Clinico-pathological associations and concomitant mutations of the RAS/RAF pathway in metastatic colorectal cancer.

BACKGROUND: Over the past few years, next-generation sequencing (NGS) has become reliable and cost-effective, and its use in clinical practice has become a reality. A relevant role for NGS is the prediction of response to anti-EGFR agents in metastatic colorectal cancer (mCRC), where multiple exons from KRAS, NRAS, and BRAF must be sequenced simultaneously. METHODS: We optimized a 14-amplicon NGS panel to assess, in a consecutive cohort of 219 patients affected by mCRC, the presence and clinico-pathological associations of mutations in the KRAS, NRAS, BRAF, and PIK3CA genes from formalin-fixed, paraffin-embedded specimens collected for diagnostics and research at the time of diagnosis. RESULTS: We observed a statistically significant association of RAS mutations with sex, young age, and tumor site. We demonstrated that concomitant mutations in the RAS/RAF pathway are not infrequent in mCRC, and as anticipated by whole-genome studies, RAS and PIK3CA tend to be concurrently mutated. We corroborated the association of BRAF mutations in right mCRC tumors with microsatellite instability. We established tumor side as prognostic parameter independently of mutational status. CONCLUSIONS: To our knowledge, this is the first monocentric, consecutively accrued clinical mCRC cancer cohort tested by NGS in a real-world context for KRAS, NRAS, BRAF, and PIK3CA. Our study has highlighted in clinical practice findings such as the concomitance of mutations in the RAS/RAF pathway, the presence of multiple mutations in single gene, the co-occurrence of RAS and PIK3CA mutations, the prognostic value of tumor side and possible associations of sex with specific mutations.

Eribulin Mesylate as Third or Subsequent Line Chemotherapy for Elderly Patients with Locally Recurrent or Metastatic Breast Cancer: A Multicentric Observational Study of GIOGer (Italian Group of Geriatric Oncology)-ERIBE.

BACKGROUND: Metastatic breast cancer (MBC) is highly prevalent in middle-aged or elderly patients. Eribulin is a nontaxane microtubule inhibitor, approved for the treatment of pretreated MBC. This multicentric study (sponsored by GIOGer, Italian Group for Geriatric Oncology) was designed to assess the efficacy and tolerability of eribulin, according to parameters usually used in geriatric oncology. SUBJECTS, MATERIALS, AND METHODS: An observational study was conducted on 50 consecutive elderly patients with MBC. The primary endpoint was to evaluate the change in items score of comprehensive geriatric assessment (CGA) and health-related quality of life (HRQL). Italian versions of the CGA and HRQL questionnaires were administered at baseline, before the third and fifth cycles, and then every three cycles until treatment discontinuation. Secondary endpoints were efficacy and safety. RESULTS: Overall, both EQ-5D scores and EQ-5D-3 L visual analogic scale did not significantly change from baseline; the percentage of subjects without problems doing usual activities tended to decrease during treatment (p for linear trend .018), and the percentage of patients with minor problems performing usual activities tended to increase (p for linear trend.012). Among CGA items, Instrumental Activities of Daily Living tended to decrease during treatment and Geriatric Depression Scale tended to increase. After 12 months follow-up, 24 patients (out of 47) showed clinical benefits; median progression-free survival was 4.49 months (2.10-10.33) and median OS was 7.31 months (3.70-14.03). The treatment was associated with mild toxicity. CONCLUSION: Eribulin treatment preserved quality of life and geriatric parameters included in the CGA, except for instrumental functioning and geriatric depression, in elderly patients with MBC. IMPLICATIONS FOR PRACTICE: A collaboration between oncologist and geriatric specialists is essential in the management of patients with metastatic breast cancer, who are frequently elderly or frail. The assessment of geriatric parameters in the decision-making process can contribute to direct toward the most appropriate therapeutic plan and preserve the quality of life of patients. Eribulin does not seem to affect quality of life or worsen the overall geriatric status; therefore, it can be considered a suitable option for elderly patients with metastatic breast cancer.

Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC.

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.

[Cancer treatment in elderly patients: evidence and clinical research]. / Il trattamento oncologico nel paziente anziano tra evidenze e ricerca clinica.

In 2020 the percentage of patients with a diagnosis of cancer in people with more than 65 years will exceed 70% and 28% in ethnic minorities. The treatment of cancer in these populations is challenging for the oncologists due to socio-economic issues such as poverty, reduced access to the hospital care, level of education. The clinical pathway "diagnosis-treatment-cure", typical of the care of young patients has to be integrated in elderly patients with a more individualized treatment by means of comprehensive geriatric assessment (CGA). IADL (Instrumental Activities of Daily Living) have the best predictive role in oncological setting and their impairment significantly correlate with overall survival, chemotherapy toxicities and thirty days postoperative morbidities. The CGA is universally accepted as the most appropriate instrument to analitically evaluate the age related problems of elderly patients. The role of CGA is crucial to identify geriatric issues not easily diagnosed, to predict treatment toxicities, functional or cognitive decline, post operative complications and to estimate life expectancy. The CGA items are predictive of severe toxicity, however it is not clearly established which are the best performers and the best cut-offs points. Today CGA is integrated with physical performance tests (the most widely used is the "time up and go" test) and laboratory assay of Interleukin 6 and D-Dimer that correlate with mortality and physical decline. There are few prospective studies that evaluated the role of CGA in treatment choice. The first is a phase II study in solid tumors, the second is a haematological trial on non Hodgkin lymphoma. The largest trial is a 571 patients observational series that confirmed the role of CGA in decision making. The administration of CGA is time consuming and consequently some screening tools were developed. VES-13 is a 13 items tool that explores prevalently the functional status and the self reported health status. VES-13 showed a good sensibility (87.3%) but a low specificity (62%) with respect to CGA for the diagnosis of patients with disabilities. Overcash et al. proposed an abbreviated form of CGA using a reduced number of items of ADL, IADL, MMSE and GDS. There was a good correlation between complete and reduced scales (coefficient of correlation 0.8). G8 is a screening tool composed of 8 questions that explore functional, cognitive and nutritional status. The score with the best equilibrium between sensibility and specificity was 14 (sensibility 85% and specificity 65%). In the first observational trial age, hystotype, chemotherapy dose, haemoglobin (man: 11 g/dL; women: 10 g/dL), creatinine clearance less than 34 mL/min (Jelliffe formula), earing problems, at least a fall in the last six months, walking problems, low social activity, were related to a major risk of toxicity; in another trial IADL, diastolic blood pressure, LDH and MAX2 index were predictive of haematological toxicity, while performance status, Mini-Mental Status score, Mini-Nutritional Assessment (MNA) score and MAX2 index were predictive of non haematological toxicity. Based on these parameters a 0-2 score was developed. A recent "position article" of EORTC (European organization for Research and Treatment of Cancer) and SIOG analyzed the pro and the contra of the use of some indicators in elderly patients. The overall survival (OS) frequently used in classical clinical trial could give wrong messages as there are some competitive risks of death in elderly patients. Another important indicator is the disease specific survival (DSS). Concerning the design of clinical trials, a possible strategy is to enrol elderly patients without upper age limit and to plan stratification. An interesting trial design is the so called "extended trial" that allow to re-open the arm of a trial in which a too low number of older patients was enrolled.

International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer.

PURPOSE: To update the International Society of Geriatric Oncology (SIOG) 2005 recommendations on geriatric assessment (GA) in older patients with cancer. METHODS: SIOG composed a panel with expertise in geriatric oncology to develop consensus statements after literature review of key evidence on the following topics: rationale for performing GA; findings from a GA performed in geriatric oncology patients; ability of GA to predict oncology treatment­related complications; association between GA findings and overall survival (OS); impact of GA findings on oncology treatment decisions; composition of a GA, including domains and tools; and methods for implementing GA in clinical care. RESULTS: GA can be valuable in oncology practice for following reasons: detection of impairment not identified in routine history or physical examination, ability to predict severe treatment-related toxicity, ability to predict OS in a variety of tumors and treatment settings, and ability to influence treatment choice and intensity. The panel recommended that the following domains be evaluated in a GA: functional status, comorbidity, cognition, mental health status, fatigue, social status and support, nutrition, and presence of geriatric syndromes. Although several combinations of tools and various models are available for implementation of GA in oncology practice, the expert panel could not endorse one over another. CONCLUSION: There is mounting data regarding the utility of GA in oncology practice; however, additional research is needed to continue to strengthen the evidence base.

Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging?

Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how these markers can be integrated in future research aimed at providing such data.

How circulating tumor cells escape from multidrug resistance: translating molecular mechanisms in metastatic breast cancer treatment.

Resistance to anthracyclines is responsible for treatment failure in most patients with metastatic breast cancer. According to recent studies, the expression of specific drug transporters (MRPs) on circulating tumor cells is predictive of prognosis in different cancer types. We observed that patients whose circulating tumor cells expressed MRP1 and MRP2, two drug-export pumps responsible for anthracyclines efflux, who received conventional anthracyclines had a significantly shorter time to progression compared with patients sharing same characteristics who received non pegylated liposomal doxorubicin (P < 0.005). These results may highlight a new appealing role of the liposomal doxorubicin formulation, not only because of its reduced cardiac toxicity but especially referring to its theoretical efficacy in anthracycline-resistant breast cancer patients.

Depression, hypertension, and comorbidity: disentangling their specific effect on disability and cognitive impairment in older subjects.

We aimed to demonstrate that depression and hypertension are associated independently of each other with disability and cognitive impairment in older subjects and that such an association is not attributable to number and severity of comorbidities. An observational study was performed on elderly patients admitted to the Hospital Network of the Italian National Research Center on Aging (INRCA) from January 2005 to December 2006. Depression was defined according to 15-item geriatric depression scale (GDS) score; physical disability according to activities of daily living (ADL) and instrumental activities of daily living (IADL) scores; cognitive impairment on the mini-mental state examination (MMSE) test; the number and severity of comorbidities by means of physician-administered cumulative illness rating scale (CIRS). Among 6180 older subjects (age=79.3 ± 5.8 years; 47% men), 48.3% were normotensive, 21.8% normotensive depressed, 21.7% hypertensive, and 8.2% hypertensive and depressed. Both depression and hypertension remained significantly associated with functional disability and cognitive impairment. When controlling for age, gender, the number and severity of comorbidities, hypertension was associated with a significantly higher likelihood of having functional disability or cognitive impairment only in the presence of depression (odds ratio=OR=2.02, 95% confidence interval=95%CI=1.60-2.54, p<0.001 for functional disability; OR=2.21, 95%CI=1.79-2.74, p<0.001 for cognitive impairment) as compared to normotensive controls without depression. We conclude that depression per se' or co-occurrence of hypertension and depression is associated with higher functional disability and cognitive impairment in older subjects. This effect is not attributable to the number or to the severity of comorbidities.

Suicide and cancer: where do we go from here?

Although suicide in cancer patients is a burdening public health problem with ethical, medical and psychiatric implications, it still has to be clarified why cancer patients commit suicide and how cancer suicides differ from others. Therefore, a review of the literature on suicide and suicidal ideation in cancer patients was conducted, starting from an overview of these issues in the general population. Evidence suggests that suicidality in the general population can be explained according to a genetic and psychological vulnerability to stress. The psychological and physical stressors found to be associated with suicide in cancer patients corroborate this model. Nevertheless, based on the well-described immunological disturbances due to cancer, we propose that suicide is not just a secondary reaction to cancer but is linked to an intrinsic bio-psychological vulnerability to distress. Upcoming studies should better characterize the neurobiology of suicidality in cancer, opening new avenues for treatment and prevention.

Geriatric syndromes in peri-operative elderly cancer patients.

Due to the expanding geriatric population and the high incidence of cancer in this age group, there is an increased burden on clinical oncologists. Elderly patients suffer from one or more chronic diseases, especially cardiovascular diseases, COPD, or diabetes. Besides affecting life expectancy, comorbid conditions may complicate major surgery. Accurate prediction of surgical risk is of paramount importance. Numerous papers have documented that older patients can undergo surgery with similar cancer related survival to younger patients. It has been demonstrated that age related variables are associated with an increased risk in post-surgical complications. The term "geriatric syndrome" needs further clinical evaluation and understanding. It is used to capture those clinical conditions in older persons that do not fit into discrete disease categories. Geriatric syndromes including delirium, falls, frailty, dizziness, syncope and urinary incontinence, are among the most common conditions facing geriatricians. This article focuses on geriatric syndromes in post-surgical patients and their management.

Incidence and clinical impact of chemotherapy induced myelotoxicity in cancer patients: an observational retrospective survey.

PURPOSE: To evaluate the frequency of chemotherapy-induced myelotoxicity in cancer patients, the related treatment (G-CSF, rHuEPO), and the occurrence of chemotherapy dose reductions, delays or discontinuations. PATIENTS AND METHODS: We retrospectively collected data from 1175 patients who completed at least four chemotherapy courses at 64 Italian Centres. Myelotoxicity was defined as anemia (Hb < 10 g/dL) and neutropenia (ANC < 1500/mm(3)). The study population was divided by age, in 664 adult patients aged < or =65 years and 511 elderly patients, aged > 65 years. The association between events during chemotherapy and myelotoxicity indices were assessed by logistic regression. RESULTS: The median age of the patients was 64 years. Myelotoxicity was observed in 633 patients (53.9%), anemia (< 10 g/dL) in 263 (22.4%) and neutropenia in 530 (45.1%); 686 patients (58.5%) showed mild anemia (Hb < 12 g/dL). Dose reductions were observed in 199 patients (16.9%), dose delays in 338 (28.7%), and discontinuations in 157 (13.4%), with no significant difference between age groups. Myelotoxicity accounted for 20% of treatment withdrawals with no differences between age groups. G-CSF was administered to 53.4% of the neutropenic patients, and rHuEPO to 53.1% of the anemic patients. Logistic regression analyses showed a significant (P < 0.001) association between chemotherapy dose delays, dose reductions and myelotoxicity. Considering age strata, the association between dose reduction and myelotoxicity was significant. The risk of neutropenia in the adults was higher than in elderly (50.0% vs 38.7%). CONCLUSION: Our results show that anemia and neutropenia occur in a substantial proportion of cancer patients receiving chemotherapy, and have an impact on chemotherapy dose delivery. G-CSF and rHuEPO are treatments widely used in about one half of neutropenic and anemic patients. Particular attention should be given to elderly patients, who are at high risk of myelotoxicity and should be carefully evaluated for the prophylactic use of G-CSF and monitored for the appropriate use of rHuEPO.

Erlotinib-induced hepatitis complicated by fatal lactic acidosis in an elderly man with lung cancer.

OBJECTIVE: To report a case of erlotinib-induced hepatitis complicated by fatal lactic acidosis in an elderly patient with lung adenocarcinoma and diabetes mellitus. CASE SUMMARY: A 77-year-old man with stage IIIB lung adenocarcinoma was treated with erlotinib 100 mg/day, an epidermal growth factor receptor inhibitor, after failure of chemotherapy and radiotherapy. The patient also had type 2 diabetes mellitus; metformin therapy had been initiated 5 years before presentation. Twelve days after the start of erlotinib therapy, he developed drug-related acute hepatitis complicated by renal deterioration (aspartate aminotransferase 1400 U/L, alanine aminotransferase 1299 U/L, creatinine 4.4 mg/dL, urea nitrogen 55 mg/dL). Viral causes of hepatitis were excluded and a recent computed tomography scan had ruled out liver metastases. According to the Roussel-Uclaf causality assessment method, the erlotinib-related hepatitis was classified as probable. The patient's condition was soon complicated by the onset of lactic acidosis, which caused death 2 hours after admission. DISCUSSION: In this patient, lactic acidosis was promoted by erlotinib-related hepatitis with initial liver failure (decreased lactate clearance), concomitant metformin treatment (increased lactate production), and acute renal deterioration (metformin accumulation). This is the second case of fatal erlotinib-induced liver toxicity in a patient with lung cancer. In the previous case, death occurred after about 11 days and was entirely due to fulminant hepatitis, whereas in our patient, the liver injury only initiated a drug-disease interaction that caused fatal lactic acidosis within a few hours. CONCLUSIONS: Liver function should be carefully monitored during erlotinib treatment, particularly in elderly and frail patients on multiple medications. Further studies are therefore needed for better testing the safety of erlotinib in such people, commonly encountered in the real world, but often excluded from participation in randomized trials of cancer treatment.

Communicating cancer diagnosis and prognosis: when the target is the elderly patient-a GIOGer study.

BACKGROUND: Effective communication to cancer patients allows better emotional response to diagnosis, coping with health professionals and compliance to treatment. We lack specific studies on patterns of clinical communication in elderly patients, their involvement in decision making and the role of their families. PATIENTS AND METHODS: Structured interviews to collect information on diagnosis and prognosis disclosure, satisfaction with information, compliance to disease experience and willingness toward receiving more information and coping, were administered to patients age 65 years and older and receiving chemotherapy. RESULTS: Six hundred and twenty two patients completed the interviews and were evaluated. Four hundred and twelve (66.2%) were informed, 210 (33.8%) were not informed. Information was associated with age, degree of education, geographical area, ECOG-PS, tumour site and family composition and the patient's perception of being supported in the disease experience. The majority of the patients consider their families as the main source of support in the disease experience (86.5%), wish to have a family member participating in oncology consultation (79.1%) and consider the information received complete and understandable or clear and reassuring (80%). Receiving adequate information facilitates a better patient-health professional relationship for 84.8% of the patients. 63% of the patients dealt positively with cancer and 62.2% showed positive expectations for the future. Informed patients refer better expectation than those not informed. CONCLUSION: Our study underlines the importance of clinical information for older cancer patients and the need to involve family members in the processes of diagnosis and prognosis disclosure and decision making. Health professionals must consider specific age-related issues including social, cultural and emotional aspects and understand the role that the family members play in the disease experience of elderly patients. Competent caring for elderly cancer patients must provide adequate information and emotional support not only to the patients but also to their family to assure appropriateness of care.

Depression and cancer: an unexplored and unresolved emergent issue in elderly patients.

Despite the high prevalence of depressive disorders in cancer patients and elderly people, the topic of depression in elderly cancer patients still remains unexplored. This emerges from a systematic review of the literature conducted to investigate issues of depression, diagnosis, pathogenesis, treatment and their complex neuroimmunobiological interactions. Indeed, it becomes apparent that depression in elderly patients with cancer may have a peculiar phenomenology. In addition, the moderate rate of major depressive disorder and the high rate of minor depressive disorder are accompanied by subthreshold forms of depression that are at risk to be underrecognized and untreated. Immune dysfunction may represent a common pathogenic ground of depression, cancer and aging. This may have important implications for treatment. In the near future, we need to develop validated mood disorder diagnoses and verify antidepressant treatment efficacy for elderly cancer patients with depression in order to improve their clinical outcome and quality of life.