Time Of Primary Cancer Diagnosis Research Articles

Sequential learning for pan-tumor detection of metastatic disease progression.

e13591 Background: Detection of progression of patients with early stage cancer is a challenge for real world data from electronic health records (EHR). Temporal patterns common to patients’ data can detect patients with metastatic progression. A deep learning approach on longitudinal patient records of cancer lab testing, visit diagnosis codes, and cancer treatments was used to identify metastatic status. Methods: ICD-10-CM diagnosis codes, clinical lab values specific to cancer testing, and antineoplastic treatments were evaluated from longitudinal data of 128,614 patients who did not progress and 5,884 who did develop metastasis, across 47 tumor types in the Syapse Learning Health Network. Patients metastatic at diagnosis were excluded. Data were included beginning at the time of primary cancer diagnosis and ended for all surviving patients at an established administrative cutoff date. In the metastatic group, visits after the progression event were included but censored if they contained diagnosis codes specifically for secondary malignant neoplasms. A binary classification was developed using a multi-headed attention transformer in order to determine metastatic status. Patient history was sequentially aggregated to visit-level embeddings across their longitudinal record. Categorical layers were used for antineoplastics and diagnosis codes. Linear layers were used to embed lab values, as well as for visit intervals from primary cancer date and administrative cutoff date. All embeddings were used as feature inputs for the classifier. Pre-training random sampling of the non-metastatic population was applied to establish equally-weighted labels in a 80:10:10 split for training, validation, and testing sets; to account for the smaller population of patients who progressed to metastatic status. Results: This classification approach achieved 0.86 PR-AUC, 0.79 ROC-AUC, and 0.75 F1. This performance is comparable to published models trained for single tumor cohort prediction. With our censoring constraints, these model results are robust in the absence of routine signals of metastasis in the EHR, such as staging reports and diagnosis coding for distant metastases. Conclusions: This method generalizes, across multiple cancer types, an accurate classification of metastatic progression from patient visit history. This work is immediately useful for real world evidence data analysis complementing patients with metastases already captured in hospital registries. Using sequential deep learning with EHR data classes, this approach may be used to forecast metastatic progression for early intervention.

Abstract P3-05-10: Disease features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients

Abstract Background: Breast cancer in younger women has been characterized as a more aggressive disease with relatively poor outcomes compared to breast cancer in older women. This pattern has been attributed to a variety of clinicopathologic characteristics including the enrichment of aggressive HER2+ and TNBC subtypes in younger patients. However, similar to older breast cancer patients, the majority of young breast cancer patients are HR+/HER2-. Here we have evaluated the clinicopathologic characteristics and genomic profiles of real-world HR+/HER2- MBC patients to examine the determinants of outcome for younger vs. older patients in this subtype. Patients and Methods: This study included 65 Chinese patients presenting with HR+/HER2- MBC at the Peking University Cancer Hospital. Blood samples were collected upon metastatic disease diagnosis before treatment and profiled with the targeted 152-gene PredicineCARETM sequencing panel. Fourteen patients were < 40 years, 19 were 40-50 years, and 32 were > 50 years at the time of primary cancer diagnosis. Kaplan-Meier survival analysis was performed to analyze outcomes including overall survival (OS), disease free survival (DFS) and progression free survival (PFS) in association with clinicopathologic and genomic variables. OS was also evaluated in association with age in separate multivariate models using Cox proportional hazards regression. Results: Significant variation across age groups was observed for several clinicopathological features, including molecular subtype classification (p = 0.045), de novo Stage IV disease (p = 0.011), type of adjuvant endocrine therapy (p = 5.56E-06), resistance to adjuvant endocrine therapy (p = 0.015) and receipt of adjuvant chemotherapy (p = 0.042). Luminal B status was most frequent in patients < 40 years (92.31%), whereas de novo Stage IV disease was more prevalent in patients > 50 years (37.5%). Aromatase inhibitors (AIs) were administered as adjuvant endocrine therapy (ET) to 73.68% of women > 50 years vs. 16.67% and 0% of women aged 40-50 years and < 40 years, respectively. Resistance to adjuvant ET was observed in 23.08% of patients < 40 years but was not observed in the other age groups. Adjuvant chemotherapy was received by a higher proportion of patients in the 40-50 year age group (94.44%) compared to patients < 40 years (69.23%) and patients > 50 years (60%). No differences in somatic gene alteration frequencies were observed across age groups, menopausal status, germline mutation status or tumor grade. However, a higher frequency of FGFR1 alterations was observed in patients classified as Luminal B vs. A (p = 0.048). Comparison of profiles across women who received adjuvant ET revealed a higher prevalence of FGFR1 (p = 0.012), ATM (p = 0.047) and CCND2 (p = 0.04) alterations in patients treated with AIs vs. SERMS. In addition, a higher frequency of APC alterations was observed in patients with high (≥ 20%) vs. low (< 20%) Ki67 index (p = 0.035). At the univariate level OS was significantly associated with age (p = 0.039). OS was shortest in patients > 50 years, intermediate in patients < 40 years, and longest in patients 40-50 years. Across all patients, shorter OS was also associated with de novo Stage IV disease (p = 0.0001), Luminal B subtype (p = 0.008), adjuvant ET with AIs vs SERMS (p = 0.028) and the presence of an FGFR1 (p = 0.028) or CCND2 (p = 0.033) alteration. In multivariate analyses, OS remained significantly longer for patients aged 40-50 years after adjustment for de novo Stage IV disease, Luminal B subtype and FGFR1 status (all p < 0.05). Conclusions: In this group of real-world HR+/HER2- MBC breast cancer patients, younger age was not associated with worse outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients. Citation Format: Jinhao Wang, Yaxin Liu, Bin Shao, Hang Dong, Tiantian Zheng, Pan Du, Shidong Jia, Bonnie King, Jing Wang, Xiaoran Liu, Huiping Li. Disease features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-10.

Immunotherapy Plus Stereotactic Body Radiation Therapy or Whole-Brain Radiation Therapy in Brain Metastases

Aim: To investigate the association of stereotactic radiation therapy (SRT) or whole-brain radiation therapy (WBRT) plus immunotherapy with the overall survival (OS) of cancer patients with brain metastases (BMs) regardless of the primary cancer. Patients & methods: Patients diagnosed with BMs were identified from the National Cancer Database. Results: A total of 34,286 patients were included. SRT plus immunotherapy was associated with improved OS compared with SRT without immunotherapy (hazard ratio: 0.774; 95% CI: 0.687-0.872; p<0.001), and WBRT plus immunotherapy was associated with improved OS compared with WBRT without immunotherapy (hazard ratio: 0.724; 95% CI;0.673-0.779; p<0.001). Conclusion: SRT plus immunotherapy was associated with improved OS compared with SRT. WBRT plus immunotherapy was associated with improved OS compared with WBRT in cancer patients who hadBMs at the time of primary cancer diagnosis.

Oncologic Outcome after Pulmonary Metastasectomy as Part of Multidisciplinary Treatment in a Tertiary Oncological Center

(1) Background: Pulmonary metastases are encountered in approximately one-third of patients with malignancies, especially from colorectal, lung, breast, and renal cancers, and sarcomas. Pulmonary metastasectomy is the ablative approach of choice, when possible, as part of the multidisciplinary effort to integrate and personalize the oncological treatment. (2) Methods: The study includes 58 consecutive cases of pulmonary metastasectomies, retrospectively analyzed, performed in 12 consecutive months, in which the pathology reports confirmed lung metastases. (3) Results: Most frequent pathological types of metastases were: 14 of colorectal cancer, 10 breast, 8 lung, and 8 sarcomas. At the time of primary cancer diagnosis, 14 patients (24.14%) were in the metastatic stage. The surgical approach was minimally invasive through uniportal VATS (Video-Assisted Thoracic Surgery) in 3/4 of cases (43 patients, 74%). Almost 20% of resections were typical (lobectomy, segmentectomy). Lymphadenectomy was associated in almost 1/2 of patients and lymph node metastases were found in 11.11% of cases. The mortality rate (intraoperative and 90 days postoperative) is zero. The OS after pulmonary metastasectomy is 87% at 18 months, and the estimated OS for cancer is 90% at 5 years. The worst outcome presents the patients with sarcomas and the best outcome-colorectal and lung cancer. The patients with 1 or 2 resected metastases presented 96% survival at 24 months. (4) Conclusions: After pulmonary metastasectomy, survival is favored by the small number of metastases resected (1 or 2), and by the dimension of metastases under 20.5 mm. The non-anatomic (wedge) type of lung resection may present a lower risk of death compared to lobectomy. No statistical significance on survival has the presence of lymphadenectomy, the laterality right/left lung, the upper/lower lobes. In the future, longer follow-up and prospective randomized trials are needed for drawing definitive conclusions.

Clinicopathologic features, genomic profiles and outcomes of younger vs. older Chinese hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer patients.

Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with de novo Stage IV disease (p = 0.002), Luminal B subtype (p = 0.006), high Ki67 index (p = 0.036), resistance to adjuvant endocrine therapy (p = 0.0001) and clinical stage (p = 0.015). Reduced OS was also observed in association with somatic alterations in FGFR1 (p = 0.008), CCND2 (p = 0.012), RB1 (p = 0.029) or TP53 (p = 0.029) genes, but not in association with germline variants. In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients.

Epidemiological trends, prognostic factors, and survival outcomes of synchronous brain metastases from 2015 to 2019: a population-based study.

Brain metastases (BM) constitute a significant cause of oncological mortality. Statistics on the incidence of BM are limited because of the lack of systematic nationwide reporting. We report the incidence of synchronous brain metastases (sBM), defined as BM identified at the time of primary cancer diagnosis from 2015 to 2019 using National Cancer Institute's (NCI's) Surveillance, Epidemiology, and End Results Program database. We identified 1,872,057 patients with malignancies diagnosed between 2015 and 2019 from the SEER 17 Registries database, including 35,986 (1.9%) patients with sBM. Age-adjusted incidence rates were examined using the NCI Joinpoint software. Kaplan-Meier curves and a multivariate Cox regression model were used to investigate survival. The incidence rate of sBM from 2015 to 2019 was 7.1 persons per 100,000. Lung and bronchus cancers had the highest incidence of sBM (5.18 to 5.64 per 100,000), followed by melanoma (0.30 to 0.34 per 100,000) and breast cancers (0.24 to 0.30 per 100,000). In children, renal tumors had the highest sBM incidence. sBM were associated with poorer survival than extracranial metastases only (hazard ratio [HR]: 1.40 [95% CI: 1.39-1.42], P < .001). We observed better survival in white patients relative to nonwhite patients with sBM (HR: 0.91 [95% CI: 0.90-0.94], P < .001). The incidence rate of sBM has remained similar to rates reported over the last 9 years, with the majority associated with primary lung and bronchus cancers. sBM represent a national healthcare burden with tremendous mortality in pediatric and adult populations. This population may benefit from improved screening and treatment strategies.

Socioeconomic Disparities in Brain Metastasis Survival and Treatment: A Population-Based Study

In the present study, we used a validated socioeconomic status (SES) index and population-based registry to identify and quantify the impact of SES on access to treatment and overall survival for patients diagnosed with synchronous brain metastases. The Surveillance, Epidemiology, and End Results database was used to extract all patients between 2010 and 2016 with brain metastases at initial presentation. SES was stratified into tertiles and quintiles using the validated Yost index. Multivariable logistic regressions were used to evaluate the impact of demographic, tumor, and socioeconomic covariates on receipt of radiotherapy and chemotherapy. Kaplan-Meier curves were used to estimate survival. Between 2010 and 2016, 35,595 patients presented with brain metastases at the time of primary cancer diagnosis. Most patients received radiation and/or chemotherapy as part of the initial course of their treatment; 71.6% (n= 25,484) were irradiated while 54.4% (n=19,371) received chemotherapy and 44.9% (n=15,984) received chemoradiation. Patients in the highest Yost tertile and quintile experienced longer overall survival (P < 0.001). Additionally, multivariable logistic regression revealed that the lowest Yost quintile was significantly less likely to receive either radiation (adjusted OR: 0.82; 95% confidence interval: 0.75-0.89; P<0.001) or chemotherapy (adjusted OR: 0.62; 95% confidence interval: 0.58-0.67; P < 0.001). In a large, population-based analysis of brain metastasis patients, we found significant differences in treatment access and mild survival differences along socioeconomic strata. More specifically, patients in lower SES tiers suffered worse outcomes and received radiation and chemotherapy less frequently than patients in higher tiers, even after accounting for other tumor- and demographic-related information.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes

Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Epidemiology of liver metastases

AimsThe objectives of this study were to (1) characterize the epidemiology of liver metastases at the time of primary cancer diagnosis (synchronous liver metastases), (2) characterize the incidence trends of synchronous liver metastases from 2010−2015 and (3) assess survival of patients with synchronous liver metastases. MethodsThe Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015 was queried to obtain cases of patients with liver metastases at the time of primary cancer diagnosis. The primary cancers with an incidence rate of liver metastasis >0.1 are presented in this analysis. ResultsAmong 2.4 million cancer patients, 5.14 % of cancer patients presented with synchronous liver metastases. The most common primary site was breast cancers for younger women (ages 20–50), and colorectal cancers for younger men. As patients get older, a more heterogenous population of the top cancers with liver metastases emerges including esophageal, stomach, small intestine, melanoma, and bladder cancer in addition to the large proportion of lung, pancreatic, and colorectal cancers. The 1-year survival of all patients with liver metastases was 15.1 %, compared to 24.0 % in those with non-hepatic metastases. Regression analysis showed that the presence of liver metastasis was associated with reduced survival, particularly in patients with cancers of the testis, prostate, breast, and anus, and in those with melanoma. ConclusionsThe most common primary sites for patients with liver metastases varied based on age at diagnosis. Survival for patients with liver metastasis was significantly decreased as compared to patients without liver metastasis.

Epidemiology of synchronous brain metastases.

BackgroundThe objectives of this study were to characterize (1) epidemiology of brain metastases at the time of primary cancer diagnosis, (2) incidence and trends of synchronous brain metastases from 2010 to 2015, and (3) overall survival (OS) of patients with synchronous brain metastases.MethodsA total of 42 047 patients with synchronous brain metastases from 2010 to 2015 were identified from the Surveillance, Epidemiology, and End Results database. Descriptive analysis was utilized to analyze demographics and incidence. The Kaplan–Meier method and a Cox proportional hazards model were utilized to evaluate potential prognostic factors for OS.ResultsThe majority of patients were diagnosed from age older than 50 (91.9%). Common primary sites included lung (80%), melanoma (3.8%), breast (3.7%), and kidney/renal pelvis (3.0%). Among pediatric patients, common primaries included kidney/renal pelvis and melanomas. The incidence was roughly 7.3 persons/100 000. Synchronous brain metastases were associated with significantly poorer OS compared to extracranial metastases alone (hazard ratio [HR] =1.56; 95% CI: 1.54–1.58; P < .001). Among patients with brain metastases, male gender (HR = 1.60 vs 1.52), age older than 65 years (HR = 1.60 vs 1.46), synchronous liver, bone, or lung metastases (HR = 1.61 vs 1.49), and earlier year of diagnosis (HR = 0.98 for each year following 2010) were associated with significantly poorer OS.ConclusionsThe vast majority of brain metastases are from lung primaries. Synchronous brain metastases are associated with poorer OS compared to extracranial metastases alone.

Therapy-Related Myeloid Neoplasms with Balanced Chromosome Rearrangements Frequently Arise from Pre-Existing Clonal Haematopoiesis

IntroductionTherapy-related myeloid neoplasms (tMN) are an increasing healthcare problem resulting from rising long-term survival from primary cancers. Approximately 80% of cases are associated with an adverse karyotype and have a dismal prognosis; pre-existing clonal haematopoiesis (CH) appears to be a predisposing factor and mutations in genes including TP53, PPM1D and DNMT3A have been detected prior to chemo- or radiotherapy exposure. In contrast ~20% of tMN are characterised by balanced chromosome rearrangements and have a relatively favourable outcome; chemotherapy agents targeting topoisomerase II have been implicated in generating these rearrangements however the involvement of CH has not previously been described.Methods and resultsWe performed whole exome sequencing (WES) of samples taken at diagnosis (D) and molecular complete remission (mCR) followed by targeted capture and error-corrected deep sequencing (ECS) on ≥2 mCR samples for 11 patients with therapy-related acute promyelocytic leukemia (tAPL) and 20 patients with de novo APL (dnAPL). All patients had t(15;17) / PML-RARA at diagnosis with no additional cytogenetic abnormality.The median age of patients with tAPL was 46.7y (range 30-78); primary cancer types were breast (4), colorectal (2), lymphoma (3), CNS (1) and testicular (1). Ten patients had received chemotherapy and 4 radiotherapy. The median latency between primary cancer treatment and tAPL diagnosis was 3.9y (range 2.2-6.1). Patients received a mixture of chemotherapy- and arsenic-based treatments.The median age of patients with dnAPL was 40.3y (range 18-69); all patients were treated with the AIDA regimen and none developed tMN subsequently.There were no significant differences between the number or type of mutations between dnAPL and tAPL however disease associated somatic mutations were detectable in mCR samples by ECS in 4/11 tAPL samples compared to 0/20 dnAPL samples (p=0.04).Mutations detected in mCR were UPN1: PPM1D exon (e) 6 1bp deletion (del, variant allele fraction, VAF, D 32% mCR 11.3%); UPN2: DNMT3A e8 1bp del (VAF D 40.2% mCR 0.48%); UPN3: DNMT3A e10 1bp del (VAF D 35.4% mCR 2.9%); UPN4: MYCN e3 6bp insertion (ins, VAF D 38% mCR 0.37%).We screened samples from these patients and a further 39 dnAPL patients for a panel of genes with known CH associated mutations (CH-M) using ECS and detected additional mutations in 2 tAPL patients (UPN4, DNMT3A G104R, VAF D 0% mCR 3% and UPN5 DNMT3A R693H VAF D 2% mCR 25%, who subsequently developed tMN with complex karyotype). We did not detect CH-M in diagnostic samples from any patient with dnAPL and publicly available NGS datasets encompassing 220 patients only showed 1 APL case with a CH-M (DNMT3A e8 ins, prior cytotoxic exposure unknown). We detected treatment-emergent CH clones in mCR by ECS in 6/59 dnAPL patients treated with AIDA (DNMT3A n=3, PPM1D n=2, TP53 n=1, SF3B1 n=1).Applying the same techniques to six patients with therapy-related core-binding factor AML, we identified a persistent CH-M in mCR in one (DNMT3A e15 del, VAF D 38%, mCR 11.8%).DNA samples taken at the time of primary cancer diagnosis were available from UPN 1-3. In UPN1 we detected the PPM1D mutation in a lymph node (LN) involved with T-cell lymphoma (LN) (VAF 2.1%) and an uninvolved staging bone marrow (VAF 3.3%). In UPN3 the DNMT3A mutation was detected in a breast biopsy (VAF 0.7%) and LN involved with carcinoma (VAF 0.9%). In UPN2 the DNMT3A mutation was not detected in the LN biopsy diagnostic for Hodgkin lymphoma.We used FACS to isolate T, B, monocyte, granulocyte and CD34+ cells from complete remission samples from UPN1-4 with >99% purity and detected the persistent mutations in each cell compartment e.g. UPN3 VAF: T cell 1.3%, B cell 8.6%, monocyte 4%, granulocyte 3.7%, CD34+ 3.9%.Diagnostic material from UPN1 and 4 was injected into irradiated NSG mice. After 12 weeks we detected multilineage human engraftment in both samples by FACS in 1/3 mice from UPN1 and 2/3 mice from UPN4. We detected the PPM1D and MYCN mutations respectively in bone marrow samples from each engrafting mouse.ConclusionsTogether these findings indicate that tMN with balanced chromosome rearrangements can occur on a background of non-malignant CH. Using ECS we observed this phenomenon in 5/17 (29%) patients with therapy-related APL or CBF AML. This has important implications for planning curative therapy, notably for tAPL where effective cytotoxic-free regimens are available. DisclosuresRussell:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Hills:Daiichi Sankyo: Consultancy, Honoraria.

P2.13-02 ALK-Translocation and Brain Metastases: A Retrospective Study. Correlation Between Clinical Outcome, Disease Burden and Management.

Brain metastases from non-small cell lung cancer is often regarded as the ominous sign of disease progression . In the ALK-translocated population, brain metastases are seen in a higher incidence, either at diagnosis or as a common site of progression for patients receiving tyrosine kinase inhibitors (TKI). The management of brain metastases in this population remains a challenge since several methods of treatment are available. TKI-treatment, especially with second or third generation drugs can be effective but the role of radiation therapy, with either whole brain radiotherapy (wbrt) or stereotactic radiosurgery (srs), has not been fully elucidated. A retrospective study was conducted at ou Institution in order to evaluate the frequency of brain metastases in this subggroup of patients and in order to explore clinical features associated with survival. 88 consecutive patients with advanced ALK+ adenocarcinoma were treated at our institution. During the period 2011-2018. Data on CNS imaging modality, treatment strategy and outcome was collected by chart review. Cns-imaging with either MRI or CT (in 38% and 62% of the cases respectively) was performed in 73 cases. 44 patients (61%) were found to have CNS metastases (Male/female ratio 48/52%; median age 60y). 23% were found at the time of primary cancer diagnosis, 36% on time of PD on chemotherapy, 34% on PD on crizotinib and 7% at PD on 2nd gen ALKinh . 27% of the patients had 1-3 metastases, 34% 4-10 met and 39 % >10. Pharmacological treatments in the group as a whole: chemotherapy (n=38); crizotinib (n=35); alectinib (n=10); ceritinib (n=20); brigatinib (n=3), lorlatinib (n=1). Radiotherapy was administered in 57% as either SRS or WBRT (52/48%) . Treatment strategies upon discover of CNS-metastes: Radiotherapy solely 27%, combination of radiotherapy and pharmacological treatment in 25%, switch to crizotinib and to 2nd gen ALKi in 18 and13 % respectively. Median OS from the diagnosis of CNS metastasis was 29months (95% CI 11-59). 1- and 2-year survival was 61% and 51%, respectively. Neither gender, age, timing for diagnosis of CNS metastases nor the use of radiotherapy were significant prognostic factors for OS (Cox proportional hazard analysis). Use of 2nd gen ALKin as treatment strategy seemed to be superior to crizotinib and radiotherapy alone even if median OS not yet was reached. The high incidence of CNS metastases in this subpopulation of patients (Caucasian with advanced ALK+ NSCLC) was confirmed in this study. The wider implementation of 2nd generation ALKi in clinical practice will probably change the prognosis of these subjects.

Estimating the annual frequency of synchronous brain metastasis in the United States 2010-2013: a population-based study.

Brain metastases (BM) are one of the most common types of brain tumors and are a relatively common event in the disease process for several high-incidence cancer types, including breast and lung cancers. Historically, information on metastases including BM have not been collected as part of national cancer registration in the US, but BM at time of primary cancer diagnosis (SBM), is now collected by the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) system. Using data from 18 SEER registries from 2010 to 2013, we assessed the frequency of SBM at time of primary diagnosis in the US by site, histology group, sex, race, age, and insurance status. There were 1,634,954 total primary cancer cases in SEER from 2010 to 2013, 1.7% of which presented with SBM. The cancer type with the highest proportion of SBM was lung cancer (10.8% of cases with SBM), followed by esophageal (1.5%), kidney (1.4%), and melanoma (1.2%). SBM varied by age, sex, race, and insurance status for most histologies. Our results reflect the high proportion of patients who are diagnosed with lung cancer at late stages and present with SBM, in contrast to other common cancers in the US where SBM is less common. Demographic variation in molecular subtype and risk behavior may influence variation in SBM. BM is a relatively common event in late stage cancer and cause significant morbidity and mortality, and assessment of accurate population-based data is critical to estimate total disease burden.

Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study

BackgroundTherapy-related myeloid neoplasms (t-MNs) are often fatal secondary malignancies. Risk factors for t-MNs are not well understood. Recent studies suggested that individuals with clonal hematopoiesis have higher risk of developing hematological malignancies. We hypothesized that cancer patients with clonal hematopoiesis have increased risk of developing t-MNs.MethodsWe conducted a retrospective case-control study to compare the prevalence of clonal hematopoiesis between patients who developed t-MNs (cases) and who did not develop t-MNs (control). For cases, we studied14 patients with various types of cancers who developed t-MNs and whose paired samples of t-MN bone marrow (BM) and peripheral blood (PB) that were previously obtained at the time of primary cancer diagnosis were available. Fifty four patients with lymphoma who received combination chemotherapy and did not develop t-MNs after at least 5 years of follow up were studied as a control. We performed molecular barcode sequencing of 32 genes on the pre-treatment PB samples to detect clonal hematopoiesis. For the t-MN cases, we also performed targeted gene sequencing on t-MN BM samples and investigated clonal evolution from clonal hematopoiesis to t-MNs. To confirm association between clonal hematopoiesis and t-MN development, we also analyzed prevalence of clonal hematopoiesis in a separate cohort of 74 patients with lymphoma. All of these patients were treated under the prospective randomized trial of frontline chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without melatonin and 5 (7%) of them had developed t-MNs.FindingsIn 14 patients with t-MNs, we detected pre-leukemic mutations in 10 of their prior PB samples (71%). In control, clonal hematopoiesis was detected in 17 patients (31%), and the cumulative incidence of t-MNs at 5 years was significantly higher in patients with clonal hematopoiesis (30% [95% CI: 16% – 51%] vs. 7% [95% CI: 2% – 21%], P = 0.016). In the separate cohort, 5 patients (7%) developed t-MNs and 4 (80%) of them had clonal hematopoiesis. The cumulative incidence of t-MNs at 10 years was significantly higher in patients with clonal hematopoiesis (29% [95% CI: 8%–53%] vs. 0% [95% CI: 0%–0%], P = 0.0009). Multivariate Fine and Gray model showed that having clonal hematopoiesis significantly increased the risk of t-MN development (HR = 13.7, P = 0.013).InterpretationPre-leukemic clonal hematopoiesis is frequently detected in patients with t-MNs at the time of their primary cancer diagnosis and before patients were exposed to chemotherapy/radiation therapy. Detection of clonal hematopoiesis significantly increased the risk of t-MN development in patients with lymphoma. These data suggest potential approaches of screening clonal hematopoiesis in cancer patients to identify patients at risk of t-MNs and warrants a validation in prospective trial investigating a role of clonal hematopoiesis as a predictive marker for t-MNs.

Clonal Hematopoiesis Increases Risk of Therapy-Related Myeloid Neoplasms

IntroductionTherapy-related myeloid neoplasms (t-MNs) are often fatal secondary malignancies. There is no predictive biomarker for t-MNs. Recent studies suggested that individuals with clonal hematopoiesis have higher risk of developing leukemia. We hypothesized that cancer patients with clonal hematopoiesis have increased risk of developing t-MNs.MethodsWe studied 14 patients with t-MNs who had paired samples of t-MN bone marrow (BM) and peripheral blood (PB) that were previously obtained at the time of primary cancer diagnosis and before therapy. We performed targeted capture sequencing (median depth 245x) on t-MN BM and detected driver mutations. Then we performed molecular barcode deep sequencing (median 1,606x) on the prior PB samples to detect pre-leukemic driver mutations. Using the same method, we detected clonal hematopoiesis in the pre-treatment PB samples from 54 patients with lymphoma who did not develop t-MNs (control cohort). We further validated association between clonal hematopoiesis and t-MNs in a separate cohort of 74 patients with lymphoma.ResultsTargeted capture sequencing of the 14 t-MN BM samples revealed 29 driver mutations in 16 genes. TP53 mutations were detected in 5 patients (36%). The median variant allele frequency (VAF) of the mutations was 26.2% (range: 8.8% - 97.2%). Among the 29 driver mutations detected in t-MN BM samples, 21 mutations (72%) were detectable as pre-leukemic clonal hematopoiesis in 10 patients’ prior PB samples (71%). The median VAF of the clonal hematopoiesis was 8.5% (range: 0.7-36.9%). There were also 12 mutations in prior PB samples that did not become drivers in t-MN BM. The VAF was significantly higher in the mutations that became drivers than in the mutations that did not become drivers (8.5% [range: 0.7-36.9%] vs. 1.2% [range: 0.1-7.6%], P < 0.001).The control cohort included 54 patients with lymphoma who did not develop t-MNs after therapy. Using the same molecular barcode sequencing, we detected 22 mutations in 17 (31%) patients' pre-treatment PB samples. Compared to the 14 t-MN cases, patients who developed t-MNs had significantly higher incidence of clonal hematopoiesis at the time of cancer diagnosis (71% vs. 31%, P = 0.008). The rate of t-MN development at 5 years was significantly higher in patients with clonal hematopoiesis than in patients without (30% [95% CI: 16-51%] vs. 7% [95% CI: 2-21%], P = 0.015). The median VAF of the mutations detected as clonal hematopoiesis was significantly higher in the t-MN cases than in the control (2.4% [range: 0.1-37%] vs. 0.8% [range: 0.3-1.8%], P = 0.001).The validation cohort included 74 patients with lymphoma who received frontline CHOP-based regimen. Median age was 56 years (range: 17-83 years) and 35 (47%) and 16 (22%) patients received radiation therapy and autologous stem cell transplant (auto-SCT), respectively. During the median follow up duration of 14.8 years (95% CI: 14.5-15.1 years), 5 patients (7%) developed t-MNs with the median 5.4 years latency (range: 1.5-12.8 years). Molecular barcode sequencing of pre-treatment PB samples detected total 17 mutations as clonal hematopoiesis in 15 patients (23%). Clonal hematopoiesis was detected in 4 of 5 patients (80%) who developed t-MNs, while it was detected in 11 of 69 patients (16%) who did not develop t-MNs (P = 0.005). The positive predictive value and negative predictive value of clonal hematopoiesis were 26.7% (95% CI: 7.8-55.1%) and 98.3% (95% CI: 90.9-99.9%), respectively. The rate of t-MN development at 10 years was significantly higher in patients with clonal hematopoiesis than in patients without (29% [95% CI: 12-59%] vs. 0% [95% CI: 0-0%], P = 0.001). Multivariate Cox model revealed that clonal hematopoiesis and auto-SCT significantly increased the risk of t-MNs (clonal hematopoiesis: HR 12.0 [95% CI: 1.3-108.7], P = 0.027 and auto-SCT: HR 10.5 [95% CI: 1.2-95.1], P = 0.037).ConclusionPre-leukemic clonal hematopoiesis was frequently detected in patients with t-MNs at the time of primary cancer diagnosis and before exposure to therapy. Detection of clonal hematopoiesis significantly increased the risk of t-MN development in both case-control and validation study. These data suggest potential approaches of screening clonal hematopoiesis in cancer patients to identify patients at risk of t-MN development and warrants a validation in prospective trial investigating a role of clonal hematopoiesis as a predictive marker for t-MNs. DisclosuresDiNardo:Abbvie: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Samaniego:Karus Therapuetics: Research Funding.

Abstract 5033: Clonal origin of therapy-related myeloid neoplasms

Abstract Background: Therapy-related myeloid neoplasms (t-MNs) are secondary malignancies that develop in patients (pts) treated with chemo-radiation therapy (CRT). Patient-related risk factors for t-MN susceptibility is unknown. Recent studies reported that canonical hematological driver mutations (DMs) could be detected in peripheral blood (PB) from healthy individuals or pts with solid tumors, a phenomenon referred to as clonal hematopoiesis of indeterminate potential (CHIP). We hypothesized that there are canonical DMs likely important in t-MNs that pre-exist as detectable CHIP in pts at time of diagnosis of their original cancer. Methods: We sequenced 300 leukemia-relevant genes on diagnostic bone marrow (BM) samples from 13 t-MN pts to detect DMs. We then assessed the presence of the same DMs in the pts’ matched PB samples, which were obtained after primary cancer diagnosis but before CRT. Results: Four pts (31%) had t-AML and 9 (69%) had t-MDS. The median age at primary cancer diagnosis and t-MN diagnosis was 62 years (y) (range: 25-74 y) and 66 y (range: 28-77 y), respectively. The median latency time to t-MN development was 3 y (range: 1-8 y). Targeted gene sequencing revealed 17 canonical DMs in 8 genes. At least one clonal DM was detected in each pt. The most frequently detected mutation was TP53 mutations in 4 patients (31%), followed by DNMT3A (N = 3, 23%), IDH2 (N = 2, 15%), TET2 (N = 2, 15%), and RUNX1 mutations in 2 (15%). Analysis of deep sequencing PB sample revealed that DMs identical to those detected in t-MN BM were detected in 7 of 13 pts (54%). For example, Case UID6982 had small cell lung cancer and received concurrent CRT with carboplatin and etoposide. He developed t-AML 3 y later and was found to have an IDH2 p. R140Q mutation in the diagnostic BM with a VAF of 40%. His PB obtained before CRT showed the same IDH2 p.R140Q mutation with a VAF of 14%. The most common DM detected in paired PB samples was TP53 mutation in 3 cases, followed by DNMT3A, TET2, IDH2, and RUNX1 mutation in 1 case each. Of note, DMs that were subclonal in t-MN BM were not detected in the PB at the time of primary cancer diagnosis. The median VAF of the detected variants in the paired PB samples was 6% (range: 0.6-27%). We found no significant differences between pts with and pts without evidence of CHIP in terms of median age at primary cancer diagnosis or median latency time to t-MN development. Conclusion: In this study we have demonstrated evidence of detectable mutations in multiple canonical leukemia driver genes at time of diagnosis and before therapy of primary cancer in pts whose subsequent t-MN also harbored identical DMs. This work suggests that a substantial fraction of t-MN pts likely exhibit CHIP with detectable canonical mutations in a number of leukemia driver genes at time of diagnosis for their primary cancer. Further, these data suggest the potential to develop a risk stratification model based on presence of CHIP with canonical DMs at the time of primary cancer diagnosis. Citation Format: Koichi Takahashi, Feng Wang, Hagop Kantarjian, Doss Denaha, Erika Thompson, Curtis Gumbs, Keyur Patel, Sattva Neelapu, Yan Wang, Zachary Bohannan, Courtney DiNardo, Farhad Ravandi, Zeev Estrov, Simona Colla, Jianhua Zhang, Xifeng Wu, Guillermo Garcia-Manero, Andrew Futreal. Clonal origin of therapy-related myeloid neoplasms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5033.

Clinical Characteristics of Pancreatic Metastases

Histologically confirmed metastatic pancreatic cancers are infrequent. The aim of this study was to analyze clinical, therapeutic and prognostic features of pancreatic metastases. We retrospectively evaluated stage of primary malignancies, interval between diagnosis of primary tumors and detection of pancreatic metastases, treatment for metastases to the pancreas, survival rate, and prognostic factors in 31 patients with pancreatic metastases. The mean age at the time of primary cancer diagnosis was 52.4 ± 13.2 years. Primary cancers were renal cell carcinoma (n=16), non-small cell lung cancer (n=6), small cell lung cancer (n=3), colorectal carcinoma (n=2), osteosarcoma (n=1), gastric carcinoma (n=1), malignant melanoma (n=1), and thymic carcinoma (n=1). Pancreatic metastases were synchronous in six cases and metachronous in twenty five cases, with median interval time of 40.8 months (range 3-186) between the diagnosis of primary tumor and detection of pancreatic metastases. The median survival after the detection of the metastases was 16 months. In multivariate analysis, non-renal cell carcinoma as primary malignancy and positive symptom related to pancreatic metastases were associated with poor prognosis (hazard ratio [HR], 8.33; 95% CI, 2.1-33; p=0.003, and HR, 4.02; 95% CI, 1.27-12.7; p=0.018). Metastatic tumors to the pancreas have to be kept in mind when a patient with pancreatic mass has a history of other malignancy, even if treated several years before. In the absence of widely metastatic disease, aggressive diagnostic and therapeutic approach may offer the chance of long-term survival in selected patients.

Effectiveness and prognosis of initial pericardiocentesis in the primary management of malignant pericardial effusion

We retrospectively reviewed the records of 100 patients with malignant disease and symptomatic pericardial effusion initially treated with pericardiocentesis at the National Cancer Institute of Mexico between 1985 and 2009. We analyzed predictive factors for recurrence of pericardial effusion by bi- and multivariate analyses. The group comprised 74 women and 26 men. Twenty patients had developed malignant pericardial effusion at the time of primary cancer diagnosis. Recurrence rate after pericardiocentesis was 33%. Progression-free survival for pericardial effusion at one year was 59% (range, 47-71%). Median overall survival (OS) after pericardiocentesis was 40.3+/-7.9 weeks (95% Confidence interval, 24.9-55.7). The sole factor that correlated with increased progression-free survival for pericardial effusion was the presence of bloody pericardial effusion. For OS, multivariate analysis yielded that female gender and presence of pericardial effusion at time of primary malignancy diagnosis were associated with higher life expectancy. Initial pericardiocentesis can provide successful management of patients with a control rate of 67%. In spite of the high effectiveness of the primary management of pericardial effusion with pericardiocentesis in oncologic patients, it might be considered for initial treatment, especially those with poor prognosis, leaving pericardial window as a secondary strategy for recurrence.