Exploring the Genomic Landscape of Hepatobiliary Cancers to Establish a Novel Molecular Classification System.

Taxonomy of hepatobiliary cancer (HBC) categorizes tumors by location or histopathology (tissue of origin, TO). Tumors originating from different TOs can also be grouped by overlapping genomic alterations (GA) into molecular subtypes (MS). The aim of this study was to create novel HBC MSs. Next-generation sequencing (NGS) data from the AACR-GENIE database were used to examine the genomic landscape of HBCs. Machine learning and gene enrichment analysis identified MSs and their oncogenomic pathways. Descriptive statistics were used to compare subtypes and their associations with clinical and molecular variables. Integrative analyses generated three MSs with different oncogenomic pathways independent of TO (n = 324; p < 0.05). HC-1 "hyper-mutated-proliferative state" MS had rapidly dividing cells susceptible to chemotherapy; HC-2 "adaptive stem cell-cellular senescence" MS had epigenomic alterations to evade immune system and treatment-resistant mechanisms; HC-3 "metabolic-stress pathway" MS had metabolic alterations. The discovery of HBC MSs is the initial step in cancer taxonomy evolution and the incorporation of genomic profiling into the TNM system. The goal is the development of a precision oncology machine learning algorithm to guide treatment planning and improve HBC outcomes. Future studies should validate findings of this study, incorporate clinical outcomes, and compare the MS classification to the AJCC 8th staging system.

Age-related next-generation sequencing mutational analysis in 1196 melanomas.

BACKGROUND AND OBJECTIVES: Melanoma mutational burden is high and approximately 50% have oncogenic mutations in BRAF. We sought to evaluate age-related mutational differences in melanoma. METHODS: We analyzed melanoma samples in the Genomics Evidence Neoplasia Information Exchange database. Targetable mutations were identified using the Precision Oncology Knowledge Base (OncoKB). RESULTS: We found 1194 patients with a common set of 30 genes. The top mutated genes in patients <40 years old (y/o) (n = 98) were BRAF (59%), TP53 (31%), NRAS (17%), and PTEN (14%); in 40-59 y/o (n = 354) were BRAF (51%), NRAS (30%), TP53 (26%), and APC (13%); and in ≥60 y/o (n = 742) were BRAF (38%), NRAS (33%), TP53 (26%), and KDR (19%). BRAF mutations were almost mutually exclusive from NRAS mutations in <40 y/o (58/59). Mutational burden increased with age, with means of 2.39, 2.92, and 3.67 mutations per sample in patients <40, 40-59, and ≥60 y/o, respectively (p < 0.0001). There were 10 targetable mutations meeting OncoKB criteria for melanoma: BRAF (level 1), RET (level 1), KIT (level 2), NRAS (level 3A), TP53 (level 3A), and FGFR2, MET, PTEN, PIK3CA, and KRAS (level 4). CONCLUSIONS: Mutations in melanoma have age-related differences and demonstrates potential targetable mutations for personalized therapies.

Evolving management of early stage pancreatic adenocarcinoma in older patients.

BACKGROUND: Due to the aging population, the number of older patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) will continue to rise. STUDY DESIGN: Utilizing the NCDB from 2010 to 2016, patients with early stage, clinically node negative PDAC who were ≥70 years old and had a Whipple were identified. Multivariable logistic regressions were used to determine independent factors for R0 resection and NAT. Cox-proportional-hazards regression analyses examined for the impact of NAT on the risk of death. RESULTS: Of 5086 patients, 51.7% received upfront surgery + adjuvant therapy (UFS + AT), followed by 29.9% UFS only, and the remainder NAT. NAT significantly improved OS compared to a combined cohort of those that had UFS ± AT. NAT retained its independent survival benefit when compared to only patients that had UFS + AT. CONCLUSION: For older patients diagnosed with early stage PDAC, NAT was associated with improved R0 resection rates and a significant survival benefit when compared to the current standard of care.

Validating biologic age in selecting elderly patients with pancreatic cancer for surgical resection.

BACKGROUND AND OBJECTIVES: Selecting frail elderly patients with pancreatic cancer (PC) for pancreas resection using biologic age has not been elucidated. This study determined the feasibility of the deficit accumulation frailty index (DAFI) in identifying such patients and its association with surgical outcomes. METHODS: The DAFI, which assesses frailty based on biologic age, was used to identify frail patients using clinical and health-related quality-of-life data. The characteristics of frail and nonfrail patients were compared. RESULTS: Of 242 patients (median age, 75.5 years), 61.2% were frail and 32.6% had undergone pancreas resection (surgery group). Median overall survival (mOS) decreased in frail patients (7.13 months, 95% confidence interval [CI]: 5.65-10.1) compared with nonfrail patients (16.1 months, 95% CI: 11.47-34.40, p = 0.001). In the surgery group, mOS improved in the nonfrail patients (49.4%; 49.2 months, 95% CI: 29.3-79.9) compared with frail patients (50.6%, 22.1 months, 95% CI: 18.3-52.4, p = 0.10). In the no-surgery group, mOS was better in nonfrail patients (54%; 10.81 months, CI 7.85-16.03) compared with frail patients (66%; 5.45 months, 95% CI: 4.34-7.03, p = 0.02). CONCLUSIONS: The DAFI identified elderly patients with PC at risk of poor outcomes and can identify patients who can tolerate more aggressive treatments.

Survivorship, Quality of Life, and Transition to Adult Care for Pediatric and Adolescent Thyroid Cancer Survivors.

The importance of long-term survivorship care to reduce survivor and family anxiety and burden, decrease emergency visits and health care costs, improve knowledge, as well as implement timely surveillance is widely accepted. Most childhood cancer survivors suffer from an increased number of medical and psychosocial comorbidities as they age and are at a higher risk for early mortality, which differs by cancer diagnosis. Childhood thyroid cancer survivors fall within this spectrum. Some have significant complications and/or late effects from treatment, whereas others have no long-term medical late effects, but almost all will require life-long thyroid hormone replacement therapy. Therefore, providing survivorship and transitional care, including a survivorship and/or transitional care plan (SCP/TCP), as well as periodically assessing the needs and quality of life for the patient and their family, should be implemented for our young thyroid cancer survivors.

Systemic Therapy Is Associated with Improved Oncologic Outcomes in Resectable Stage II/III Intrahepatic Cholangiocarcinoma: An Examination of the National Cancer Database over the Past Decade.

Limited evidence-based management guidelines for resectable intrahepatic cholangiocarcinoma (ICC) currently exist. Using a large population-based cancer registry; the utilization rates and outcomes for patients with clinical stages I-III ICC treated with neoadjuvant chemotherapy (NAT) in relation to other treatment strategies were investigated, as were the predictors of treatment regimen utilization. Oncologic outcomes were compared between treatment strategies. Amongst 2736 patients, chemotherapy utilization was low; however, NAT use increased from 4.3% to 7.2% (p = 0.011) over the study period. A higher clinical stage was predictive of the use of NAT, while higher pathologic stage and margin-positive resections were predictive of the use of adjuvant therapy (AT). For patients with more advanced disease, the receipt of NAT or AT was associated with significantly improved survival compared to surgery alone (cStage II, p = 0.040; cStage III, p = 0.003). Furthermore, patients receiving NAT were more likely to undergo margin-negative resections compared to those treated with AT (72.5% vs. 62.6%, p = 0.027), despite having higher-risk tumors. This analysis of treatment strategies for resectable ICC suggests a benefit for systemic therapy. Prospective and randomized studies evaluating the sequencing of treatments for patients with high-risk resectable ICC are needed.

Treatment Utilization and Outcomes for Locally Advanced Rectal Cancer in Older Patients.

Importance: The number of older patients (80 years and older) diagnosed with locally advanced rectal cancer (LARC) is expected to increase. Although current guidelines recommend neoadjuvant chemoradiation therapy (NACRT) followed by resection, little is known about management and outcomes in this older population. Objective: To assess the trends in management of older patients diagnosed with LARC who had a surgical resection. Design, Setting, and Participants: Patients 80 years and older who had a surgical resection for LARC were identified in the 2004-2016 National Cancer Database. Patients were grouped based on therapy sequence: (1) surgery followed by adjuvant therapy (AT), ie, chemotherapy or radiation; (2) surgery alone; or (3) NACRT followed by surgical resection. Data were analyzed in May 2021. Exposures: NACRT followed by surgery, and surgery with or without AT. Main Outcomes and Measures: Overall survival (OS) was assessed using Kaplan-Meier analyses with inverse probability of treatment weighting (IPTW) and Cox proportional hazards regression were performed to examine the association of NACRT with the risk of death. Results: Of 3868 patients with LARC who underwent surgical resection, 2042 (52.8%) were male, and the mean (SD) age was 83.4 (3.0) years. A total of 2273 (58.8%) received NACRT followed by surgical resection. Factors independently associated with NACRT were more recent diagnosis, age 80 to 85 years (vs 86 years and older), fewer comorbidities, larger tumors, and node-positive disease. The Kaplan-Meier analyses with IPTW showed that 3-year and 5-year OS for NACRT (3-year: 68.9%; 95% CI, 67.0-70.8; 5-year: 51.1%; 95% CI, 49.0-53.4) vs surgery with AT (3-year: 64.4%; 95% CI, 59.0-70.2; 5-year: 43.0%; 95% CI, 37.4-49.5) vs surgery alone (3-year: 55.8%; 95% CI, 52.0-60.0; 5-year: 34.7%; 95% CI, 30.8-39.0) was significantly different (P < .001). After adjusting for confounders, patients who received NACRT were more likely to undergo an R0 resection (adjusted odds ratio, 2.16; 95% CI, 1.62-2.88), which independently improved OS (P < .001). Moreover, receipt of NACRT was independently associated with a 25% decreased risk of death (adjusted hazard ratio, 0.75; 95% CI, 0.69-0.82) compared with alternative treatment sequences. Conclusions and Relevance: Approximately 40% of older patients with LARC did not receive the current standard of care. In this cohort, NACRT was associated with a higher likelihood of an R0 resection and improved OS. Clinicians should advocate for receipt of NACRT in older patients with LARC.

Differences in the management of thyroid nodules in children and adolescents as compared to adults.

PURPOSE OF REVIEW: To describe recent advances in the diagnosis and management of thyroid nodules in both children and adults, highlighting differences between the two groups. RECENT FINDINGS: Thyroid nodules are less common in children than adults but the risk of malignancy is higher. Screening recommendations for patients with certain genetic syndromes or specific risk factors for thyroid nodules and cancer continue to evolve ultrasound is the most appropriate imaging modality for evaluating thyroid nodules in all patients, but radiographic risk stratification systems validated in adults have not been extensively studied in children. Criteria for proceeding to fine needle aspiration (FNA) biopsy differ some between children and adults, with nodule size being less of a consideration in young patients. Molecular testing continues to improve the diagnostic capabilities of FNA for all age groups, but options for pediatric thyroid nodules are currently limited. In children, only oncogene panels are validated and their exact utility, along with miRNA classifiers, is an evolving area of study. For adults, data support selection of a specific molecular test based on ultrasound characteristics and pretest probability of malignancy. Multiple series have shown that fusion mutations are more common in pediatric thyroid nodules, while point mutations are seen more often in adult thyroid nodules. Molecular data help guide management recommendations regarding the need for surgery when FNA is indeterminate, but clinical use is still being refined. Radiofrequency ablation is a nonoperative approach that has gained significant traction for the treatment of symptomatic benign nodules in adults, but data are currently extremely limited in children. SUMMARY: There are difference in the diagnosis and treatment of thyroid nodules in adults and children, the nuances of which are important for clinical management.

Prognostic indicators for undifferentiated carcinoma with/without osteoclast-like giant cells of the pancreas.

BACKGROUND: Undifferentiated carcinoma of the pancreas (UPC) is a rare malignancy. There are no standardized guidelines for treatment. Current management has been extrapolated from smaller reviews. METHODS: 858 patients with UPC were identified in the 2004-2017 NCDB. Kaplan-Meier method followed by Cox proportional-hazards regression examined independent prognostic factors associated with overall survival (OS). Logistic regression analyses were performed to determine independent predictors of surgical intervention and the status of surgical resection by histologic subtype. RESULTS: Patients with osteoclast-like giant cells (OCLGC) had a longer median OS compared to those without (aHR 0.52: 95% CI 0.41-0.67). Of the non-OCLGC subtypes, pleomorphic large cell demonstrated the shortest median OS (2.4 months). Surgical resection was associated with improved survival in all histologies except for pleomorphic cell carcinoma. R0 resection and negative lymph nodes were independently associated with an improved OS. CONCLUSION: This is the largest database review published to date on UCP. OCLGC histology is associated with an improved survival compared to those without OCLGC. Of the non-OCLGC subtypes, pleomorphic large cell is associated with the shortest overall survival. Surgical resection is associated with a significant survival advantage for all histologies except for pleomorphic cell carcinoma.

Does Residual Invasive Disease in Wide Local Excision after Diagnosis with Partial Biopsy Technique Influence Survival in Melanoma? Matched-Pair Analysis of Multicenter Selective Lymphadenectomy Trial I and II.

BACKGROUND: Current guidelines recommend excisional/complete biopsy for melanoma diagnosis, owing to high rates of residual disease found at wide local excision (WLE) after partial biopsy techniques. We sought to determine any survival disadvantage associated with the presence of residual invasive melanoma in the WLE after diagnosis with a partial biopsy technique. STUDY DESIGN: Data were examined from Multicenter Selective Lymphadenectomy Trials I and II (MSLT-I and -II), 2 large melanoma trials. Patients diagnosed with excisional/complete biopsy were excluded. Clinicopathologic characteristics, melanoma-specific survival (MSS), distant disease-free survival (DDFS), and disease-free survival (DFS) of those with residual invasive melanoma in the definitive WLE and those with no residual melanoma were compared. Matched pairing was used to reduce variability between groups. RESULTS: From 1994 through 2014, 3,939 patients were enrolled in these trials and 874 (22%) were diagnosed using partial biopsy techniques. Of these, 399 (46%) had residual tumor in the WLE. Only 6 patients had residual tumor in their WLE resulting in T-upstaging of their tumor. Match-pairing formed two cohorts (1:1) of patients with and without residual invasive tumor after WLE. A total of 514 patients were paired; 288 (56%) males, 148 (28.8%) aged 60 or older, 192 (37.4%) with truncal melanomas, 214 (41.6%) had Breslow thickness 2 mm or greater, and 376 (73.2%) had positive sentinel nodes. Kaplan-Meier analysis showed no statistical difference in 10-year MSS (73.6% ± 3.3% vs 73.9% ± 3.7%, p = 0.891), DDFS (68.7% ± 3.4% vs 65.3% ± 4.0%, p = 0.548), or DFS (59.6% ± 3.7% vs 59.4% ± 3.9%, p = 0.783). CONCLUSIONS: Survival in patients with primary melanoma does not appear to be worse in patients who undergo a partial biopsy technique and are later found to have residual invasive tumor in the WLE specimen.

Disparities in the impact of the AJCC 8th edition staging system on differentiated thyroid cancer outcomes.

BACKGROUND: The impact of AJCC8 among self-reported racial/ethnic groups on differentiated thyroid cancer (DTC) outcomes is unknown. METHODS: Multivariate-regression evaluated the association between AJCC7 to AJCC8 stage change and race/ethnicity in patients with DTC in the NCDB. Cox-proportional-regression evaluated whether AJCC7 to AJCC8 stage change affects overall survival (OS) differently based on reported race/ethnicity. RESULTS: After adjusting for confounders, Hispanics and Asian-Pacific-Islanders (APIs) were 27% and 12% less likely to be down-staged compared to white-non-Hispanics (WNHs) (p < 0.001); black-non-Hispanics (BNHs) had no significant down-staging difference. Down-staged patients had an increased risk of death compared to patients with unchanged staging, regardless of race/ethnicity. However, based on two-way interaction, the magnitude of this negative change on survival from down-staging was only different between WNHs (HR = 2.64) and BNHs (HR = 1.77), (p = 0.04). CONCLUSIONS: Outcome disparities persist among self-reported racial/ethnic groups with AJCC8. Down-staged patients across all racial/ethnic groups had decreased survival compared to those with unchanged stage, with the least impact in BNHs.

Influence of Socioeconomic Status on Incident Medical Conditions in Two-Year Survivors of Adolescent or Young Adult Differentiated Thyroid Cancer.

Purpose: We sought to enumerate secondary medical conditions from hospitalization records in adolescent and young adult (AYA) differentiated thyroid cancer (DTC) survivors and identify characteristics of patients with increased likelihood of subsequent medical diagnoses. Methods: Using data from the California Cancer Registry and statewide hospitalization data, we examined incident oncologic, endocrine, pulmonary, hematologic, and cardiovascular diagnoses in 12,312 AYA (aged 15-39) patients diagnosed with DTC in 1996-2012 and surviving >2 years after diagnosis with follow-up through 2014. We calculated the cumulative incidence of each condition accounting for the competing risk of death and used multivariable Cox proportional hazards regression to evaluate sociodemographic and clinical characteristics associated with each incident condition. Results: The 10-year cumulative incidences of multiple medical conditions were particularly high in blacks and Hispanics. Asian/Pacific Islander survivors were most likely to develop subsequent cancers. Men had higher rates of cardiovascular and diabetes diagnoses than women, but lower rates of asthma and cytopenias. Low socioeconomic status and/or public or no insurance were associated with a higher risk of several diagnoses. More extensive disease stage and thyroid surgery increased the risk of calcium and phosphorus metabolism disorders. Neck reoperation associated with the risk of cytopenias, as well as subsequent endocrine, cardiovascular, and respiratory diagnoses. Conclusion: The incidence of medical conditions after thyroid cancer diagnosis and treatment differ among racial/ethnic groups and sexes. Those residing in lower socioeconomic neighborhoods, those with public or no insurance, and those who require further neck surgery have substantially higher burdens of subsequent medical diagnoses.

Disparities in Amputation Rates for Non-metastatic Extremity Soft Tissue Sarcomas and the Impact on Survival.

BACKGROUND: There are no definitive recommendations guiding amputation use in extremity soft tissue sarcomas (STSs). This study explores disparities in amputation rates and survival in patients with non-metastatic adult-type extremity STSs. METHODS: Patients with non-metastatic adult-type extremity STSs were identified from the 1998-2012 National Cancer Database. Factors affecting amputation were examined across all ages and separately in adults (> 40 years), adolescent/young adults (AYA: ages 15-39), and children (age < 15). Impact on 10-year overall survival (OS) was explored. RESULTS: Of 15,886 patients, 4.65% had an amputation. AYAs had the most amputations (6.4%) compared to children (5.9%) and adults (4.2%) (p < 0.001). Patients with public insurance (OR 1.3, CI 1.08-1.58) and from central states (OR 1.5, CI 1.2-1.86) were more likely to undergo amputation, whereas those from high income brackets (OR 0.8, CI 0.62-0.94) and treated at community cancer centers were less likely (OR 0.7, CI 0.62-0.90). Amputation was an independent risk factor for death at 10 years, with the greatest impact in AYAs compared to older adults (HR 1.7, p < 0.001). Treatment in eastern or central states, lower income, lack of private insurance, and comorbidities were all associated with decreased OS (all p < 0.05). Female gender (HR 0.8, CI 0.78-0.89) and high-volume centers (HR 0.8, CI 0.74-0.94) were associated with improved OS. CONCLUSIONS: Although amputations for extremity STSs are rare, disparities exist across age groups, insurance and geography when it comes to the use of amputation in patients with extremity STSs. Moreover, having an amputation is an independent risk factor for death, with the greatest impact in AYAs.

Development of a Risk Score and Nomogram to Predict Individual Benefit Attained from the Addition of Adjuvant Chemotherapy in the Treatment of Stage II Colon Cancer.

BACKGROUND: Current guidelines recommend considering adjuvant chemotherapy (AC) for stage II colon cancer (CC) with poor prognostic clinicopathologic and molecular features. However, the relative impact of individual or constellations of high-risk features remains undefined. We developed an individualized point-of-care tool to predict survival benefit attained from the addition of AC. METHODS: The National Cancer Database was queried for all patients with resected stage II CC from 2004 to 2015. A prognostic risk score and nomogram were constructed using twelve clinicopathologic and molecular prognostic factors associated with outcomes for CC. Overall survival (OS) was compared between surgery alone and AC groups. The nomogram was validated for discrimination and calibration using bootstrap-adjusted Harrell's concordance index (C-index). For population-level estimation, OS was compared based on quartiles. RESULTS: Of 132,666 patients with stage II CC, 16.8% received AC. The calibration curve of the constructed nomogram showed a good agreement between predicted and observed median and 3-, 5-, and 10-year survival (bootstrap-adjusted C-index 0.699, CI: 0.698-0.703). Population-level risk score analysis (median [Q1, Q3]; 4.9 [4.6, 5.5]) demonstrated that patients with scores > 3.34 had significantly decreased risk of death with the addition of AC (all p < 0.001). No survival advantage was associated with AC among patients with low risk scores (risk score < 3.34: HR: 0.94, 95% CI: 0.80-1.11, p = 0.47). DISCUSSION: A composite weighted risk score is critical to individualizing AC in select high-risk patients. Our nomogram provides individualized prognostication and estimation of benefit attained from AC. This may better inform treatment decisions and aid future trial design.

Delay in surgery is associated with axillary upstaging of clinically node negative breast cancer patients.

BACKGROUND AND OBJECTIVES: Most breast cancer (BC) patients present with early disease and clinically negative lymph nodes (cN0). Timing of surgery has not been standardized. We hypothesized that surgical delay results in an increased likelihood of nodal metastasis. METHODS: Patients diagnosed with cN0 BC undergoing surgery with sentinel lymph node biopsy as initial therapy between 2006 and 2014 were identified in the NCDB and divided into four groups based on time intervals between diagnosis and surgery (<4 weeks, 4-8 weeks, 8-12 weeks, and >12 weeks). Regression analysis evaluated the independent impact of surgical timing on axillary upstaging and survival. RESULTS: Of 355,443 patients with cN0 BC, 39.6% had surgery within 4 weeks and 5.4% more than 12 weeks from diagnosis. After controlling for relevant factors, a month delay in surgery was associated with an increased likelihood of nodal positivity (odds ratio: 1.04; 95% confidence interval [CI]: 1.04-1.05; p < .001) and decreased overall survival (hazard ratio: 1.03; 95% CI: 1.02-1.04; p < .001). When compared to patients who underwent surgery less than 4 weeks from diagnosis, the absolute increase in nodal positivity and relative risks were 5.3% (95% CI: 0.047-0.059) and 1.34 (95% CI: 1.30-1.38), respectively, in the more than 12 weeks group. CONCLUSIONS: Delay in BC surgery in cN0 patients was associated with an increased likelihood of axillary upstaging and decreased survival.

Disparities in the Occurrence of Late Effects following Treatment among Adolescent and Young Adult Melanoma Survivors.

BACKGROUND: Melanoma is the third most common cancer in the adolescent and young adult (AYA) population; however, no studies have addressed the occurrence of adverse health conditions following melanoma treatment in these survivors. METHODS: Data for patients ages 15 to 39 years diagnosed with cutaneous melanoma from 1996 to 2012 and surviving ≥2 years were obtained from the California Cancer Registry and linked to statewide hospitalization data. The influence of age at diagnosis, sex, race/ethnicity, neighborhood socioeconomic status (SES), health insurance, and surgery on the development of adverse health conditions was evaluated using Cox proportional hazards regression models. RESULTS: Of 8,259 patients, 35.3% were male, 83.3% were non-Hispanic White, 82.4% had private health insurance, and 60.5% were considered high SES. In Cox regression models, males had an increased risk of developing adverse health conditions across all systems, including cardiac [HR, 1.73, 95% confidence interval (CI), 1.47-2.03], lymphedema (HR, 1.56; 95% CI, 1.37-1.77), hematologic disorders (HR, 1.17; 95% CI, 1.03-1.33), major infection/sepsis (HR, 1.59; 95% CI, 1.39-1.82), and second cancers (HR, 1.51; 95% CI, 1.31-1.74). Patients with public/no insurance (vs. private) had a greater risk of developing all studied adverse health conditions, including subsequent cancers (HR, 2.34; 95% CI, 1.94-2.82). AYA patients residing in low SES neighborhoods had similar increased risk of developing adverse health conditions. CONCLUSIONS: Of AYA melanoma survivors, males, those with public/no health insurance, and those living in low SES neighborhoods had a greater likelihood of developing adverse health conditions. IMPACT: Strategies to improve surveillance and secondary prevention of these adverse health conditions are needed among AYA melanoma survivors, specifically for the at-risk populations identified.