Tumors In Long-term Survivors Research Articles

Abstract B045: Deep genomic and single cell molecular profiles define immunogenic pancreatic cancer

Abstract Background: Most pancreatic cancers (PC) are resistant to immunotherapy and have a poor prognosis with advanced stage (III/IV, 80%). However, recent cancer vaccine trials have demonstrated that long-term host anti-cancer immunity can improve outcomes of patients (pts) with resectable PC (stage I/II, 20%), harboring high-quality neoantigens or select KRAS alterations. It has been proposed that immunogenic PC is a genetically defined subgroup (5-10%), enriched by hypermutated PC with DNA-damage repair deficiencies including homologous repair (HRD) and mismatch repair (dMMR). Until now, comprehensive molecular studies have been mostly conducted in resected PC. Methods: All tissues were collected following an Institutional Review Board (IRB 21-275) protocol at the Memorial Sloan Kettering. Whole-exome from N=78, exome-captured bulk RNA from N=61, and single-nucleus RNA from N=23 biopsy samples of advanced PC were analyzed. Gene set enrichment and digital cytometry, singe base substitution (SBS) mutational signature, neoantigen, and genomic instability score (GIS) for HRD and immunogenicity were evaluated. Demographics, treatment history, and overall survival (OS) for pts with PC with or without HRD and dMMR were abstracted from the medical record. Results: A total of N=77 WES samples included N=21 core HRD (cHRm: 3 BRCA1, 17 BRCA2, 1 both), N=7 non-core HRD (ncHRm: 3 ATM, 2 CHEK2, 1 RAD50, 1 BARD1), and N=7 dMMR, and N=42 No DDR. N=46 males. Median age 65 years. Median OS (95% confidence interval): 26 months (m) (17-NR) for cHRm, 90m (14-NR) for dMMR, 7.4m (6.8-NR) for ncHRm, and 19m (15-27) for No DDR group. N=49 (63%) pts received first-line platinum chemotherapy. Median tumor mutation burden (TMB-WES): 2 (IQR: 2-3), 35 (30-47), 1 (1-2), and 1, respectively for cHRm, dMMR, ncHRm, and No DDR. TMB-WES significantly higher for dMMR vs. No DDR (95%CI: 35 [30-47] vs 1 [1-2], p=0.001). GIS higher for cHRm vs. No DDR (95%CI: 31 [18-38) vs 14 [9-18], p=0.008). Only two BRCA1m tumors had significant SBS3. N=61 exome captured RNAseq analysis showed cHRm (N=17) vs. No DDR (N=39) had highly enriched gene programs for upregulated immune activity in adaptive immune response (odds ratio [OR]: 0.49, p=1.7e-10), humoral immune response, and T cell activation (OR: 0.44, p=2.7e-8). Digital cytometry showed higher infiltration of gamma delta T cells (p=0.039) and lower regulatory T cells (p=0.001) in cHRm vs. No DDR. 59,771 nuclei were profiled from 23 (16 baseline and 7 follow-ups [5 matched]) biopsy samples from pts with HRD [gBRCA1 (N=3), gBRCA2 (N=14)] and No DDR (N=6). HRD tumors vs. No DDR had higher level of infiltrating CD8+ cytotoxic T cells (p<0.01). Tumors of long-term survivors (> 18m) vs. short-term survivors had significantly lower-level infiltration of macrophages (p<0.01) and Tregs (p=0.05). Conclusions: Our deep genomic and single-cell resolution transcriptomic analyses successfully profiled advanced PC enriched with DDR. HRD and dMMR render PC immunogenic. Further investigations for targeted immunotherapy is warranted. Citation Format: Wungki Park, Shigeaki Umeda, Catherine O'Connor, Haochen Zhang, Roshan Sharma, Allison Richards, Yingjie Zhu, Elias-Ramzey Karnoub, Xin Pei, Anna M. Varghese, Kevin Soares, Alejandro Jimenez Sanchez, Hulya Ozkan Sahin, Kenneth Yu, Vinod P. Balachandran, Joanne Chou, Fergus Keane, David Kelsen, Olca Basturk, Chaitanya Bandlamudi, Marinela Capanu, Tal Nawy, Michael Berger, Ronan Chaligne, Ghassan Abou-Alfa, Jorge S. Reis-Filho, Nadeem Riaz, Dana Pe'er, Christine A. Iacobuzio-Donahue, Eileen M. O'Reilly. Deep genomic and single cell molecular profiles define immunogenic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B045.

The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.

Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches. We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load. Patients clustered into survival groups based on genomic and immune cell signatures, including three subsets of patients with BRCA1 alterations with distinctly different outcomes. Specific combinations of germline and somatic gene alterations, tumor cell phenotypes and differential immune responses appear to contribute to long-term survival in HGSC.

Immunoediting Removes High-Quality Neoantigens in Pancreatic Cancer.

Recurrent tumors in long-term survivors of pancreatic cancer have less high-quality neoantigens.

Predicted probabilities of brain injury after carbon ion radiotherapy for head and neck and skull base tumors in long-term survivors

Background and purposeWe aimed to determine the risk factors for radiation-induced brain injury (RIBI11Abbreviations: RIBI, radiation-induced brain injury; CIRT, carbon ion radiotherapy; HNC/SBT, head and neck cancers and skull base tumors; AE, adverse event; DVH, dose volume histogram; LQ, linear–quadratic; MRI, magnetic resonance imaging; CT, computed tomography; GTV, gross tumor volume; CTV, clinical target volume; OAR, organs at risk; RBE, relative biological effectiveness; CTCAE, Common Terminology Criteria for Adverse Events; EUD, equivalent uniform dose; AIC, Akaike Information Criterion; SOBP, Spread-Out Bragg Peak; IMRT, intensity-modulated radiotherapy) after carbon ion radiotherapy (CIRT) to predict their probabilities in long-term survivors. Materials and methodsWe evaluated 104 patients with head, neck, and skull base tumors who underwent CIRT in a regimen of 32 fractions and were followed up for at least 24 months. RIBI was assessed using the Common Terminology Criteria for Adverse Events. ResultsThe median follow-up period was 45.5 months; 19 (18.3 %) patients developed grade ≥2 RIBI. The maximal absolute dose covering 5 mL of the brain (D5ml) was the only significant risk factor for grade ≥2 RIBI in the multivariate logistic regression analysis (p = 0.001). The tolerance doses of D5ml for the 5% and 50% probabilities of developing grade ≥2 RIBI were estimated to be 55.4 Gy (relative biological effectiveness [RBE]) and 68.4 Gy (RBE) by a logistic model, respectively. ConclusionD5ml was most significantly associated with grade ≥2 RIBI and may enable the prediction of its probability.

Abstract 2202: Genetic characterization of metastasis and prognosis in high-grade serous ovarian cancer

Abstract High-grade serous ovarian cancer (HGSC) is the most lethal histotype of ovarian cancer and is highly prone to metastasis, with the majority of patients presenting at advanced stages of disease. There are few targeted treatment options for HGSC patients, especially for women with high metastatic tumor burdens. In order to identify potential genetic targets in metastatic disease, we characterized the genomic and transcriptomic alterations of metastatic tumors in HGSC patients. In this study, matched normal tissue, primary, and metastatic tumors from 23 HGSC short-term (ST) survivors (overall survival [OS] <3.5 years) and 14 long-term (LT) survivors (OS >5 years) underwent whole exome and RNA sequencing. We compared somatic mutations, copy number alternations, mutational burdens, differential expression, immune cell fractions, and gene fusion predictions between the primary and metastatic tumors of the ST and LT survival groups. We confirmed that tumors of LT survivors were more likely to have BRCA1 alterations and more copy-altered segments when compared to tumors of ST survivors. There was a higher percentage of shared variants between the primary and metastatic tumors for ST survivors compared to LT survivors. ST survivors also had a greater mutational burden and more predicted gene fusions than LT. We observed few differentially expressed genes between primary and metastatic tumors, but we did observe significant differences between the transcriptomes of LT and ST survivors' tumors. Overall, we observed that HGSC primary and metastatic tumors had similar genomic and transcriptomic landscapes, but we identified genetic characteristics specific to metastatic tumors that correlate with survival. Citation Format: Emilee N. Kotnik, Nicholas C. Spies, Tiandao Li, Matthew Inkman, Jin Zhang, Fernanda Martins-Rodrigues, Ian S. Hagemann, Carolyn K. McCourt, Premal H. Thaker, Andrea R. Hagemann, Matthew A. Powell, David G. Mutch, Christopher A. Maher, Christopher A. Miller, Katherine C. Fuh. Genetic characterization of metastasis and prognosis in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2202.

Abstract A17: Characterization of primary-metastasis pairs in high-grade serous ovarian cancer with short- and long-term survival

Abstract High-grade serous ovarian cancer (HGSC) is a highly metastatic cancer with the majority of patients presenting at advanced stages. Over the last few decades, the overall survival and standard of care for patients have not significantly improved and there are limited targeted treatment options for patients. Although we have learned much about the genomic characteristics of HGSC primary tumors, there has been a lack of characterization of metastatic tumors. In order to identify genetic markers of metastasis and poor prognosis, we have characterized the genomic and transcriptomic alterations of primary and metastatic tumors in HGSC patients with different survival outcomes. In this study, matched normal tissue, primary, and metastatic tumors from 23 HGSC short-term (ST) survivors (OS <3.5 years) and 14 long-term (LT) survivors (OS >5 years) underwent whole-exome and RNA sequencing. We compared somatic mutations, copy number alternations, mutational burdens, differential expression, homologous recombination (HRD) scores, and gene fusion predictions between the primary and metastatic tumors of the ST and LT survival groups. We confirmed previously published findings that tumors of LT survivors were more likely to have BRCA1 alterations, higher HRD scores, and more copy-altered segments when compared to tumors of ST survivors. We identified 10,124 somatic mutations in the tumors of LT survivors and 13,599 somatic mutations in ST survivors. There was a higher percentage of shared variants between the primary and metastatic tumors for ST survivors compared to LT survivors. ST survivors also had a greater mutational burden than LT survivors. We observed little differences in differential expression between primary and metastatic tumors, but we did observe unique clustering between the transcriptomes of LT and ST survivors’ tumors. Although there was no significant difference between the number of gene fusions predicted between primary and metastatic tumors, there was a total of 1,218 gene fusions predicted in ST survivors’ tumors, which was significantly more than the 240 gene fusions predicted in LT survivors. The ST primary tumor group had the highest number of predicted gene fusions. Interestingly, we observed that patients with HRD-positive primary tumors but HRD-negative metastatic tumors had significantly shorter overall survival compared to matched tumor pairs with no, or very little, difference in HRD scores. This finding suggests that differences in HRD scores between primary and metastatic tumors in HGSC patients may correlate with survival. Overall, we observed similar genomic and transcriptomic findings in the landscape between primary and metastatic tumors in HGSC patients and identified genetic characteristics specific to tumors of LT and ST survivors. Citation Format: Emilee N. Kotnik, Nicholas C. Spies, Christopher A. Miller, Tiandao Li, Matthew Inkman, Jin Zhang, Christopher A. Maher, Carolyn K. McCourt, Premal H. Thaker, Andrea R. Hagemann, David G. Mutch, Matthew A. Powell, Katherine C. Fuh. Characterization of primary-metastasis pairs in high-grade serous ovarian cancer with short- and long-term survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A17.

P1.08-073 Experience of Third Primary Lung Tumors after Treatment of First and Second Primary Lung Cancer

Widespread adoption of lung cancer screening and development of high-resolution computed tomography (HRCT) have led to a marked increase in the detection of early lung cancer in Japan. After curative resection for early lung cancer, second primary lung cancers develop in a significant proportion. The majority of these cancers are detected at an early stage because of careful follow-up using HRCT. In our experience, more than 80% of these patients were treated with surgery or radiation therapy, and some of them have acquired with long-term survival. Recently we have experienced with third primary lung tumors in long-term survivors. In this paper, we reviewed the incidence, management, and outcome of third primary lung tumors. Between April 1996 and March 2016, 1194 patients underwent complete resection for primary lung cancer in our institution. Of these individuals, patients who developed a third primary lung tumor were selected for this study. Of 1194 consecutive patient, 105 patients (8.8%) developed second primary lung cancers, and 11 patients (1%) of them developed third primary lung tumors. The patients included 10 men and one woman. The initial resection for primary lung cancer was lobectomy in 9 patients and segmentectomy in 2. Surgical resection for second primary lung cancer was performed in 8 patients, and radiation therapy was performed in 3. Four of the 11 patients underwent resection for third primary lung tumors. One patient had completion pneumonectomy, 1 had segmentectomy, and 2 had wedge resections. Five patients were treated by radiation therapy. The two remaining patients received best supportive care. Survival after resection of first primary lung cancer ranged from 50 months to 185 months, with a median survival of 138 months and an average survival of 137 months. Currently, 4 patients are alive without evidence of recurrence. Among them, three patients were treated by their third pulmonary resection, and one patient was treated by radiation therapy. During 20 years, third primary lung tumors were diagnosed in only 11 patients (1%). But long-term survivors after resection of lung cancer are increasing. Careful follow-up and early detection of second primary lung cancers using HRCT will induce the increase of experience for treatment of third primary lung tumors. In our little experience, aggressive surgery for third primary lung tumors may improve survival.

Disease Recurrence and Second Tumors in Long-term Survivors of Lung Cancer

Introduction and objectivesAs cancer survival improves, the appearance of multiple tumors in a single patient is becoming more common. The aim of this study was to analyze long-term evolution, focusing particularly on disease recurrence and second primary tumors, in patients with lung cancer (LC) and ≥3 years overall survival. Materials and methodsRetrospective study of 1769 patients with LC. A total of 218 (136 treated with surgery and 82 with other treatments), followed up for between 5 and 23 years were enrolled. LC progress and intercurrent diseases were recorded. ResultsA total of 65 patients presented tumor relapse, of which 60.9% occurred in the first 3 years; 26 patients developed secondary primary tumors (84.6% after 5 years) and 24 developed 2 or more second extrapulmonary tumors (66.6% after 5 years), most of which were smoking-related. The incidence of second primaries was greater than the expected incidence of cancer in the general population matched for age and sex. ConclusionThe multiple carcinogenic effect of smoking persists and manifests in various organs, more than 5 years after the diagnosis of LC, even in patients with long survival. After 5 years, a second tumor is more likely than a relapse of the primary disease, and the lung is the most common site of development of a second tumor.

Abstract 1299: Tumor-infiltrating B cells are predictive of human lung squamous cell survival

Abstract Recent studies in human lung squamous cell carcinoma (SqCC) have shown that upregulation of B cell-associated genes strongly correlate with patient survival. More than any genetic factor (immunologic or otherwise) CD79A, a pan-B cell marker, was found to have the strongest predictive value. Expression of this marker was capable of identifying short (< 2 years) and long (> 6 years) term lung SqCC survivors, with greater than 80% accuracy. These data suggest that the presence of CD79A-expressing tumor-infiltrating B (TIL-B) cells may be contributing to patient outcome. The aim of this study was to characterize CD79A+ TIL-B cells in SqCC patient samples and evaluate their role in lung SqCC survival. We evaluated human lung cancer specimens from long and short term survivors for the presence of CD79A+ TIL-B cells by immunofluorescence and found that their presence directly correlates with survival time. Further analysis showed that CD79A expression found in tumors of long term survivors (>6 years) co-localizes with CD20 staining but not CD138 staining, indicating that the cells responsible for producing a survival signature are not plasma cells. These data indicate that CD79A+ TIL-B cells are contributing to the generation of an efficient immune response in lung SqCC and may be doing so through non-humoral functions. Citation Format: Sara Centuori, Samuel Kim, Cecil Gomes, Charles Putnam, David Mount, Linda Garland, Jesse Martinez. Tumor-infiltrating B cells are predictive of human lung squamous cell survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1299. doi:10.1158/1538-7445.AM2015-1299

Downregulation of Prominin 1/CD133 expression in colorectal cancer by NSAIDs following short-term preoperative treatment

Expression of Prominin 1/CD133 is associated with poor prognosis and chemoresistance in several types of solid tumors. The aim of the present study was, therefore, to evaluate Prominin 1/CD133 expression in colorectal carcinoma after short-term preoperative treatment by non-steroidal anti-inflammatory drugs (NSAIDs). Patients aimed at curative operation for colon cancer were randomized to receive NSAIDs (indomethacin 50 mg x2 or celecoxib 100 mg x2) three days preoperatively. Antisecretory prophylaxis (esomeprasol 40 mg x1) was provided to all patients and served as sham intake. CD133 expression in tumor tissue was also assessed in tumors from Dukes' B patients selected for either long or short postoperative survival. No patients received perioperative chemoradiotherapy. Tumor tissue was collected at surgery for quantification of mRNAs (Prom1 and Wnt4) by qPCR. Immunohistochemistry stained for CD133, Ep-CAM, CD34 and CD45. PGE2 content in tumor tissue was determined. Transcript of CD133 in tumor tissue was lower in patients treated with NSAIDs (0.28 ± 0.07 vs. 0.51 ± 0.08; p<0.03) as well as some other stem cell-related transcripts. In treated patients 36% of all tumors stained positive for CD133 compared to 71% in sham-treated control patients (p<0.05). Short survivors with Dukes' B tumors displayed 78% CD133 expression as compared to 33% of tumors in long-term survivors (p<0.002). Tumor tissue PGE(2) content was negatively related to patient survival. Our results show that short-term preoperative NSAID treatment downregulates colon cancer tissue expression of Prominin 1/CD133, a stem cell marker indicative of survival prognosis as confirmed.

Surgery for multiple hepatic colorectal metastases.

The purpose of this review is to address three important questions concerning hepatic resection for multiple colorectal metastases. (1) Is the number of tumors truly a significant prognostic factor? (2) Are patients with four or more tumors contraindicated for hepatic resection? (3) Up to how many nodules should we attempt to resect? Although the efficacy of surgical resection for one to three hepatic metastases is clear, based on several reports, the literature regarding the resection of four or more metastatic lesions is conflicting. Review of the data at our institutions showed that the number of tumors was a significant prognostic factor, because patient survival after liver resection for multiple metastases was worse than that for single metastasis. However, patients with two or three nodules and those with four or more nodules showed the same survival curves, or those with four or more metastases fared even better. Therefore, patients with four or more metastases should be considered for hepatic resection. The maximum number of hepatic tumors in longterm survivors reported in the literature has been increasing, and the limit for the number of respectable metastases has not yet been determined. Because liver resection is still the only treatment that offers a cure, surgery for multiple metastases may be justified as long as the operation is safe and technically feasible.

The incidence of second primary tumors in long-term survivors of small-cell lung cancer : Heyne KH, Lippman SM, Lee JJ, Lee JS, Waun Ki Hong. Department of Medical Oncology, MD Anderson Cancer Center, Box 80, 1515 Holcombe Blvd, Houston, TX 77030. J Clin Oncol 1992;10:1519–1524

The incidence of second primary tumors in long-term survivors of small-cell lung cancer : Heyne KH, Lippman SM, Lee JJ, Lee JS, Waun Ki Hong. Department of Medical Oncology, MD Anderson Cancer Center, Box 80, 1515 Holcombe Blvd, Houston, TX 77030. J Clin Oncol 1992;10:1519–1524

The incidence of second primary tumors in long-term survivors of small-cell lung cancer.

A review of 446 patients who were enrolled consecutively in small-cell lung cancer (SCLC) protocols was performed to identify in long-term survivors the frequency of new primary tumors and their clinical impact. Forty-seven patients (10.5%) were identified to be free of disease at 2 years. Second primary tumors (SPTs) were diagnosed in 14 patients. The overall risk for developing an SPT was 10.3% per person-year. Actuarial risk at 8 years was 50.3% for an SPT. In this review, SCLC showed one of the highest incidences of SPTs reported in aerodigestive tract malignancies. A long-term survivor was more likely to have an SPT than a relapse of SCLC. Consequently, the odds of death from an SPT compared with that from a relapse increased sharply from 1:13 within 4 years from diagnosis to 8:1 afterwards. Long-term survivors of SCLC would be excellent candidates for chemoprevention trials.

Measurements of dose from secondary radiation outside a treatment field

Radiation dose to organs outside the radiotherapy treatment field can be significant and therefore is of clinical interest. We have made measurements of dose at distances up to 70 cm from the central axes of 5 × 5, 15 × 15 and 25 × 25 cm radiation fields of 300 kVp, 4 MV and 8 MV X rays, and 60Co gamma rays, at the surface and at depths in water of 5 and 10 cm. Contributions to the total secondary radiation dose from water scatter, machine (collimator) scatter and leakage radiation have been separated. We have found that the component of dose from water scatter can be described by a simple exponential function of distance from the central axis of the radiation field for all energies and field sizes. Machine scatter contributes 20 to 40% of the total secondary dose depending on machine, field size and distance from the field. Leakage radiation contributes very little dose, but becomes the dominant component at distances beyond 60 cm from the central axis. Estimates of the risk of second tumors in long term survivors indicate a small incremental increase above the natural incidence rate based on information from the 1980 BEIR Committee report.