Body composition measures as a determinant of Alpelisib related toxicity.

BACKGROUND: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. METHODS: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, hospitalizations, time to treatment failure and overall survival. RESULTS: Sarcopenia was observed in half of the patients (n = 19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P = 0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P = 0.04) and hospitalizations (P = 0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. CONCLUSION: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to caution toxicity risk, allowing for personalized therapeutic observation and intervention.

Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. METHODS: The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. RESULTS: Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). CONCLUSION: Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Effectiveness and safety of standard chemotherapy in older patients with ovarian cancer: a retrospective analysis by age group and treatment regimen.

Objective: To evaluate the effectiveness and safety of standard chemotherapy administered to patients >70 years with advanced ovarian cancer (OC). Methods: Medical records of 956 advanced-stage patients with OC treated between 2002-2020 with standard surgery and paclitaxel-carboplatin chemotherapy in a three-weekly (PC-3W) or weekly (PC-1W) regimen were reviewed. Treatment response and tolerability were compared between patients ≤70 years (N=723) and >70 years (N=233) with stratification to septuagenarians (>70-80 years) and octogenarians (>80 years). Results: Median overall survival (mOS) in patients >70 was 41.26 months (95% confidence interval [Cl], 37.22-45.14) and median progression-free survival (mPFS) was 11.04 months (95% Cl, 8.97-15.74). No statistically significant differences in mPFS and mOS were observed between septuagenarians and octogenarians. Patients >70 treated with PC-1W versus PC-3W had significantly longer mOS (57.17 versus 30.00 months) and mPFS (19.09 versus 8.15 months). Toxicity rates were mostly similar between younger and older patients. Among patients >70 treated with PC-1W, the rate of neutropenia (75.7% versus 51.8%, p=0.0005), thrombocytopenia (41.0% versus 22.2%, p=0.0042) and anemia (78.1% versus 51.9%, p<0.0001) were significantly higher and the rate of grade 2 alopecia was statistically significantly lower compared with those >70 treated with PC-3W. Significantly more patients treated with PC-1W completed ≥6 chemotherapy cycles, suggesting better tolerability of this regimen. Conclusions: Older patients with OC may benefit from improved OS with reasonable toxicity if treated with standard chemotherapy. Older patients treated with PC-1W are more likely to complete the full chemotherapy course and survive longer compared with those treated with conventional PC-3W.

First-Line Efficacy of Anti-HER2 Treatments in Previously Treated HER2-Positive Metastatic Breast Cancer Patients: A Retrospective Observational Study Investigating the Efficacy of Re-Exposure to Anti-HER2 Therapy for HER2-Positive Metastatic Breast Cancer Patients in Comparison with Naïve Patients.

Background: Most patients with HER2-positive metastatic breast cancer (MBC) receive first-line treatment with anti-HER2 agents and have already received anti-HER2 therapy as adjuvant or neoadjuvant therapy in the local setting of their disease presentation. Despite that, they constitute only a minority among clinical trials, and their response to reintroduction to anti-HER2 treatments is inconclusive based upon conflicting studies. We aimed to examine if previous exposure influences the clinical outcome of patients treated with anti-HER2 treatments compared to patients who were naïve to anti-HER2 agents. Methods: We conducted a retrospective observational study of HER2-positive MBC patients who were treated with trastuzumab and pertuzumab from 2014 to 2018. We collected and analyzed data including patients' demographic characteristic as well as extracted data of previous treatment regimens and the efficiency of the anti-HER2 therapy measured by response rate (RR), time to tumor progression (TTP), and overall survival (OS). Results: Eighty patients met the inclusion criteria, 26 (32.5%) of them were previously exposed to anti-HER2 treatments and 54 (67.5%) were not previously exposed to anti-HER2 therapy. No significant differences were detected in RR after 3 months of treatment (p = 0.684). TTP was significantly better among patients with no previous exposure in comparison with patients with previous exposure to anti-HER2 therapy (21 vs. 14 months, p = 0.044) and we noted a trend in better OS (p = 0.056). Conclusion: Our analysis suggests that previous exposure to anti-HER2 agents might influence the clinical outcome of first-line treatment in metastatic HER2 patients. These findings justify further exploration of the benefit of reintroduction of anti-HER2 treatment enabling the optimal treatment for patients with previous anti-HER2 therapy exposure.

Sexual dysfunction among adolescent and young adult cancer patients: diagnostic and therapeutic approach.

PURPOSE OF REVIEW: We present a review for healthcare professionals, formulated by a multidisciplinary team, for screening and interventions, describing common sexual impairments encountered by adolescent and young adult cancer patients (AYACP), and suggest a comprehensive evidence-based assessment approach and interventions for treatment of sexual dysfunction (SD). RECENT FINDINGS: We discuss the various aspects of SD in AYACP, including causes, challenges and etiologies, and then go on to recommend increased awareness and guidance in healthcare workers, in order to optimize diagnosis and treatment of SD. SUMMARY: Although the extent of SD among AYACP is widely recognized, oncological clinicians rarely address SD in their routine practice, lacking a clear approach of interdisciplinary diagnostic and therapeutic interventions. Here, we suggest guiding clinical management to optimize treatment quality.

Brain metastases in patients with ovarian cancer.

BACKGROUND: Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. METHODS: We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers (BRCAm) due to women of Ashkenazi Jewish descent. RESULTS: Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BRCA mutations was more common among women with BM (56.5% vs. 34.3%, p = 0.033). The BM rate in patients with BRCAm was higher than the BM rate in those with wildtype BRCA (BRCAw; 5.1% vs. 2.1%, OR = 2.6; 95% CI: 1.2-5.4, p = 0.013). Median time from diagnosis to BM and from disease recurrence to BM was longer among patients with BRCAm. Median OS was not significantly different among patients with BM versus those without BM (59.4 vs. 73.4 months, p = 0.243). After BM diagnosis, median OS was not statistically significantly different between patients with BRCAm and those with BRCAw (20.6 vs. 12.3 months, p = 0.441). Treatment with poly (ADP-ribose) polymerase inhibitors and bevacizumab had no impact on subsequent development of BM. CONCLUSIONS: BM are rare among EOC patients. However, the risk is three-fold higher among patients with BRCAm. BM do not significantly alter OS among EOC patients. The higher rate of BM in patients with BRCAm may be related to longer OS in this subpopulation.

Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis.

Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted.

The impact of tumor detection method on genomic and clinical risk and chemotherapy recommendation in early hormone receptor positive breast cancer.

BACKGROUND: Symptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendations. PATIENTS AND METHODS: Patients with early hormone receptor positive (HR+) HER2neu-negative (HER2-) breast cancer, and known OncotypeDX Breast Recurrence Score test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared. RESULTS: The NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX recurrence score (RS) varied between the groups. In the symptomatic group there were lower proportions of low RS (13% vs 23%) and higher proportions of high RS (24% vs. 13%) compared to the screen-detected group. Symptomatic tumors were significantly more likely to have a high clinical risk (59% vs 40%). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with a symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (60% vs. 37%). CONCLUSIONS: We demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans.

Cancer Therapeutics-related Cardiac Dysfunction in Patients Treated With Immune Checkpoint Inhibitors: An Understudied Manifestation.

The widespread use of immune checkpoint inhibitors (ICI) has become a mainstay of care for a variety of malignancies. However, these therapies portend a range of adverse effects, including a potentially fatal form of cardiotoxicity which to date has not been elucidated. We aimed to evaluate the baseline characteristics of ICI-mediated cardiotoxicity. We performed a retrospective study evaluating patients treated with ICI who performed at least 2 echocardiography examinations, before and after the initiation of ICI. Cardiotoxicity was defined as Cancer Therapeutics-related Cardiac Dysfunction (CTRCD) development, with an absolute left ventricular ejection fraction reduction of >10%, to a value <53%. Fifty-two patients were included with a male preponderance (65%) and a mean age of 66 (±12) years. Twelve (23%) patients developed CTRCD, of which 2 patients were diagnosed with myocarditis. Among the CTRCD group, patients tended to be older and more likely to have baseline diastolic dysfunction: lower e' septal (P=0.026), higher E/e' septal (P=0.035), and a trend of E/e' average (P=0.076). All-cause and cardiovascular hospitalizations were significantly more common among the CTRCD group (P=0.028 and 0.001, respectively). Higher prevalence of cardiovascular mortality was observed among the CTRCD group (25% vs. 2%, P=0.034). We evaluated the development of CTRCD among patients treated with ICI therapies. Our findings suggest that baseline diastolic parameters may be associated with CTRCD development assisting in the early diagnosis of ICI-induced cardiac injury.

Pathology Consultation Clinic for Patients With Cancer: Meeting the Clinician Behind the Microscope.

PURPOSE: Traditionally, pathologists have been branded the doctor's doctor, with a position behind the microscope and limited interaction among patients, despite their rich understanding of disease development and ability to navigate personalized medicine in an era of dynamic molecular testing. METHODS: We piloted a unique patient-pathology consultation service, whereby pathologists review tissue specimens with oncology patients, facilitating a platform for heightening patient understanding of their disease and guiding additional genetic and molecular evaluation. We conducted a retrospective survey assessing patient experience. RESULTS: Fifty-nine patients participated in the patient-pathology clinic consultation, with a median age of 64 years and a female predominance (33, 55.9%). The majority of patients were treated for sarcomas (11, 18.6%), breast cancer (10, 17%), and GI tumors (10, 17%). Half of the participants consulted regarding a metastatic disease (28, 47.5%). Thirty patients (50.8%) were referred to additional workup, 11 patients (18.6%) to a second opinion, and 25 participants (42.4%) were counseled to complete genetic sequencing or additional molecular profiles on their pathologic samples. Twelve patients (20.3%) were referred for pathology revision within our institution. Three patients (5.1%) had a change in treatment plan resulting from the clinic visit. The majority (90%) would recommend the patient-pathology clinic to other oncology patients. CONCLUSION: To our knowledge, this is the largest study of patient-pathologist consultation services implemented at a single institution. Our work suggests that the program may provide effective patient understanding and reinforce the role of the pathologist as the patient's doctor. This work surfaced the concerns of patients, regarding their pathology reports, and demonstrated that the patient-pathology clinics are a valuable platform to address patients' distress regarding uncertainty of their diagnosis and an integral resource engaging directly with patients, driving additional evaluation and patient-targeted treatment.

Kambô-Induced Systemic Inflammatory Response: A Case Report of Acute Disease Progression of Cholangiocarcinoma.

Kambô is a cleansing ritual involving the application of a toxin produced by the giant leaf frog (Phyllomedusa bicolor). The Kambô ritual has increasingly been adopted among cancer patients in Europe. Accumulating data indicate various adverse effects. We report another severe adverse reaction to Kambô, a systemic inflammatory response syndrome mimicking disease progression in a patient with cholangiocarcinoma. We describe a systemic reaction to Kambô, manifested as tachycardia, tachypnea, impaired liver cholestatic enzymes, and enlargement of lymphadenopathy mimicking disease progression. The clinical features and onset of symptoms, the rapid reaction, and the lack of other identified causes make the diagnosis of Kambô-induced SIRS highly probable. This case report calls for future studies examining standard oncological care such as chemotherapy, radiotherapy, and immunotherapy in conjunction with alternative therapy. Additionally, greater awareness and physician education should be promoted, encouraging inquiry of oncology patients' administration of alternative, complementary, and integrative medicine.

Rapid Implementation of Telemedicine During the COVID-19 Pandemic: Perspectives and Preferences of Patients with Cancer.

INTRODUCTION: The use of telemedicine in oncology practice is rapidly expanding and is considered safe and cost effective. However, the implications of telemedicine on patient-physician interaction, patient satisfaction, and absence of the personal touch have not been studied to date. Following the spread of COVID-19, telemedicine services were rapidly incorporated at the Oncology Division of Tel Aviv Medical Center. We aimed to evaluate patients' perspectives and preferences regarding telemedicine and to assess whether this virtual communication platform affects the patient-physician relationship. METHODS: Between March 2020 and May 2020, adult cancer patients who conducted at least one successful telemedicine meeting were interviewed by trained medical personnel. The interview was based on validated patient satisfaction questionnaires and focused on patient-physician interaction in relation to the last in-patient visit. RESULTS: Of 236 patients, 172 (74%) patients agreed to participate. The study population comprised mainly patients with gastrointestinal malignancies (n = 79, 46%) with a median age of 63 years (range 21-88). The majority of patients were male (n = 93, 54%). Eighty-nine (51.7%) patients were receiving active oncologic treatment, and 58 (33.7%) were under routine surveillance following completion of active therapy. Almost all had a sense of secured privacy (n = 171, 96%), the majority of patients affirmed that their concerns were met (n = 166, 93%) and perceived that eye contact with the treating physician was perceived (n = 156, 87%). Only a minority felt that the absence of physical clinic visits harmed their treatment (n = 36, 20%). Most patients (n = 146, 84.9%) wished to continue telemedicine services. A multivariate analysis revealed that higher satisfaction and visits for routine surveillance were both predictors of willingness to continue future telemedicine meetings over physical encounters (odds ratio [OR] = 2.41, p = .01; OR = 3.34, p = .03, respectively). CONCLUSION: Telemedicine is perceived as safe and effective, and patients did not feel that it compromised medical care or the patient-physician relationship. Integration of telemedicine is ideal for patients under surveillance after completion of active oncologic treatment. Physician communication skills workshops are warranted with implementing this platform. IMPLICATIONS FOR PRACTICE: During the COVID-19 pandemic, telemedicine was rapidly implemented worldwide to facilitate continuity of quality care and treatment. Despite many potential setbacks, telemedicine has become a useful and safe tool for oncology practitioners to care for their patients. The use of telemedicine regarding patients' perspectives, emotions, and patient-physician communication in daily oncology practice has not been studied to date. This study demonstrated telemedicine is perceived as safe and effective and does not compromise medical care or the patient-physician relationship. Its use is ideal for surveillance after completion of active oncologic treatment. Physician communication skills workshops are warranted with implementing this platform.

R269C variant of ESR1: high prevalence and differential function in a subset of pancreatic cancers.

BACKGROUND: Estrogen receptor α (ESR1) plays a critical role in promoting growth of various cancers. Yet, its role in the development of pancreatic cancer is not well-defined. A less studied region of ESR1 is the hinge region, connecting the ligand binding and DNA domains. rs142712646 is a rare SNP in ESR1, which leads to a substitution of arginine to cysteine at amino acid 269 (R269C). The mutation is positioned in the hinge region of ESR1, hence may affect the receptor structure and function. We aimed to characterize the activity of R269C-ESR1 and study its role in the development of pancreatic cancer. METHODS: Transcriptional activity was evaluated by E2-response element (ERE) and AP1 -luciferase reporter assays and qRT-PCR. Proliferation and migration were assessed using MTT and wound healing assays. Gene-expression analysis was performed using RNAseq. RESULTS: We examined the presence of this SNP in various malignancies, using the entire database of FoundationOne and noted enrichment of it in a subset of pancreatic non-ductal adenocarcinoma (n = 2800) compared to pancreatic ductal adenocarcinoma (PDAC) as well as other tumor types (0.53% vs 0.29%, p = 0.02). Studies in breast and pancreatic cancer cells indicated cell type-dependent activity of ESR1 harboring R269C. Thus, expression of R269C-ESR1 enhanced proliferation and migration of PANC-1 and COLO-357 pancreatic cancer cells but not of MCF-7 breast cancer cells. Moreover, R269C-ESR1 enhanced E2-response elements (ERE) and AP1-dependent transcriptional activity and increased mRNA levels of ERE and AP1-regulated genes in pancreatic cancer cell lines, but had a modest effect on MCF-7 breast cancer cells. Accordingly, whole transcriptome analysis indicated alterations of genes associated with tumorigenicity in pancreatic cancer cells and upregulation of genes associated with cell metabolism and hormone biosynthesis in breast cancer cells. CONCLUSIONS: Our study shed new light on the role of the hinge region in regulating transcriptional activity of the ER and indicates cell-type specific activity, namely increased activity in pancreatic cancer cells but reduced activity in breast cancer cells. While rare, the presence of rs142712646 may serve as a novel genetic risk factor, and a possible target for therapy in a subset of non-ductal pancreatic cancers.

Unusually long-term responses to vemurafenib in BRAF V600E mutated colon and thyroid cancers followed by the development of rare RAS activating mutations.

INTRODUCTION: V600E BRAF mutation is an established driver mutation in a variety of tumors. Vemurafenib is a selective inhibitor of the BRAF V600E kinase, known to be highly effective in BRAF V600E-positive metastatic melanoma. As a single agent, vemurafenib is relatively ineffective in other V600E-positive malignancies. Case 1: A 72 year old man with metastatic CRC who failed several previous lines of chemotherapy. Genetic analysis of 315 cancer-related genes (Foundation Medicine, FMI) revealed a BRAF V600E mutation. The patient was treated with vemurafenib resulting in a partial response of 18 months. Genetic analysis following development of resistance revealed a new mutation in KRAS-G12R. Case 2: V600E mutation was identified in a 59 year old woman with metastatic PTC refractory to radioiodine therapy. The patient was treated with vemurafenib resulting in a partial response lasting 43 months. Genetic analysis following development of resistance revealed a new mutation in NRAS-Q61K. The presented cases demonstrated the development of rare RAS mutations as a genetic mechanism of acquired BRAF inhibitor resistance. This observation is strongly supported by the analysis of a large database consisting of 712 BRAF V600E-positive melanoma samples showing higher rates of BRAF V600E and RAS mutations co-occurrence in metastatic lesions compared to local tumors (OR = 3.8, p = 0.035). This enrichment is likely a result of the development of RAS mutations following treatment with BRAF inhibitors. DISCUSSION: We report two cases showing extreme response to vemurafenib, which could not be predicted prior to treatment commencement. Genetic testing demonstrated a resistant mechanism not previously reported in CRC or PTC patients, namely an acquired mutation of RAS. This is supported by an analysis of a large cohort of BRAF V600E-positive melanomas. Further studies are needed in order to identify predictive markers for response to vemurafenib and to explore novel strategies to overcome RAS-mediated resistance.