Treatment Of Primary Malignancies Research Articles

Treatment Options in Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP): Case Presentation and Review of the Literature

ABSTRACT Purpose To outline the therapeutic approach for a rare case of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) and examine the current management recommendations of this uncommon condition. Methods-Results Literature review on the current treatment options in BDUMP cases. An 82-year-old woman was referred to our clinic due to bilateral visual loss. She was treated elsewhere with anti-vascular endothelial growth factors (anti-VEGF) in both eyes for presumed choroidal neovascularization (CNV) without improvement. Her past medical history (PMH) entailed colon cancer, treated with surgical resection and adjuvant chemotherapy 15 years ago. The patient presented with low visual acuity in both eyes, multiple oval orange patches in the fundus with striking hyperfluorescent pattern in fluorescein angiography (FA), giraffe pattern in fundus autofluorescence (FAF) and rapidly progressive cataracts. Intravitreal dexamethasone implants were administered with mild improvement and subretinal fluid absorption. Conclusions The management strategy in BDUMP should focus on the systemic, often occult malignancy. There is no standard treatment protocol for BDUMP; however, plasmapheresis in combination with primary malignancy treatment seems to yield promising results in current literature reports. Anti-VEGF injections failed to control BDUMP sequelae, however intravitreal dexamethasone implants may offer temporary relief.

7639 A Rare Cause of Lung Adenocarcinoma with Metastasis to the Thyroid

Abstract Disclosure: E. Echevarria-Torres: None. C.G. Yap: None. K.E. Izuora: None. A rare cause of lung adenocarcinoma with metastasis to the thyroid. Metastasis to the thyroid gland from non-thyroid malignancies is rare. When metastasis occurs, presenting symptoms are typically nonspecific, representing a diagnostic challenge. With the goal of raising awareness, we present a case of lung adenocarcinoma with metastasis to the thyroid. An 85-year-old man with a history of hypertension, hyperlipidemia and 60 years smoking history presented to the endocrine clinic for evaluation of subclinical hyperthyroidism. On the physical exam, there was fullness in the right thyroid area which on ultrasound showing a large right thyroid nodule occupying the entire lobe. There was also a solid 4.5 cm x 3.4 cm x 4.6 cm nodule in the mid-anterior left thyroid lobe. Fine needle aspiration cytology of right nodule revealed malignant cells and cell block material positive for TTF-1 (Thyroid Transcription Factor 1) concerning for malignancy. The left thyroid nodule cytology was consistent with benign follicular nodule. Chest CT ordered for surgical planning showed right upper lobe pleural-based lung opacity measuring 3.7 cm x 2.9 cm with supra clavicular lymphadenopathy. Biopsy of lung mass and supra clavicular lymph nodes revealed primary lung adenocarcinoma involving the lymph nodes consistent with stage Iva (cT3NxM1b). The patient was referred to oncology for further management. Discussion: Metastatic lesions to the thyroid gland account for less than 1 % of all malignant thyroid tumors with most cases found on autopsy. This is hypothesized to be due to the rich blood supply and high iodine content of the thyroid gland. Thyroid metastasis usually presents several years after initial diagnosis and treatment of non- thyroid malignancy. Patients can present with enlarging thyroid nodules, neck swelling, dysphagia and, in rare instances, upper airway obstruction. We present a rare case of lung cancer with metastasis into the thyroid. The thyroid nodule initially palpated upon physical exam led to eventual thyroid ultrasound and subsequently to his diagnosis of lung adenocarcinoma after findings of lung nodule which was biopsied and showed primary lung adenocarcinoma. TTF-1 was also positive which is typically expressed by lung adenocarcinomas. Treatment for thyroid metastasis is surgery, along with treatment of primary malignancy. The earlier the diagnosis and treatment the more favorable the prognosis. Radiotherapy and chemotherapy are other means to reduce the recurrence. Thyroid hormone replacement will be warranted post operatively for hypothyroidism. We present this uncommon case to raise awareness about the presentation of thyroid metastasis to enhance timely diagnosis and intervention. Presentation: 6/1/2024

Clinical outcome of therapy-related acute myeloid leukemia patients. Real-life experience in a University Hospital and a Cancer Center in France.

t-AML occurs after a primary malignancy treatment and retains a poor prognosis. To determine the impact of primary malignancies, therapeutic strategies, and prognostic factors on clinical outcomes of t-AML. A total of 112 adult patients were included in this study. Fifty-Five patients received intensive chemotherapy (IC), 33 non-IC, and 24 best supportive care. At t-AML diagnosis, 42% and 44% of patients presented an unfavorable karyotype and unfavorable 2010 ELN risk profile, respectively. Among treated patients (n = 88), 43 (49%) achieved complete remission: four out of 33 (12%) and 39 out of 55 (71%) in non-IC and IC groups, respectively. With a median follow-up of 5.5 months, the median overall survival (OS) and disease-free survival (DFS) for the whole population were 9 months and 6.3 months, respectively, and for the 88 treated patients 13.5 months and 8.2 months, respectively. Univariate analysis on OS and DFS showed a significant impact of high white blood cells (WBC) and blast counts at diagnosis, unfavorable karyotype and ELN classification. Multivariate analysis showed a negative impact of WBC count at diagnosis and a positive impact of chemotherapy on OS and DFS in the whole population. It also showed a negative impact of previous auto-HCT and high WBC count on OS and DFS and of IC on OS in treated patients which disappeared when we considered only confounding variables (age, previous cancers, marrow blasts, and 2010 ELN classification). In a pair-matched analysis comparing IC treated t-AML with de novo AML, there was no difference of OS and DFS between the two populations. We showed, in this study that t-AML patients with unfavorable features represented almost half of the population. Best outcomes obtained in patients receiving IC must be balanced by known confounding variables and should be improved by using new innovative agents and therapeutic strategies.

Therapy-Related Cytopenia of Undetermined Significance (t-CCUS) As a Precursor to Therapy-Related Myeloid Neoplasms (t-MN)

BackgroundClonal cytopenia of undetermined significance (CCUS) is a risk factor for development of myeloid neoplasms (MN) such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Therapy-related myeloid neoplasm (t-MN) is defined as the development of a MN in the context of prior DNA damaging therapies including chemotherapy, radiation, and immunosuppressive therapies. CCUS diagnosed in the setting of prior DNA damaging therapy (t-CCUS) and its outcomes are not known. The aim of this study was to study clinicopathological features and outcome of t-CCUS and compare it with t-MN.MethodsPatients who had received DNA-damaging therapy and subsequently determined to have CCUS or t-MN were identified. The diagnosis of CCUS was made if the patient had non-diagnostic bone marrow biopsy evaluation combined with evidence of pathogenic myeloid somatic genetic alterations using conventional cytogenetics or next generation sequencing (NGS) panel. Pathogenic/likely pathogenic variants (PV) were stratified by DTA (DNMT3A, TET2, and ASXL1) genes vs. others. Event-free survival (EFS) was calculated using interval from t-CCUS to t-MN with death as a competing risk. Overall survival (OS) for t-CCUS and t-MN patients was calculated using interval from t-CCUS or t-MN diagnoses respectively to the last follow up. Statistical analysis was performed using JMP (v14.1, SAS Institute).ResultsWe identified 30 patients with t-CCUS and 259 patients with t-MN. Eleven (37%) t-CCUS patients developed t-MN and were included in both cohorts (Fig. A). Clinical characteristics of t-CCUS patients are shown in Table 1. Briefly, age (median, interquartile range or IQR) at the diagnosis of primary malignancy and t-CCUS was not different between those who developed t-MN and those did not (P=0.09 and 0.378 respectively). There was no difference in hemoglobin, white blood cells, or ANC between the two groups. Patients who developed t-MN had a significantly lower platelet count (68 vs. 130, P<0.01) and higher bone marrow blast percent (2 vs. 0, P=0.04) compared to those who did not.At t-CCUS diagnosis, cytogenetics was abnormal in 11 (37%) patients and none had complex karyotype (CK). Paired cytogenetic analysis at t-CCUS and t-MN was available for 10 patients: 4 had unchanged karyotype at t-MN, whereas 6 had cytogenetic evolution. In contrast, 213 (83%) of 256 t-MN patients with available cytogenetics had abnormalities and 126/256 (49%) had CK. Thus, a significantly higher proportion of patients had CK t-MN compared to t-CCUS (χ 2 26.4, P<0.01).A 42-gene NGS panel identified 36 PV in 21 patients (median 1, range 1-4) at t-CCUS. The most common PV were in TET2 (37.1%), TP53 (11.4%), DNMT3A (8.6%), and ZRSR2 (8.6%) genes. Two patients had paired NGS available at t-CCUS and t-MN: one had BCOR and U2AF1 PV at t-CCUS and acquired an additional NRAS PV at t-MN. The second patient had 2 PV in TP53 at t-CCUS diagnosis, that remained the only PV identified at t-MN. In the t-MN cohort, median number of PV was 2 (range 1-9). The most common PV identified were TP53 (21.5%), TET2 (6.7%), DNMT3A (6.4%), and ASXL1 (6.4%), whereas 4.8% patients had no PV. Three of 22 patients in the t-CCUS cohort had TP53mut, compared to 55 of 157 in the t-MN cohort (χ 2 4, P=0.05).Management strategies for t-CCUS included observation (20), growth factors (4), treatment of primary malignancy (2), immunosuppressives (1), hypomethylating agent followed by allogeneic SCT (1), and others (2). Following t-CCUS, 9 patients progressed to MDS and 2 to AML with a median of 3.5 months (IQR 1.7-43.4). EFS was 43.4 months (IQR 6.8-80.9). The presence of abnormal cytogenetics (Fig. B) and the absence of DTA-mutations (Fig. C) predicted shorter EFS.At last follow up, 12 (40%) deaths were noted. Four (33%) patients died without developing t-MN. Causes of death in the t-CCUS cohort were: t-MN (3), primary malignancy (1), progressive cytopenia without MN (1), infection (1), graft-vs.-host-disease (1), and undetermined (5). t-MN patients had a significantly shorter survival compared to t-CCUS (Fig. D).ConclusionMore than 10% of t-MN patients had a precursor t-CCUS. On the other hand, t-CCUS patients are at a high risk of progression to MN. t-MN is characterized by the acquisition of TP53mut, genomic instability, and a significantly shorter survival compared to t-CCUS. The presence of abnormal cytogenetics and the absence of DTA mutations at t-CCUS predict shorter EFS. [Display omitted] DisclosuresLitzow: Omeros: Other: Advisory Board; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Actinium: Research Funding; Biosight: Other: Data monitoring committee. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

STIFF PERSON SYNDROME (SPS) THE IMPORTANCE OF EXTENSIVE PHYSICAL EXAMINATION

Stiff Person Syndrome (SPS) is a rare condition with a prevalence of one to two cases per million and an incidence of one case per year. Characterized by progressive muscle stiffening, rigidity and spasm, mainly involve the axial muscles, resulting in severely impaired ambulation. The pathogenesis is not that clear. Classic SPS presents with extreme and persistent rigidity and stiffness of truncal and proximal limb muscles, significant lumber/cervical lordosis resulting from simultaneous actions of opposing paraspinous muscles are the hallmark. Wide and unsteady gait (Frankenstein’s gait) resulting from stiff muscles increases the risk of fall and fracture. Patient’s ADLs get severely restricted progressively. Startle reflex which is a superimposed episodic muscle spasm precipitated by sudden movement, noise, or emotional upset is a sensitive and specific feature of SPS and can be visible and palpable. Autonomic dysfunctions are common and are common cause of death in patients with SPS. In cases of partial SPS, we can find that truncal muscles are spared and limb muscles are affected, hence the term stiff-limb syndrome is used sometimes. Can involve a limb or focal part of a limb. As for treatment, symptom control and improving mobility and overall functionality is the primary target. High dose benzodiazepine is the best initial treatment. Those who are refractory can be benefit from Baclofen, IVIG, Plasma exchange, biological agent, e.g. Rituximab. Treatment of primary malignancies in paraneoplastic SPS can achieve remission. Keywords: Stiff Person Syndrome, clinical features, diagnosis and treatment.

Genetic Pathway in the Pathogenesis of Therapy-Related Myeloid Neoplasms: A Literature Review.

Therapy-related myeloid neoplasms are a life-threatening and often fatal complication, associated with poor prognosis outcomes and with high-risk unfavorable cytogenetic abnormalities including complex karyotype. They occur after the treatment of primary malignancies using chemotherapy and/or radiation therapy. Such therapy is not specific to cancer cells, and also damages the deoxyribonucleic acid (DNA) of normal cells, resulting in unbalanced and balanced translocations. There are eight genetic pathways, whose details are summarized in this review, depending on the cytogenetic abnormalities induced. This abnormality is the major contributor to the development of therapy-related myeloid neoplasms. The etiology of these neoplasms depends on the complex interaction between the nature and dose of the cytotoxic agent, the environment, and the presence of subsequent inherited mutations. This review aims to elaborate upon recent knowledge regarding the etiology, pathogenesis, and genetic pathways of therapy-related myeloid neoplasms. A deeper understanding of their etiology would aid physicians in more careful monitoring of patients during or after cytotoxic therapy for hematological malignancy. Ultimately, this knowledge could influence initial treatment strategies, with the aim of reducing both the incidence and serious complications of neoplasms. Therefore, early detection of DNA lesions is vital. The authors recommend that primary malignancy be treated with targeted therapy.

Geographic and Patient Characteristics Associated With Election of Prophylactic Mastectomy in Young Breast Cancer Patients With Early Disease.

To examine the association between geography and utilization rates of contralateral prophylactic mastectomy (CPM) relative to patient-level factors in patients with early stage breast cancer. Using the Truven Health MarketScan Commercial Database, a descriptive analysis of geographic variation in genetic testing and CPM rates of 38,108 women ages 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012 was conducted. Multivariate hierarchical analysis was used to examine the relationship between CPM likelihood and patient characteristics, with metropolitan statistical area (MSA) serving as a random effect. Patient characteristics included age group, BRCA1/2 carrier status, family history of breast cancer, breast surgery type, radiation therapy, drug therapy, and payer type. All MSAs in the United States were included, with areas outside MSAs within a given state aggregated into a single area for analytical purposes. Descriptive analysis demonstrated significant geographic variation in rates of CPM irrespective of risk inferred from primary malignancy treatment course (P<0.01 to <0.001). Odds of CPM were higher among BRCA1/2 carriers (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.52-2.06), followed by MSA (median OR among all MSAs was 1.61; 95% CI, 1.51-1.73) and family history of breast cancer (OR, 1.49; 95% CI, 1.28-1.53), respectively. Patients who were not tested for BRCA1/2 were less likely (OR, 0.66; 95% CI, 0.61-0.71) to undergo CPM than patients with a negative BRCA test. The large geographic variation we observed in CPM indicate a need to understand and optimize clinical decision-making.

P2.10-004 Efficacy and Safety of Viscum Album (Helixor M) to Treat Malignant Pleural Effusion in Patients with Advanced Lung Cancer

Lung cancer, the most common metastatic tumor to the pleura, accounts for approximately 40% of all malignant pleural effusion (MPE). Regarding symptomatic MPE, local therapies including pleurodesis and treatment of primary malignancy are required to alleviate dyspnea and/or pleuritic pain. Helixor-M made from European mistletoe (Viscum album) has been used as adjuvant anticancer treatment by boosting immune system. We have used Helixor-M as sclerosing agent for pleurodesis to control MPE. The aim of this study is to evaluate efficacy and safety of Helixor-M to control MPE.

A case of membranous glomerulopathy associated with lung cancer and review of the literature.

Membraneous nephropathy (MN) is the most commonly occurring nephrotic syndrome in adults as well as the most common paraneoplastic nephropathy associated with solid tumors, and it is mostly associated with gastrointestinal system and lung carcinomas. Accurate diagnosis is important as the treatment of paraneoplastic glomerulonephritis is very varied from that of idiopathic ones. In the current report, a case of a patient that was referred with proteinuria and edema and was diagnosed with lung cancer, and responded markedly to treatment of malignancy, with improvement of MN, is presented. Active cancer is present in all patients with paraneoplastic MN. In numerous patients, the paraneoplastic MN and cancer diagnoses are made within one year of each other. The treatment of paraneoplastic syndromes is usually associated with the treatment of primary malignancy. There are conflicting data on which treatment modality is more suitable. In conclusion, further studies are required in order to determine the actual incidence of cancer in patients with nephropathy, explain the physiopathological association between cancer and nephropathy and to determine the most suitable treatment approaches.

Mutation Profiling of Therapy-Related Myeloid Neoplasms Using Next-Generation Sequencing Demonstrates Distinct Profiles from De Novo Disease

Therapy-related Myeloid Neoplasms (tMN) comprise a poor risk subset of myelodysplastic syndromes and acute myelogenous leukemia, are increasing in incidence, and represent a serious complication following treatment for primary malignancies. In our previous study of 11 genes in 38 tMN patient samples, the data suggested that the mutational spectrum of tMN was distinct from de novo myeloid malignancies. To confirm this finding and to refine the tMN mutation profile, we investigated the mutation profile in samples from 88 patients and 28 genes using Sanger and next-generation sequencing approaches. We performed amplification using RainDance microfluidic PCR, followed by HiSeq next-generation sequencing. Mutations were identified using a modified pipeline for SNP calling employing variant detection software programs.Our study cohort included 88 patients, 71 of whom had complete clinical data for analyses. Patients had a history of epithelial and hematologic malignancies (³2 malignancies n=11; breast n=9; colorectal n=5; head and neck n=4; genital-urinary n=6; lung n=1; lymphoma n=25; melanoma n=2; ovarian n=1; sarcoma n=2; other, n=5). Treatment of primary cancers included chemotherapy alone (n=27), radiation alone (n=8), autologous stem cell transplant (n=11), or chemotherapy plus radiation (n=25). The median latency time between primary malignancy treatment and tMN diagnosis was 5.7yrs (range, 0.7 - 30.9 yrs). Median age at tMN diagnosis was 64yrs (range, 26 - 85 yrs). International Prognostic Scoring System (IPSS) risk group for MDS at tMN diagnosis were Low risk (n=8), Int-1 (n=11), Int-2 (n=30), High risk (n=9).We identified somatic mutations in 56 of 88 (64%) patients (83 patients were evaluated by next-generation sequencing and 5 by Sanger sequencing only). Mutations in TP53 were most common and were detected in 27/88 patients (30.7%), followed by mutations in TET2 in 12/88 (13.6%), DNMT3A in 9/88 (10.2%), NRAS in 8/83 (9.6%), KRAS in 5/83 (6.0%), and KIT in 5/83 (6.0%). Gene mutations detected at lower frequencies included those in ASXL1 in 5/88 (5.7%), RUNX1 in 2/83 (2.4%), EZH2 in 1/88 (1.1%), and SF3B1 in 1/88 (1.1%). Of the 58 patients with complete sequencing and FISH data, 4 patients exhibited biallelic somatic TP53 mutations and 3 patients had TP53 mutation combined with del 17p TP53 loss, demonstrating that 7 of 58 evaluable patients (12.1%) experienced biallelic loss of TP53. We also identified biallelic mutations in TET2 and DNMT3A in 2 separate patients. 25 patients had 2 or more concurrent somatic mutations. The highest number of co-occurring mutations in one patient was 5 mutations; 12 patients had 2 somatic mutations. The most common co-occurrence was TP53 and TET2, which was observed in 5 patients. All 5 ASXL1 mutations co-occurred with additional mutations.By analyzing variant allele frequencies (VAFs) in patients with multiple mutations, we observed that some tMN patients harbored multiple clones with distinct VAFs. This observation was also supported by the co-occurrence of typical class I driver mutations in the same patient, (e.g. KRAS 6% and NRAS 21% VAF; NRAS 9% and KIT 34%; NRAS 26% and KIT 9% in individual patients). The allele frequency data also suggested that ASXL1 is likely an early occurring mutation as the VAF was higher than for other co-occurring mutations (mean VAF ASXL1 50%, other co-occurring genes 23.5%, p<.05 t-test).Because of previous reports on the prognostic significance of point mutations in myeloid malignancies (e.g. TP53 in MDS and TET2 in AML), we tested the impact of individual mutations on prognosis. TP53 mutation or loss was associated with worse prognosis in tMN (OS 17.6 vs 25.2 mos, n=72, p<.11 log-rank test) (Fig A). TET2 mutation and KRAS or NRAS mutations did not predict for a difference in prognosis, although analysis was limited by cohort size. TP53 mutation was also associated with del 5q / monosomy 5 (p<.0001, Chi-square test, n=51).Our data reveal that tMNs display distinct mutation profile compared to de novo disease (Fig B). TP53 mutations and loss are the most common abnormalities and predict for adverse outcome. Epigenetic modifier mutations also occur in tMNs and can serve as disease-initiating mutations. Collectively our results demonstrate that characterizing these mutation profiles can enhance our understanding of disease mechanisms in tMNs and may guide the development of future therapies for these difficult to treat disorders. [Display omitted] DisclosuresSekeres:Celgene Corp.: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity’s Board of Directors or advisory committees.

Update on the prevention of local recurrence and peritoneal metastases in patients with colorectal cancer.

The prevention of a disease process has always been superior to the treatment of the same disease throughout the history of medicine and surgery. Local recurrence and peritoneal metastases occur in approximately 8% of colon cancer patients and 25% of rectal cancer patients and should be prevented. Strategies to prevent colon or rectal cancer local recurrence and peritoneal metastases include cytoreductive surgery and hyperthermic perioperative chemotherapy (HIPEC). These strategies can be used at the time of primary colon or rectal cancer resection if the HIPEC is available. At institutions where HIPEC is not available with the treatment of primary malignancy, a proactive second-look surgery is recommended. Several phase II studies strongly support the proactive approach. If peritoneal metastases were treated along with the primary colon resection, 5-year survival was seen and these results were superior to the results of treatment after peritoneal metastases had developed as recurrence. Also, prophylactic HIPEC improved survival with T3/T4 mucinous or signet ring colon cancers. A second-look has been shown to be effective in two published manuscripts. Unpublished data from MedStar Washington Cancer Institute also produced favorable date. Rectal cancer with peritoneal metastases may not be so effectively treated. There are both credits and debits of this proactive approach. Selection factors should be reviewed by the multidisciplinary team for individualized management of patients with or at high risk for peritoneal metastases.

Genotoxicity testing of combined treatment with cisplatin, bleomycin, and 5-fluorouracil in somatic cells of Drosophila melanogaster

The simultaneous treatment with the cross-linking agent cisplatin, the radiomimetic antitumoral drug bleomycin, and the anti-metabolite drug 5-fluorouracil has been used as a regimen to treat patients with squamous cell carcinoma of the head and neck. Considering that these drugs interact directly with DNA, one of the important late-occurring complications from treatment of primary malignancies is the therapy-related secondary cancers as a result of the genotoxic activity of the drugs on normal cells. In this sense, the genotoxicity of this combination was evaluated using the wing somatic mutation and recombination test in Drosophila melanogaster. The mutant spots observed in marker-heterozygous and balancer-heterozygous flies were compared in order to quantitatively and qualitatively estimate the genotoxic effect of these drugs. Cisplatin (0.003 and 0.006mM), bleomycin (0.005 and 0.01mM), and both combinations preferentially induced recombinational events, while mutation is the major event regarding the genetic toxicity of 5-fluorouracil (0.025 and 0.05mM). The combination of these drugs produced synergistic and antagonistic genotoxic effects, depending on the concentrations used, which could impose a higher risk of secondary effects associated with their genotoxic effects, emphasizing the importance of long-term monitoring in patients being treated with these drugs.

Characteristic and management of lung cancer as a secondary malignancy.

e12011 Background: New diagnostic and therapeutic strategies increase survival in cancer patients. Etiology and management of primary lung cancer (LC) are well established, but little is known about incidence of LC as a secondary neoplasm. The study analyzes the clinical characteristic, pathology and management of LC as a secondary neoplasm. Methods: We reviewed medical records of patients (pts) treated in our institution from Feb.1998 to Aug.2011 with diagnosis of LC as a second malignancy. The analysis included median age at the time of diagnosis of primary cancer, histology, type of treatment and time until diagnosis of LC. Results: 84 pts were analyzed – median age at the time of diagnosis of primary cancer was 62 years (range 35-79) (65 years in men and 58 years in women p&lt;0,05). The most frequent primary was: breast -21 pts (25%), larynx -19 pts (23%), colon - 9 pts (11%). According to etiology, tobacco-related primary cancers occurred in 37 (44%) pts. Radiotherapy/chemoradiotherapy was the treatment for primary cancer in 42 (50%) pts, surgery alone in 31 (37%) and chemotherapy in 11 (13%) pts. Adenocarcinoma as a secondary LC was diagnosed in 43 pts (51%), squamos-cell carcinoma in 30 pts (36%), small-cell lung cancer or carcinoid in 6 pts (7%), other types of non-small cell lung cancer in 5 pts (6%). Median time between diagnosis of primary cancer and LC was 50 months (range 0-354). Stage I or II LC was found in 56 pts (67%) and stage of III or IV in 26 (31%) pts (contrary to staging observed in pts diagnosed with LC as a primary malignancy in our institution concurrently). After diagnosis of LC radical and palliative treatment was offered in 65 (77%) pts and 19 (23%) pts respectively. After median follow-up of 84 months, progression of LC was noted in 27 pts (32%) and median time to progression was 16 months (range 2-89). Conclusions: Patients after treatment of tobacco-related cancers are at risk of developing LC as a second malignancy. LC as a secondary cancer is observed also after treatment of breast cancer and radiotherapy use. Close surveillance after treatment of primary malignancy allows detection of LC at early stage with a chance of radical treatment.

Mutational Analysis of Therapy-Related MDS/AML

Abstract 2802 Background:Therapy-related myelodysplastic syndromes and acute myelogenous leukemia (tMDS/AML) comprise a poor-risk subset of MDS/AML and are associated with a higher rate of cytogenetic abnormalities and complex karyotypes. Large scale mutation profiling efforts in de novo MDS have identified mutations that correlate with clinical features but such mutations have not been investigated in tMDS/AML. Methods:Cryopreserved (mononuclear cell fractions) bone marrow and peripheral blood samples from tMDS/AML patients were analyzed. Lymphocytes were depleted from these fractions by either fluorescence-activated cell sorting or affinity column selection. Genomic DNA was subjected to high throughput PCR and sequenced for TP53, TET2, DNMT3a, ASXL1, IDH1, IDH2, SF3B1, EZH2, EED, SUZ12, and RBBP4. Somatic mutations were validated by comparison to lymphocyte DNA controls. Patient selection was based on sample availability for tMDS/AML patients with untreated or active, previously treated disease. Results were correlated with clinical outcomes, cytogenetic profiles, and response to therapy. Results:Samples from 38 patients (20 males, 18 females) with tMDS/AML were analyzed. For their primary malignancy (≥ 2 malignancies, n=3; AML, n=1; breast, n=4; colorectal, n=3; Hodgkins or composite lymphoma, n=3; gastric, n=1; melanoma, n=2; NHL, n=12; ovarian, n=1; prostate, n=3; sarcoma, n=2; thyroid, n=3), patients received chemotherapy alone (n=17), radiation alone (n=4), radioactive iodine alone (n=1), chemotherapy plus radiotherapy (n=13), radiotherapy plus radioactive iodine (n=1), chemotherapy plus radiotherapy plus radioactive iodine (n=2). Median latency time between primary malignancy treatment and MDS diagnosis date was 5.68yrs (range, 0.71–30.88). Median age at MDS diagnosis was 65yrs (range, 34–83). Not surprising was the finding that of the 35 MDS patients with complete IPSS parameter data most were IPSS Int-2 (45%) or High Risk (13%) compared to Low (11%) or Int-1 Risk (24%) disease, and in contrast to expected proportions at diagnosis for de novo MDS. WHO Classifications were: RA, n=3; RCMD, n=11; RAEB-1, n=7; RAEB-2, n=7; AML, n=3; CMML-1, n=1; MDS-U, n=3; Unknown, n=3. The median survival was 16.8mo. Median time between MDS diagnosis and sample procurement was 3.0mo (range, 0–57.2) during which 2 patients progressed to AML, 11 received a DNA methyltransferase inhibitor (DNMTI), 1 induction chemotherapy, and 2 DNMTI plus induction.We identified somatic mutations in 15/38 (39.5%) patients. Including cytogenetic abnormalities, we identified somatic alterations in 34/38 (88%) of the patients in this cohort. TP53 mutations were most common, detected in 8/38 (21%) patients, followed by TET2 in 4/38 (10.5%), DNMT3a in 3/38 (7.9%), ASXL1 in 1/38 (2.6%), IDH1 in 1/38 (2.6%), and EZH2 in 1/38 (2.6%). No IDH2, SF3B1, EED, SUZ12, or RBBP4 mutations were detected. Only 2 patients had concurrent point mutations (one patient with TP53/TET2/DNMT3 mutations and one patient with TET2/EZH2 mutations). 7/38 (18.4%) patients had TP53 loss by FISH analysis or exhibited loss of chromosome 17/17p; 2 of these patients showed concurrent TP53 point mutations consistent with biallelic TP53 loss. 12/13 patients with TP53 abnormalities (point mutations, loss of TP53 by FISH, or loss of chromosome 17) had IPSS Poor Risk cytogenetics and 11/13 patients had abnormalities in chromosome 5 (del 5q or monosomy 5). In patients without TP53 abnormalities, 9/25 had Poor Risk cytogenetics and 5/25 had abnormalities in chromosome 5. The median survival for patients with TP53 abnormalities was 9.7mo compared to 64.4mo for patients with no TP53 abnormalities (p=0.0043). Of the 13 patients with TP53 abnormalities, 12 received treatment for tMDS/AML. 3/12 were refractory to the first line of therapy, and 7 were unable to receive an adequate course of therapy with hypomethylating agents due to toxicity or progressive disease. Conclusions:TP53 point mutations are more common in tMDS/AML than in de novo MDS (7.5%, Bejar et al) while incidence of TET2 and ASXL1 mutations were lower in tMDS/AML compared to de novo MDS (20.5% and 14.4%, respectively). TP53 and TET2 point mutations were more strongly associated with exposure to prior chemotherapy, but not with exposure to radiation therapy. Taken together, these data demonstrate that TP53 mutations are common in tMDS/AML and are correlated with adverse clinical outcomes. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Nonmelanoma Skin Cancer in Survivors of Childhood and Adolescent Cancer: A Report From the Childhood Cancer Survivor Study

Nonmelanoma skin cancer (NMSC) has become the most common type of cancer in many populations throughout the world. Ultraviolet and ionizing radiation are known risk factors. Because NMSCs are rarely lethal and most cancer registries do not routinely report data regarding these cancers, they have received little attention in studies evaluating long-term effects of cancer therapy. This article reports on the occurrence of secondary NMSC as a long-term effect of cancer therapy in survivors of childhood cancer. The Childhood Cancer Survivor Study (CCSS) is a cohort study of 5-year survivors of childhood and adolescent cancer from 25 participating institutions in North America. NMSC patients were defined by a history of basal cell or squamous cell carcinoma of the skin after primary malignancy treatment. Demographic and treatment data were collected and analyzed. Among the 13,132 eligible CCSS participants, 213 have reported NMSC; 99 patients (46%) have had multiple occurrences. Median age of occurrence was 31 years (range, 7 to 46 years). Location of NMSC included head and neck (43%), back (24%), chest (22%), abdomen and pelvis (5%), extremity (3%), and unknown (4%). Ninety percent of patients had previously received radiation therapy (RT); 90% of tumors occurred within the RT field. RT was associated with a 6.3-fold increase in risk (95% CI, 3.5- to 11.3-fold). Long-term survivors of childhood and adolescent cancer who were treated with RT are at highest risk for developing NMSC. Educational efforts need to be directed to this population to facilitate early diagnosis of NMSC and reduction in sun exposure.