cancer we performed a systematic review of phase III randomized controlled trials published from January 2006 to February 2013 and presentations at ESMO, ASCO, and SABCS congresses in 2010-2012. We consulted PubMed and ClinicalTrials.gov. Only studies comparing biological agents and chemotherapy versus chemotherapy alone were considered. Relevant statistical variables were log of the hazard ratio and relative variance for progression-free survival (PFS) and overall survival (OS). Of 353 PubMed publications and 229 studies registered on ClinicalTrials.gov, 10 trials were selected and 5293 patients were analyzed: 1546 had mTNBC. Biological agents considered were bevacizumab, sunitinib, sorafenib, lapatinib, iniparib and cetuximab. In addition, a meta analysis of the four studies containing bevacizumab was performed and it showed a PFS improvement with a relative risk reduction of 35% (95% CI: 25-43%). No effect on OS was observed. No PFS and OS benefit was detected with the other agents. No improvement of OS was detected in patients treated with biological agents plus chemotherapy, while a significant PFS improvement was observed only for bevacizumab and cetuximab. The overall impact of these agents on patient survival was not as great as expected, probably because the molecular basis of this illness needs to be better understood so that treatment can be more appropriately tailored.

Across the universe of K-RAS mutations in non-small-cell-lung cancer.

RAS family proteins are important signaling molecules that regulate cell growth, survival and differentiation by coupling receptor activation to downstream effector pathways. Three distinct genes encode for the three different proteins H-, K-, and N- RAS. These proteins share high sequence homology, particularly at the N-Terminal domain. Among them, K-RAS is one of the most frequently mutated in human cancer. The majority of the mutations present in K-RAS are at codon 12 (from 80 to 100%) followed by codon 13 and 61. In all cases, aminoacid change leads to a constitutively activated protein. K-RAS mutations have a role in tumor development as well as in tumor progression and resistance. Despite the various studies which have been published, the prognostic and predictive role of K-RAS mutations is still under debate. Keeping in mind that the glycine present at position 12 can be substituted by valine, aspartic acid or cysteine, it could be well understood that each different substitution plays a different role in K-RAS-dependent processes. The present article focuses on the molecular and biological characteristics of K-RAS protein, its role in NSCLC tumor development and progression. We also present an overview of the preclinical models both in vitro and in vivo available to determine the role of K-RAS in tumor progression and response to treatment and on the recent results obtained in this field. Finally, we have considered the impact of KRAS mutations in clinical practice, analyzing the different recent trials that have taken into consideration K-RAS.

Eribulin in cutaneous breast cancer metastasis treatment: clinical activity and symptom control.

AIM: This observational study evaluated the behavior and outcome of cutaneous breast cancer metastasis treated with eribulin. PATIENTS & METHODS: From November 2012 to January 2013, oncologists completed a database with patient, tumor and treatment characteristics from 14 Italian cancer centers. Skin lesions were assessed by Response Evaluation Criteria In Solid Tumors and cutaneous symptoms by present/absent criteria. RESULTS: A total of 23 metastatic breast cancer patients with skin metastasis who were treated with eribulin were analyzed. After treatment, 43% of patients exhibited a partial response, 35% stable disease and 22% progressive disease. Regarding only the skin response, 26% obtained a complete response, 22% a partial response, 39% stable disease and 13% progressive disease. We found an improvement in symptoms, infiltration and ulceration. With a median follow-up of 6 months, median progression-free survival was 4.3 months and median overall survival was 9.1 months. CONCLUSION: The response rate of skin metastasis to eribulin treatment was coherent with systemic responses. The good clinical response in most patients reflected symptom improvement.

Tumor shrinkage and improved quality of life in a heavily pretreated metastatic breast cancer patient treated with eribulin.

Eribulin mesylate is approved for the treatment of metastatic breast cancer after progression with anthracyclines and taxanes. Here we report the case of a woman with triple-negative breast cancer who, after nine lines of chemotherapy, showed striking primary tumor shrinkage and regression of metastatic lesions with eribulin treatment. This response allowed the patient to undergo debulking surgery. Even though the patient was heavily pretreated, eribulin was well tolerated and improved her quality of life. Biological analysis of tumor specimens was performed to investigate the underlying mechanism of action of the drug.

Randomised phase II trial (NCT00637975) evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients.

PURPOSE: Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy. METHODS: Patients (N = 75) with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies (arm A; N = 38) oxycodone at a fixed dose with increasing pregabalin doses; (arm B; N = 37) pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS), neuropathic pain scale (SDN), and well-being scale (ESAS). The primary endpoint was a ≥1/3 reduction in pain (NRS); secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%. RESULTS: More patients in arm A (76%) than arm B (64%) achieved ≥1/3 overall pain reduction even after controlling for baseline factors (gender, baseline pain). Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%. CONCLUSIONS: Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637975.

Lung infiltrates in cancer patients: differentiating metastases from bronchiolitis obliterans organizing pneumonia.

Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare condition that affects oncological patients, often during or after chemotherapy, and can easily be mistaken for lung metastases. BOOP should be taken into consideration in cases when patchy nodular infiltrates with uncertain behavior appear in the lung; these infiltrates are often unresponsive to treatment with antibiotics. We report a case in which a patient treated for transitional cell bladder carcinoma with surgery and adjuvant chemotherapy developed multiple bilateral pulmonary nodules one month after the end of treatment.

Safe chemotherapy and hormone therapy for treating early breast cancer in a glucose 6-phosphate dehydrogenase-deficient patient: case report.

Breast cancer is the leading cause of neoplasia-related deaths among women, but no data are available in the literature on the safe use of oncological treatments in glucose 6-phosphate dehydrogenase (G6PD)-deficient patients. This case report describes, for the first time, the treatment of a G6PD-deficient woman diagnosed with breast cancer who underwent adjuvant treatment after quadrantectomy and axillary node dissection. After conservative surgery, many patients require adjuvant treatment with hormone therapy (HT) and/or chemotherapy. Anthracyclines are considered a cornerstone in this setting but, because of their oxidative properties, are contraindicated in G6PD-deficient patients. Despite the absence of data in the literature on their use in G6PD-deficient patients, we chose to use docetaxel and cyclophosphamide because these agents were not predicted to elicit oxidative stress. The patient completed six cycles of docetaxel and cyclophosphamide chemotherapy, and no adverse reactions were observed. Tamoxifen was excluded as a HT as a nonoxidative agent was required; therefore, an aromatase inhibitor was used as adjuvant therapy. Considering the high frequency of breast cancer and G6PD deficiency worldwide, there are little data available in the literature on the oxidative properties of oncological drugs. The oncological community must report cases in which patients with hereditary enzymatic deficiencies are treated successfully with anticancer agents. This would enable clinicians to have access to data that would be very useful in the choice of a safe treatment program.

A mono-institutional prospective study on the effectiveness of a specialist psychotherapeutic intervention (POI) started at the diagnosis of cancer.

PURPOSE: We evaluated the effectiveness of an early POI in newly diagnosed cancer patients in reducing the occurrence of psychiatric disturbances. METHODS: We designed a mono-institutional prospective study involving all new patients admitted to the Oncology Department of Fatebenefratelli and Ophtalmic Hospital in Milan from January 2005 until September 2008. During the first visit, the oncologist could offer support with a psycho-oncologist. The patients who accepted had a first interview (T0), during which they took a self-evaluation test (HADS, Hospital Anxiety and Depression scale). On the basis of the score, the psycho-oncologist could offer psychotherapy and/or pharmacological intervention, if necessary. At the end of the eight sessions (T1), the patient repeated the self-evaluation test with the HADS, and we analysed both the difference in the HADS score between T0 and T1 and the clinical evaluation of the psycho-oncologist. RESULTS: Three hundred eighteen patients were evaluated with a psychoanalytical psychotherapy approach by two psycho-oncologists through a first interview and 90 of them were eligible for the present study also for the evaluation of HADS. The average HADS score in T0 was 15.26 for depression (sd=3.21) and 13.86 for anxiety (sd = 2.05). The reassessment at the end of the psychotherapy (T1) showed an average HADS score of 5.94 for depression (sd = 3.11) and 6.58 for anxiety (sd = 2.88). Only five patients were treated with a pharmacological approach alone. CONCLUSIONS: Considering all the limits of our study, we may conclude that an early POI significantly reduces patients' psychiatric symptoms and the risk of a negative evolution of pathological situations in those patients who are motivated and express a need for psychological help.