Recent National Comprehensive Cancer Network Research Articles

Clinical applicability of guideline-recommended molecular targets and genome-targeted cancer therapies.

11049 Background: Genomic testing has expanded the possibilities of precision medicine, particularly for advanced, treatment-resistant cancer cases. However, the clinical relevance of most genetic alterations remains uncertain, which can lead physicians to overestimate the benefits of tailored therapies. The National Comprehensive Cancer Network (NCCN) guidelines are cancer-specific treatment recommendations that often determine insurance coverage. We assessed the evidence for clinical benefit and actionability of molecular targets for genome-targeted cancer drugs recommended by NCCN. Methods: We identified genome-targeted therapies for solid cancers from the most recent NCCN guidelines. Trial design characteristics were obtained from publications supporting the NCCN recommendations. Genome target actionability was assessed with the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). This ranges from genome alternation-therapy combinations that lead to improved outcomes (Tier I) to treatments with potential clinical relevance (Tiers II or III) to those with undetermined relevance (Tiers IV to X). Clinical benefit was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT Tier I in combination with a given treatment associated with studies demonstrating substantial clinical benefit by ESMO-MCBS (Grades 4-5) were designated as high-benefit, while those linked to studies achieving an ESMO-MCBS Grade of 3 were categorized as promising but unproven. Results: We extracted411 recommendations from NCCN supporting 74 genome-targeted drugs targeting 50 driver alterations. Most recommendations (346/411, 84%) referred to clinical trial data, while one-sixth (65/411, 16%) relied on case reports or preclinical studies. Clinical trials were mostly Phase I or Phase II (271/346, 78%), single arm (262/346, 76%), and evaluated overall response rate as the primary endpoint (271/346, 78%). Over half of target recommendations had Tier I target actionability (246/411, 60%), over one-third were Tier II or III (142/411, 35%), and the rest were undetermined (23/411, 6%). Among 267 scorable trials,12% (32/267) demonstrated substantial clinical benefit (ESMO-MCBS Grades 4-5) and 45% (121/267) were Grade 3. When combining both frameworks,12% (32/267) genomic-based cancer treatments were high-benefit and 33% (88/267) were promising-but-unproven. Conclusions: About one-eighth of genome-targeted cancer therapies recommended in NCCN guidelines received a high benefit rating, while one-third were identified as having a promising but unproven substantial benefit according to the ESCAT and ESMO-MCBS frameworks. Ensuring NCCN recommendations are aligned with well-documented clinical benefits is crucial for promoting informed, evidence-based genomic-guided treatment decisions.

Percutaneous Ablation of T1b Renal Cell Carcinoma: An Overview.

There is increasing incidence of renal cell carcinoma (RCC) with multiple treatment options currently available. The purpose of this review is to outline patient selection and technical approaches and present the current literature for percutaneous ablation of T1b (4.1-7cm) RCC. An increasing number of retrospective studies and meta-analyses have evaluated the use of percutaneous ablation for T1b RCC. Overall, these studies tend to show that percutaneous ablation in this patient population is feasible. However, rates of major adverse events and local recurrence after percutaneous ablation for T1b RCC are both higher than when ablation is used for smaller tumors. As such, a multi-disciplinary, patient-centered approach is required. Due to the increasing literature in this area, the most recent National Comprehensive Cancer Network (NCCN) guidelines include percutaneous ablation as an option for non-surgical patients with T1b RCC.

Abstract PO5-10-08: Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer

Abstract Background: Genomic testing has expanded the possibilities of precision cancer medicine, particularly for advanced, treatment-resistant breast cancer cases. However, the clinical significance of most genetic alterations remains uncertain, potentially overestimating tailored therapies. The National Comprehensive Cancer Network (NCCN) guidelines are evidence-based cancer-specific recommendations used in clinical practice and that are often determinative for insurance coverage. In this study, we assessed the validity of the targets and the clinical benefit of genome-targeted cancer drugs recommended in the NCCN guidelines for metastatic breast cancer. Methods: We identified genome-targeted oncology therapies supporting advanced breast cancer recommendations in the most recent NCCN breast cancer guideline (version 4.2023). Genome-targeted drugs were defined as involving use of a genomic test in which the drug targeted a genomic alteration. We analyzed data from trials supporting advanced genome-targeted breast cancer drugs recommendations. When multiple (or overlapping) articles for the same study were identified, the most recent publication was included. We extracted key details of each trial, including trial design, blinding, phase of clinical trial and primary efficacy end points. We cross-referenced the FDA-approved indications as of 30 June 2023 with the NCCN recommendations for each drug. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for genome-targeted oncology therapies was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We considered a substantial clinical benefit as a grade of 4 or 5. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-targeted breast cancer treatments. Results: We identified 47 recommendations supporting 17 genome-targeted drugs, which targeted 11 driver alterations. Out of these recommendations, 29 (62%) aligned with the FDA indications. We associated 47 trials with these recommendations, most randomized (24, 51%), phase 3 (23, 49%) and open-label (42, 89%). The most common primary endpoint (22, 47%) was overall response rate, followed by progression-free survival/time to progression (21, 45%). Twenty-four trials (51%) had a I-A ESCAT targetability, 7 (15%) had a I-B targetability, 6 (13%) had a I-C targetability score and 10 (21%) were categorized as II-B. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were mainly classified as tier I-A based on randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. By contrast, RET fusions, NTRK fusions, high-tumor mutational burden and microsatellite instability were ranked as tier I-C and somatic BRCA mutations, germline PALB2 mutations and HER-2 mutations as II-B. Six trials (14%, 6/42) supporting drug approval demonstrated substantial ESMO-MCBS clinical benefit. Overall, 6 recommendations (14%) had high-benefit genomic-based cancer treatments. Conclusions: Fewer than one-fifth of molecular-targeted cancer therapies recommended in NCCN guidelines for metastatic breast cancer demonstrated substantial patient benefits. Value frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Jerry Avorn, Aaron Kesselheim. Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-08.

Real-life experiences and barriers to adjuvant chemotherapy in Saudi patients with advanced stage II and stage III colon cancer.

Colorectal cancer is the most common malignancy in Saudi males and third most common in females. Patients with locally advanced colon cancer may eventually develop metastatic disease if not treated promptly and according to guidelines. The recent National Comprehensive Cancer Network guideline recommends tumor resection followed by adjuvant chemotherapy for stage III and high-risk stage II tumors. Therefore, the objective of this study was to characterize patients with locally advanced colon cancer and identify factors associated with the use of adjuvant chemotherapy and the addition of oxaliplatin in locally advanced colon cancer patients. All patients diagnosed with locally advanced colon cancer at National Guard Health Affairs (NGHA) during 2016-2021 were investigated. Patients' characteristics were compared using Chi-square and Fisher exact test, whereas predictors of adjuvant chemotherapy/Oxaliplatin use were identified using univariate and multivariate logistic regression. Out of 222 patients diagnosed with locally advanced colon cancer, 133 received adjuvant chemotherapy. Factors associated with adjuvant chemotherapy administration were age and smoking status. In the multivariable analysis, older patients were less likely to receive oxaliplatin than younger patients. Stage III patients diagnosed during 2019-2021 had 5.61 times higher odds of receiving oxaliplatin. The findings of this study show that older patients and smokers are less likely to be treated with adjuvant chemotherapy. Moreover, age as well as diagnosis year were important determinants of oxaliplatin administration in stage III locally advanced colon cancer patients.

Patterns of Care for Patients with Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy between 2016-2020: An NCDB Analysis

Treatment for locally advanced rectal cancer (LARC), defined as T3/4 or any T with N+ disease, typically requires multi-modality management consisting of radiation (RT), chemotherapy (CHT), and surgery. Despite emerging evidence that total neoadjuvant therapy (TNT) is the preferred treatment of LARC, it remains unknown what proportion of patients are receiving TNT in the United States. Our objective was to (1) determine the proportion of patients with LARC receiving TNT over time, (2) determine the most common method in which TNT is being delivered, and (3) determine what factors are associated with a lower likelihood of receiving TNT in the United States. Retrospective data was obtained from the National Cancer Database (NCDB) for patients diagnosed with rectal cancer between 2016-2020. Patients were excluded if they had M1 disease, T1-2 N0 disease, incomplete staging information, non-adenocarcinoma histology, received RT to a non-rectum site, or received a non-definitive RT dose. Patients were determined to have received TNT if they (1) received RT and multi-agent (MA)-CHT prior to surgery, (2) had an interval of >180 days from the onset of neoadjuvant therapy to surgery if they received long course (LC)-chemoradiation (CRT) (based on 35 days for LC-CRT + 112 days for 8 cycles of MA-CHT + 30 days to surgery), or (3) had an interval of >150 days from the onset of neoadjuvant therapy to surgery if they received short course (SC)-RT (based on 5 days for SC-RT + 112 days for 8 cycles of MA-CHT + 30 days to surgery). Data were analyzed using linear regression, Chi-square test, and binary logistic regression. Of the 26,375 patients included, the median age was 60 (range 21-90) years, with the majority of patients being <65 years old (65.6%), male (62.1%), and non-Hispanic white (77.0%). A total of 5,003 (19.0%) patients received TNT, and 21,372 (81.0%) patients received classical combined modality therapy (CMT). The proportion of patients receiving TNT increased significantly over time, from 6.1% in 2016, 9.0% in 2017, 15.3% in 2018, 25.8% in 2019, to 34.6% in 2020 (slope = 7.36, 95% CI 4.58-10.15, R2 = 0.96, p = 0.040). The most common TNT regimen was MA-CHT followed by LC-CRT (73.2% of cases from 2016-2020). The proportion of patients receiving SC-RT as part of TNT significantly increased from 2.8% in 2016, 1.7% in 2017, 4.6% in 2018, 7.3% in 2019, to 13.7% in 2020 (slope = 2.74, 95% CI 0.37-5.11, R2 = 0.82, p = 0.035). On multivariate analysis, factors associated with a lower likelihood of TNT use included age >65 (OR 0.66, 95% CI 0.61-0.71, p<0.001), female gender (OR 0.92, 95% CI 0.86-0.98, p = 0.014), Black race (OR 0.87, 95% CI 0.77-0.98, p = 0.024), and T3 N0 disease (OR 0.60, 95% CI 0.52-0.70, p<0.001). TNT utilization rates have significantly increased in recent years, from 6.1% in 2016 to 34.6% in 2020. The observed trend appears to be in line with the recent National Comprehensive Cancer Network (NCCN) guidelines recommending TNT as the preferred approach.

HER2 IHC Expression and Gene Amplification in p53-aberrant High-grade Endometrial Endometrioid Carcinoma Suggests That This Population May Benefit From HER2 Testing and Targeted Therapy.

Among gynecologic cancers, uterine serous carcinoma (USC) has been shown to be human epidermal growth factor receptor 2 (HER2) amplified and trastuzumab has been included in the recent National Comprehensive Cancer Network (NCCN) guidelines for treatment of advanced stage or recurrent USC with HER2 overexpression/amplification. There is limited literature suggesting that a subset of high-grade endometrioid carcinomas with aberrant p53 expression may also be HER2 amplified and these patients could benefit from the addition of targeted therapy. We identified 59 p53-aberrant (mismatch repair proficient) FIGO 3 endometrioid carcinomas of the uterus. HER2 immunohistochemistry was performed in all 59 tumors and HER2 fluorescence in situ hybridization (FISH) was performed in 52 of the 59 cases. Four of the 59 cases were HER2 3+ by immunohistochemistry (6.7%), using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2007, 2013, and 2018 criteria. HER2 FISH was performed in 3 of the 4 cases and was amplified in all 3. Nine, 8, and 7 tumors showed 2+ HER2 staining when applying 2018, 2013, and 2007 criteria, respectively, FISH was performed in 7 tumors and none were amplified. An additional 4 cases did not perfectly meet the 2018 ASCO/CAP criteria but were assigned a score of 2+, none were amplified by HER2 FISH. The remaining 42 cases showed 1+ or no staining for HER2, FISH was successfully performed in 38 tumors and none showed amplification. Approximately half of the tumors fulfilled criteria for HER2-low or HER2-very low (10 HER2-low and 20 HER2-very low). Our data shows that a subset of p53-aberrant high-grade endometrial endometrioid carcinoma express HER2 and these patients may benefit from the addition of targeted therapy. The role of targeted therapy in HER2-low gynecologic carcinoma is currently unexplored.

Frequent Abnormal Pancreas Imaging in Patients With Pathogenic ATM, BRCA1, BRCA2, and PALB2 Breast Cancer Susceptibility Variants

Germline genetic testing guides gastroenterologists’ recommendations for prevention of gastrointestinal malignancies. This is well-appreciated for individuals at highest risk for colorectal cancer, including Lynch syndrome or polyposis syndromes.1 In the case of pancreatic cancer (PC), several inherited cancer susceptibility genes are associated with increased PC and breast cancer risk, including BRCA1 and BRCA2, ATM, and PALB2.1-3 With increased multigene panel testing performed for personal and family history (FH) of cancer, and recent National Comprehensive Cancer Network guidelines that recommend genetic testing for those with first-degree relatives diagnosed with PC, newly identified carriers of pathogenic variants will seek recommendations from gastroenterologists on PC screening and outcomes.

Increasing the use of olanzapine in patients receiving chemotherapy in a community oncology practice.

12123 Background: The addition of olanzapine to high emetic risk chemotherapy regimens substantially improves nausea and vomiting within 24 hours and is recommended in the guidelines of both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). However, the uptake of olanzapine has been low in national and institutional settings. The purpose of this project was to increase guideline-concordant prescribing of olanzapine in eligible patients in a community oncology practice. Methods: We developed a multiphase program to address the barriers to the use of olanzapine in a community oncology practice. Patients’ medical records (N = 423) were reviewed to collect baseline data. Motivational interviewing with prescribing clinicians elicited barriers to prescribing, reinforced clinical guidelines, and elicited and reinforced language that suggested a willingness to change prescribing patterns. Chemotherapy protocols were subsequently updated to include olanzapine for high emetic chemotherapy regimens, and prescriber and nurse education was provided by our pharmacists regarding the most recent ASCO and NCCN guidelines. A fellow-led educational session was provided to the infusion nursing team and care managers. At the end of a seven-month period, prescribing information was identified through a system-generated report followed by a medical record review for validation (N = 136) and was shared monthly with prescribing clinicians. Results: At baseline, the use of olanzapine was zero. Multiple barriers were identified regarding the use of olanzapine during motivational interviewing with clinicians, including lack of knowledge of the guidelines, belief that most patients do not require olanzapine, concerns about sedation with the previously recommended dose of 10 mg, and order sets that did not include olanzapine. After the interventions, there was a statistically significant increase in the use of olanzapine from 0% to 56% (p-value &lt; 0.001). Conclusions: A combination of motivational interviewing, prescriber and nurse information support, and changes to the pre-populated order sets for chemotherapy antiemetics was highly successful in improving the uptake of guideline-concordant prescribing of antiemetics. This model of quality improvement, including motivation interview, may support quality improvement efforts across oncology.[Table: see text]

Patterns of recurrence and prognosis in pathologic stage I and II Merkel cell carcinoma: A multicenter, retrospective cohort analysis

To the Editor: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor with a high risk of local and distant spread. Despite the increase in the use of sentinel lymph node biopsy as a result of recent National Comprehensive Cancer Network recommendations, there remains a paucity of data regarding outcomes in patients with clinically localized MCC with complete pathologic nodal microstaging.1 In MCC, disease relapse is a poor prognostic sign and efforts to prevent recurrences may result in improved survival.

Role of molecular imaging in the detection of localized prostate cancer.

Molecular imaging of prostate cancer continues to grow, with recent inclusion of several positron emission tomography (PET) radiotracers into the recent National Comprehensive Cancer Network guidelines and the US Food and Drug Administration approval of prostate-specific membrane antigen (PSMA)-targeted radiotracers. While much of the work for many of these radiotracers is focused on systemic staging and restaging in both newly diagnosed high-risk prostate cancer and biochemically recurrent disease patients, the potential role of molecular imaging for the detection of localized prostate cancer has not yet been fully established. The primary aim of this article will be to present the potential role for molecular imaging in the detection of localized prostate cancer and discuss potential advantages and disadvantages to utilization of both PET/computed tomography (CT) and PET/magnetic resonance imaging (MRI) for this clinical indication of use.

Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk.

Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians' need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management.

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia.

The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

Evaluation of germline genetic testing criteria in early-onset kidney cancer.

296 Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.

Treatment of Cancer-Associated Venous Thromboembolism with Low-Molecular-Weight Heparin or Direct Oral Anticoagulants: Patient Selection, Controversies, and Caveats.

The treatment of venous thromboembolism (VTE) in patients with cancer is challenging because these patients have increased risks of both recurrent VTE and major bleeding, along with patient-specific and cancer-related factors that influence the approach to treatment. Historically, anticoagulant therapy with low-molecular-weight heparin (LMWH), given for both initial and long-term treatment, has been the preferred approach recommended by practice guidelines. Most recently, the National Comprehensive Cancer Network (NCCN) guidelines indicate that the direct oral anticoagulants (DOACs) apixaban, edoxaban, or rivaroxaban are preferred for patients without gastric or gastroesophageal lesions. DOACs have been associated with an increased risk of major bleeding in patients with gastrointestinal and possibly genitourinary cancers, and DOACs should either not be used (especially in those with intact intraluminal tumors) or be used with caution in patients with these cancers. Fatal or life-threatening bleeding occurs with similar frequency with DOACs or LMWH, and most major bleeding with DOACs can be managed with transfusion and standard measures. The patient's willingness and ability to comply with LMWH injections, and their treatment preference, should also be considered. Patients with cancer who have VTE should be treated with anticoagulation for a minimum of 6 months. Anticoagulation should be continued indefinitely while cancer is active or under treatment or if there are persistent risk factors for recurrent VTE. This article summarizes the evidence from clinical trials of LMWH and DOACs that underpins the NCCN guideline recommendations, addresses several controversies and caveats regarding anticoagulant treatment, and offers evidence-based, practical suggestions on patient selection for treatment with DOACs. IMPLICATIONS FOR PRACTICE: Several randomized trials support the addition of direct oral anticoagulants (DOACs) to the therapeutic armamentarium for cancer-associated venous thromboembolism (VTE). These agents come with unique risks and patient- and cancer-specific variables that must be evaluated during the course of a patient's cancer care. This narrative review discusses findings from clinical trials of low-molecular-weight heparin and DOACs for the treatment of cancer-associated VTE, evidence that supports the recent National Comprehensive Cancer Network guideline recommendations. A personalized approach to treatment is proposed that addresses patient selection for treatment with DOACs, factors that influence efficacy and safety, controversies and caveats, and suggestions for their resolution in clinical practice.

Use of Anti-Infective Prophylaxis in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma Patients Initiating Treatment with Daratumumab

Introduction: Infections continue to be one of the main causes of morbidity and mortality in multiple myeloma (MM) patients. Compared to the general population, MM patients have a 7-fold increased risk of bacterial infections and 10-fold risk of viral infections. The recent National Comprehensive Cancer Network (NCCN) guideline has provided guidance for prevention of cancer-related infections; however, utilization of anti-infective prophylaxis among MM patients in real-world practice has not been fully established. Daratumumab, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The primary objective of the study was to describe the proportion of MM patients who received anti-infective prophylaxis when initiating a daratumumab-based treatment regimen. Methods: Medical and pharmacy claims from the Optum's de-identified Clinformatics® Data Mart Database were obtained for a cohort of US patients with NDMM or RRMM who initiated treatment with daratumumab (in combination with other antimyeloma agents or monotherapy) between 1/1/2017 and 12/24/2019. The index date was defined as the first daratumumab treatment date in the study period. Two steps were applied to identify anti-infective prophylaxis. First, use of anti-infective prophylaxis was assessed during the period between the week prior to and the week after the date of daratumumab initiation, including anti-virals for preventing herpesviruses (i.e., herpes zoster, herpes simplex, and cytomegalovirus), systemic anti-bacterials, systemic anti-fungals, Pneumocystis jiroveci pneumonia (PJP) prophylaxis, and intravenous/subcutaneous immune globulin (IVIG/SCIG). Second, use of an anti-infective drug was defined as prophylactic if there was no diagnosis for an infection treated by the anti-infective drug (i.e., patients with infection events one week prior to and one day after the start of drug prescription were excluded). Receipt of vaccines for seasonal influenza (in the year prior to daratumumab initiation) and herpes zoster and pneumococcal infections (at any time prior in the patient's claims history) were also assessed. Results: 929 newly daratumumab-treated patients were eligible for study inclusion; 92 had NDMM (median age 74 years; 48.9% female) and 837 had RRMM (median age 72 years; 46.0% female). At the time of daratumumab initiation, antibacterial prophylaxis was administered to 12.0% of NDMM and 17.0% of RRMM patients; antifungal prophylaxis to 1.1% of NDMM and 1.3% of RRMM patients; and PJP prophylaxis to 4.4% of NDMM and 10.5% of RRMM patients (Table 1). IVIG/SCIG prophylaxis was given to 1.1% of NDMM patients and 2.5% of RRMM patients. Herpesvirus prophylaxis was administered to 57.6% of NDMM and 69.4% of RRMM patients, and 17.4% of NDMM and 11.5% of RRMM patients received vaccination for herpes zoster. Seasonal influenza and pneumococcal vaccinations were given to 56.5% and 47.8% of NDMM patients and 62.5% and 51.3% of RRMM patients, respectively. Conclusion: Use of herpesvirus prophylaxis was approximately 70% in RRMM and 60% in NDMM patients at time of daratumumab initiation, with limited use of herpes zoster vaccination, suggesting that a meaningful minority of patients may not be protected against herpesvirus as recommended by NCCN guidelines for patients treated for MM. While rates of influenza and pneumococcal vaccination were higher than for herpes zoster, nearly half of patients did not have evidence of vaccination for these two pathogens in their claims data. These results indicate that a significant percentage of MM patients are not receiving care to optimally prevent potential viral infections. Further studies are needed to understand the potential benefit of infectious prophylaxis in the clinical management of MM patients. Disclosures Tai: Janssen Scientific Affairs: Current Employment. Ammann:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Kaila:Janssen Scientific Affairs: Current Employment. Pericone:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Singh:Mu Sigma: Current Employment, Other: Mu Sigma was contracted by Janssen Scientific Affairs to conduct the analyses for the present study. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Low-Dose Abiraterone in Metastatic Prostate Cancer: Is It Practice Changing? Facts and Facets.

PURPOSEIt is projected that approximately 50,000 new cases of prostate cancer will be diagnosed in 2020 in India. Survival has improved because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting.METHODSThe Science and Cost Cancer Consortium conducted a survey to evaluate the use of abiraterone in India and the opinions of medical oncologists about using low-dose treatment. Modeling was used to estimate potential financial benefits to individual patients and to estimate overall costs of health care in India if low-dose abiraterone is prescribed.RESULTSOf 251 Indian medical oncologists who were invited to participate in the survey, 125 provided their e-mail address and received the survey; 118 responded (47% of the total). Of these, 25% were not aware of the recent NCCN recommendation, 55% were already prescribing low-dose abiraterone when resources were limited, 7% had already changed their practice, and 29% agreed to switch to a universal practice of using low-dose abiraterone with food; 9% of practitioners would not use low-dose abiraterone. Estimated mean per patient savings was US$3,640, with annual savings of US$182 million in India.CONCLUSIONUse of lower-dose abiraterone would increase access to treatment in India and globally and lead to large cost savings.

Genomic Validation of 3-Tiered Clinical Subclassification of High-Risk Prostate Cancer

Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥8, or prostate-specific antigen [PSA] >20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether subclassification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. We identified 3220 patients with NCCN unfavorable intermediate-risk (n = 2000) or high-risk (n = 1220) prostate cancer from a prospective multi-institutional registry cohort. We defined the following subclassification of high-risk prostate cancer based on previously published data: favorable high risk (cT1c, Gleason 6, and PSA >20 ng/mL or cT1c, Gleason 4 + 4 = 8, PSA <10 ng/mL); very high risk (cT3b-T4 or primary Gleason pattern 5); and standard high risk (all others with cT3a, Gleason score ≥8, or PSA >20 ng/mL). We used a set of 33 previously developed genomic classifiers, including Decipher, to determine whether high-risk genomic features correlate with clinical subclasses of high-risk prostate cancer. Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, and 81.6% had a high-risk Decipher score, respectively (P < .001). Among 32 other genomic signatures, 29 had a similar trend of increasing risk scores across the 3 subclasses of high-risk disease (P < .05 after correction for multiple hypothesis testing). Patients in the 3 subclasses of high-risk disease had a median of 4, 6, and 13 high-risk signatures, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score, and the median number of high-risk signatures was3. Although NCCN guidelines currently use a 2-tiered system for high-risk prostate cancer, genomic markers of risk correlate with the clinically validated subclassification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, further confirming the prognostic utility of this 3-tiered stratification.

Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis.

Background: According to the recent National Comprehensive Cancer Network (NCCN) guidelines, the risk level in acute myeloid leukemia (AML) patients with FLT3-ITD and NPM1 double mutation (AMLFLT3-ITD+/NPM1+) depends on the allelic ratio of FLT3-ITD. But despite a low or high allelic ratio of FLT3-ITD, AMLFLT3-ITD+/NPM1+ patients belong to the favorable or intermediate risk, for whom allogeneic stem cell transplantation is not obligated. However, some latest studies pointing out that NPM1 and FLT3-ITD double mutation patients showed an inferior prognosis, which have raised concern about the risk categorization and more effective treatment of AMLFLT3-ITD+/NPM1+ patients.Methods: A total of 76 patients were selected for coexisting FLT3 and NPM1 mutations with normal cytogenetics. The prognostic risk factors were analyzed, and treatment strategies including allogeneic stem cell transplantati1on and chemotherapy were compared.Results: In 76 AMLFLT3-ITD+/NPM1+ patients, 36.8% of patients had hyperleukocytosis (HL) and DNMT3A R882 mutation was the most common concomitant gene (23.7%). For 53 patients in the complete remission (CR), 22 had received allogeneic hematopoietic stem cell transplantation (allo-HSCT) on first complete remission (CR1). Patients in transplantation group had better overall survival (OS) and disease-free survival (DFS) than chemotherapy only (P=0.002 and 0.001, respectively). In multivariable Cox model analyses, HL and DNMT3A R882 mutation were independent adverse prognostic factors (all P<0.05) for AMLFLT3-ITD+/NPM1+ patients. Nevertheless, allo-HSCT was an independent good factor of OS and DFS (P=0.001 and 0.000; HR =0.173 and 0.138; 95% CI were 0.062–0.483 and 0.049–0.389). And allo-HSCT could moderately improve the poor prognosis of AML FLT3-ITD+/NPM1+/DNMT3A R882+.Conclusion: Although, AMLFLT3-ITD+/NPM1+ patients are categorized as favorable or intermediate risk levels according to recent NCCN and ELN guidelines, these patients should receive allo-HSCT in CR1 for a longer survival. AMLFLT3-ITD+/NPM1+ patients with DNMT3A R882 mutation had a very poor prognosis, and allo-HSCT could moderately improve their survival.

Increased breast cancer risk in women with neurofibromatosis type 1: a meta-analysis and systematic review of the literature

BackgroundNeurofibromatosis type 1 (NF1) is a cancer predisposing syndrome. Studies suggest that women < 50 years old (y.o.) with NF1 have an increased breast cancer (BC) incidence and BC associated mortality. However, this has not been widely recognized secondary to small study populations.MethodsA systematic literature review was conducted through database searches for BC and NF1: 3456 articles identified, 166 reviewed, 58 used for descriptive analysis and 4 utilized for meta-analysis. Fisher’s exact tests, Kaplan-Meier curves and random-effects meta-analysis models were used for analysis.ResultsTwo hundred eighty-six cases of NF1 and female BC were identified with a median age of 46 years at diagnosis; 53% were < 50. Peak age of BC diagnosis was between 34 to 44 years. Women < 50 y.o. presented with more advanced disease vs. those ≥50 (56% vs. 22% stage III-IV, respectively; p = 0.005). Median survival for the entire cohort was 5 years vs. the reported median BC survival of over 20 years in the general population using the SEER database. Median age at BC death was 48.5 years; 64% of deceased patients were < 50. Meta-analysis of a total of 4178 women with NF1 revealed a BC standardized incidence ratio (SIR) of 3.07 (95%CI 2.16–4.38) for women with NF1 vs. the general population. Women < 50 y.o. demonstrated a higher SIR of 5.08 (95%CI 3.77–6.81) compared to 1.92 (95%CI 1.40–2.63) if ≥50 y.o.ConclusionsThis systematic literature review and meta-analysis suggests that women with NF1 < 50 y.o. have a five-fold increased risk of BC, present with more advanced disease, and may have an increased BC related mortality. Increased awareness and implementation of recent National Comprehensive Cancer Network early BC screening guidelines for this high-risk patient population is essential. Additional evaluation on the influence of NF1 gene mutations identified in patients undergoing hereditary cancer genetic testing on breast cancer risk in individuals without clinical evidence of NF1 is needed.

Genomic validation of three-tiered sub-classification of high-risk prostate cancer.

17 Background: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥ 8, or prostate-specific antigen [PSA] &gt; 20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. Methods: We identified 3,220 patients with NCCN unfavorable intermediate-risk (n=2,000) or high-risk (n=1,220) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA &gt; 20 ng/mL or cT1c, Gleason 4+4=8, PSA &lt; 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score ≥ 8, or PSA &gt; 20 ng/mL). We used a set of 37 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Results: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, 81.6% had a high-risk Decipher score, respectively (p &lt; 0.001). Among 36 other genomic signatures, 33 had a similar increasing trend across the three sub-classes of high-risk (p &lt; 0.05 after correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 5, 7, and 14 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.5%, 19.7%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score and would be re-classified as clinical-genomic high-risk. Conclusions: Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.