Memorial Sloan-Kettering Cancer Center Patients Research Articles

Abstract IA35: Novel biological insights into colorectal cancer from West Africa

Abstract The burden of colorectal cancer (CRC) is increasing in West Africa. Understanding the molecular and clinicopathologic profile of the region’s CRC patients is vital to optimizing early detection and therapeutic regimens. Clinicopathologic data from consecutive patients from a multicenter, prospectively maintained Nigerian CRC database were compared to a contemporary cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Fresh-frozen tissue from Nigerian patients was analyzed with a multigene, next-generation sequencing assay, along with immunohistochemistry and methylation analyses; data were compared to molecular data from MSKCC and The Cancer Genome Atlas (TCGA) cohorts. Adult patients with histologically confirmed colorectal adenocarcinoma enrolled in a Nigerian CRC database from April 2013-November 2018 were included. All adult patients with colorectal adenocarcinoma diagnosed from January-June 2013 were included in the MSKCC cohort. Somatic and germline next-generation sequencing of cancer-associated genes, immunohistochemistry, and methylation analyses were performed. The primary outcomes were microsatellite instability status, somatic and germline mutation frequency, and overall survival. The median age at diagnosis was 55.8 years in the Nigerian cohort (n=380) and 60.0 years in the MSKCC cohort (n=458) (p<0.001). The rate of microsatellite instability was 28.1% in the Nigerian cohort (18/64), compared to 14.2% and 8.5% in the TCGA (65/459) and MSKCC (97/1145) cohorts, respectively (p<0.001). In microsatellite-stable cases, tumors from Nigerian patients were less likely to have APC mutations (39.1% vs. 76.0% p<0.001) and WNT pathway alterations (47.8% vs. 81.9%, p<0.001), and more likely to have RAS pathway alterations (76.1% vs. 59.6%, p=0.03) compared to MSKCC patients. Overall survival was significantly longer for MSKCC vs. Nigerian patients (not reached vs. 12 months, p<0.001). The biology of CRC in Nigeria appears to be distinct from that in high-income countries, emphasizing the need for regional data to guide diagnostic and treatment approaches for patients in West Africa. Citation Format: Olusegun I. Alatise, Gregory C. Knapp, Avinash Sharma, Walid K. Chatila, Olalekan Olasehinde, Adeleye D. Omisore, Aba Katung, Samuel A. Olatoke, T.Peter Kingham. Novel biological insights into colorectal cancer from West Africa [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA35.

Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma.

The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS≥ 2 (vs. PS< 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar. Outcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs.≥ 2) to more accurately predict outcomes.

Melanoma and non-melanoma skin cancers in hairy cell leukaemia: a Surveillance, Epidemiology and End Results population analysis and the 30-year experience at Memorial Sloan Kettering Cancer Center.

Few studies have examined melanoma and non-melanoma skin cancer (NMSC) incidence rates after a diagnosis of hairy cell leukaemia (HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and Surveillance, Epidemiology and End Results (SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10-year combined melanoma and NMSC skin cancer rate of 11·3%, melanoma 4·4% and NMSC 6·9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4750 SEER patients with HCL, 55 (1·2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios (SIRs) did not show that melanoma was more common in HCL patients versus the general population (SIR 1·3, 95% CI 0·78-2·03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients.

Staging Gastric Cancer Patients after Complete Surgical Resection: Which System Should We Use?

The most commonly used staging system for gastric adenocarcinoma is the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system. The 2010 7th edition of the AJCC system made several changes from the 6th edition, including redefining T and N categories and moving the staging of proximal gastric tumors within 5 cm of the gastroesophageal junction to the esophageal cancer staging system. TNM stage grouping were also redefined, with stage II further divided into IIA and IIB and stage IIIA and IIIB further divided into IIIA, IIIB, and IIIC. Since the publication of the 7th edition AJCC staging system in 2010, several single and multi-institution studies have compared the 6th and 7th editions. Some studies have found the 7th edition to be superior. Other studies have found the 7th edition to be either inferior to or no better than the 6th edition. Two studies from the same institution found opposing results. All these studies vary in the sort of patients examined, the extent of surgery and pathological analysis, and the methods of data analysis. In this issue of Annals of Surgical Oncology, Dikken et al. compare disease-specific survival predictions for patients with gastric adenocarcinoma using the 6th and 7th editions of the AJCC staging system. Patients underwent surgery either at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York or at one of several institutions in the Netherlands as part of the Dutch Gastric Cancer Trial (DGCT). In this group of 2,196 patients, the authors find that the predictive accuracy of the 7th edition N categories is improved based on concordance measurements, but the predictive accuracy of the 7th edition TNM stages is decreased. Survivals using the AJCC 6th edition did not significantly differ for two of the six stage groups, while survivals using the 7th edition did not significantly differ for three of the seven stage groups. Thus, the authors conclude the AJCC 7th edition staging system has increased complexity with no improvement in predictive accuracy. Dikken et al. put together a large cohort of Western patients treated with relatively extensive lymphadenectomies and perform a thorough comparison of the 6th and 7th AJCC staging systems. One primary advantage of this study is the use of data from several institutions in two different countries. Most previous studies on this topic are from Asian countries, so this multi-institution study of Western patients is important in determining whether we are making progress with the AJCC staging system revisions. However, as with most studies of this nature, there are several potential problems. First, the extent of lymphadenectomy for this cohort of patients varied, which causes problems with stage migration. At MSKCC, ‘‘most patients underwent a D2 lymph node dissection’’ and DGCT patients were randomized to D1 versus D2 node dissection. Furthermore, 22–28 % of patients in this study had \15 nodes examined, and the AJCC staging system suggests ‘‘that at least 16 regional nodes be assessed pathologically.’’ Second, the varying extent of lymphadenectomy and adjuvant therapies for patients in this study may have affected pathological staging and survival. Sixteen percent of MSKCC patients received neoadjuvant chemotherapy, which can result in downstaging the T and/or N stages. The 15-years follow-up from the Dutch trial now demonstrates a significant 12 % Society of Surgical Oncology 2012

Stage migration and increasing proportion of favorable‐prognosis metastatic renal cell carcinoma patients

The Memorial Sloan-Kettering Cancer Center risk model classifies patients with metastatic renal cell carcinoma (RCC) by 5 pretreatment features as favorable, intermediate, and poor risk. The number of Memorial Sloan-Kettering Cancer Center patients in each risk group was examined by year of treatment to analyze stage migration. The distribution of risk groups was examined retrospectively in 789 Memorial Sloan-Kettering Cancer Center patients with metastatic RCC treated in a first-line therapy clinical trial from 1975 to 2007. Date of treatment onset was divided into 6 cohorts between 1975 and 2007 (1975-1980, 1981-1985, 1986-1990, 1991-1995, 1996-2001, and 2001-2007). The median age of the first-line metastatic RCC clinical trial patients was 59 years (range, 20-82 years). Most patients received cytokine therapy (55%), 37% received chemotherapy/other, and 8% received vascular endothelial growth factor-targeted therapies. Overall survival increased with each consecutive cohort year group (P < .001). Median survival was 0.43 years (95% confidence interval [CI], 0.27-0.68) in the 1973-1980 cohort and 1.5 years in the 2001-2007 cohort (95% CI, 1.15-2.11). Memorial Sloan-Kettering Cancer Center risk-group distribution shifted between 1975 and 2007 (P < .0001). The poor-risk group proportion became smaller (from 44% in 1975-1980 to 13% in 2001-2007), whereas the favorable-risk group increased (from 0% in 1975-1980 to 49% in 2001-2007). The intermediate-risk group remained stable at 50%. After adjusting for type of therapy, the shifts continue to be significant (P < .0001). The risk-group distribution for metastatic RCC patients in clinical trials shifted from 1975 to 2007. These shifts have direct implications for data analysis, interpretation of metastatic RCC trends, and drug development.

Curability of recurrent disseminated disease after surgery alone for local-regional neuroblastoma using intensive chemotherapy and anti-G(D2) immunotherapy.

A reluctance to treat local-regional neuroblastoma by surgery alone derives partly from concern that if widespread neuroblastoma develops, the chance for cure is small, and partly from hope that mild chemotherapy will prevent relapse. The authors report on a series of patients who had distant recurrences after surgery alone for local-regional neuroblastoma. Seven patients treated with surgery alone for local-regional neuroblastoma had widespread relapses 2.5 to 25 (median 7) months later and were treated at Memorial Sloan-Kettering Cancer Center (MSKCC). During the period of this study (1995-1999), MSKCC patients with high-risk neuroblastoma received the N7 protocol (dose-intensive chemotherapy, immunotherapy with the anti-G(D2) 3F8 antibody, targeted radiotherapy using 131I-3F8, local radiotherapy) if they had assessable disease, or 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by 13-cis-retinoic acid if they were in remission after treatment elsewhere. Five patients were in complete remission 3 years 11 months to 7 years 4 months from the start of retrieval therapy, including three who received all of their N7 treatment of relapsed neuroblastoma at MSKCC, one who received two cycles of chemotherapy elsewhere before starting N7, and one who was referred for 3F8/GM-CSF because of neuroblastoma cells in pretransplantation bone marrow. The encouraging survival results of our cohort are consistent with the concept that surgery alone for local-regional neuroblastoma might be beneficial to the overall neuroblastoma population because many patients will never need chemotherapy (and will therefore be spared its potential toxicities), and most of those who do have widespread relapses are likely to be cured with contemporary treatments.

How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review.

Attempts to improve outcomes of patients with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) have focused on chemotherapy dose intensification strategies. We now present results achieved with that approach, as carried out at Memorial Sloan-Kettering Cancer Center (MSKCC) and as reported in the literature. Twenty-one unselected MSKCC patients with newly diagnosed ES/PNET metastatic to bone/BM received the "P6" protocol which includes cycles of cyclophosphamide (4.2 g/m(2))/doxorubicin (75 mg/m(2))/vincristine and cycles of ifosfamide (9 g/m(2))/etoposide (500 mg/m(2)). Patients in complete/very good partial remission (CR/VGPR) after P6 received myeloablative therapy with either total-body irradiation (TBI) (hyperfractionated 15 Gy)/melphalan (180 mg/m(2)) or thiotepa (900 mg/m(2))/carboplatin (1,500 mg/m(2)). We reviewed the literature. Only one MSKCC patient became a long-term event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while receiving or shortly after completing P6. Eight patients were treated with TBI/melphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiotepa/carboplatin relapsed 3 to 4 months after transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poor outcome was seen with use of active agents for ES/PNET-cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive regimens for short or prolonged periods of time. No improvements in event-free survival rates occurred with successive cooperative group or large single-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no difference nor did consolidation of remission with myeloablative chemoradiotherapy. Secondary leukemia emerged as a major risk with dose-intensive regimens. The MSKCC experience and findings reported in the literature suggest that dose-intensive use of the chemotherapy agents with established activity against ES/PNET is reaching its efficacy and toxicity limits. A major impact on prognosis awaits the development of entirely novel therapies.

Neuroblastoma and treatment-related myelodysplasia/leukemia: the Memorial Sloan-Kettering experience and a literature review.

To assess treatment-related myelodysplasia/leukemia (t-AML) in neuroblastoma patients by a review of the Memorial Sloan-Kettering Cancer Center (MSKCC) data and the literature. We studied 380 previously untreated and treated MSKCC patients. Low-risk patients received no cytotoxic therapy. High-risk patients received the N4, N5, or N6 regimens. Dosing per cycle and cumulative dosing of leukemogenic agents peaked with N6, which included four cycles of cyclophosphamide 4,200 mg/m2 and doxorubicin 75 mg/m2, plus three cycles of cisplatin 200 mg/m2 and etoposide 600 mg/m2. We reviewed the literature. t-AML occurred in six MSKCC patients, which included three of 53 patients in whom the only chemotherapy consisted of N6, and three patients treated for relapsed or refractory neuroblastoma; no case of leukemia emerged among the 50 low-risk patients. Four cases were found incidentally in routine follow-up bone marrow tests. The 36-month cumulative incidence of t-AML in the N6 cohort was 7% (95% confidence interval, 0 to 15). Published data parallel the MSKCC experience in that t-AML after neuroblastoma was once rare but has become less so since the mid-1980s, when the intensified use of topoisomerase-II inhibitors and alkylators first gained wide acceptance and produced better response rates and longer survival. Neuroblastoma itself is not associated with a host susceptibility to leukemia. However, current neuroblastoma treatment programs that use high-dose cyclophosphamide, cisplatin, and topoisomerase-II inhibitors may entail a considerable risk for t-AML. The incidence of t-AML in neuroblastoma patients may be underestimated because treatment and clinical factors can mask its presence. Efforts to devise effective but less leukemogenic treatment for neuroblastoma or to truncate leukemogenic therapy, eg, by exploiting molecular techniques for the early identification of complete remission, are warranted.

Cisplatin and 5-fluorouracil infusion for metastatic colorectal carcinoma. Differences in survival in two patient groups with similar response rates.

Because of reported synergism between 5-fluorouracil (5-FU) and cisplatin (CDDP) in L1210 leukemic mice and activity of this combination in clinical studies, a trial was initiated in previously untreated patients with advanced colorectal carcinoma. Cisplatin at 20 mg/m2 and 5-FU as a continuous infusion at 1000 mg/m2 were both administered for 5 consecutive days every 4 weeks. Forty-one patients were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) and 46 were treated by the Community Clinical Oncology Program (CCOP) physicians. A 50% reduction in measurable disease was seen in 12 of 35 (34%) MSKCC patients and in nine of 41 (22%) of the CCOP patients with 95% confidence intervals of 0.18 to 0.50 and 0.10 to 0.35 in the two groups, respectively. The predominant toxicities were as follows: nausea and vomiting, 32%; mucositis, 26%; leukocyte counts less than 2000 cells/mm3, 17%; platelet counts less than 25,000 cells/mm3, 8%; and severe neurotoxicity, 5%. Dose attenuation was similar in the two groups. The median survival was 16.4 months for the MSKCC group and 9.6 months for the CCOP group (P = 0.0003). Although the baseline characteristics (age, sex, performance status, and baseline lactic dehydrogenase [LDH] and alkaline phosphatase) were similar, on further examination differences between the two groups were evident. In the MSKCC group, 14% of patients with liver metastases had greater than 50% of their liver involved with tumor whereas this occurred in 41% of the CCOP group (P = 0.03). The LDH values greater than 500 U/l were observed in 10% of patients in the MSKCC group and in 37% of the patients in the CCOP group (P = 0.007). Characteristics which reflect the bulk of disease, such as the percent of liver involvement, need to be analyzed in order to evaluate purported survival differences in randomized and nonrandomized trials of colorectal carcinoma.

Mammary angiosarcoma. The prognostic significance of tumor differentiation.

Mammary angiosarcoma appears to be a heterogeneous group of neoplasms morphologically, in which growth pattern or grade is an important prognostic factor. In this report, 63 patients whose slides were seen in consultation and/or who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) are described. Included are 32 MSKCC patients from an earlier study (with additional follow-up for 15 who are alive) and 31 new cases. Twenty-five (40%) patients had low-grade (Type I) lesions (including the only man in the series), 12 (19%) patients had intermediate-grade (Type II) tumors, and 26 (41%) patients had high-grade (Type III) angiosarcomas. Because prognosis is significantly related to the type of angiosarcoma, the lesion should be thoroughly studied microscopically to establish tumor type. Estimated probabilities of disease-free survival 5 years after initial treatment were as follows: Type I: 76%; Type II: 70%; and Type III: 15%. The median length of disease-free survival also was related to tumor type (Type I: greater than 15 years; Type II: greater than 12 years; and Type III: 15 months). Pretreatment duration of the lesion and primary tumor size were not significantly related to the risk of recurrence or to survival. Total mastectomy is recommended for most mammary angiosarcomas. Adjuvant chemotherapy was used in 31 of 63 (49%) patients and, in this group, recurrences developed in 14 (45%) patients. Among 32 (51%) patients not treated with adjuvant chemotherapy, 18 (56%) had recurrences. Whereas the few long-term survivors with Type III tumors received adjuvant chemotherapy, recurrences developed in most patients with comparable lesions who were given this treatment. Because Type III angiosarcoma has a poor prognosis, such treatment may be appropriate for these patients. We were unable to demonstrate that adjuvant chemotherapy significantly improved prognosis for patients with Type I and Type II tumors, although recurrences tended to be less frequent among treated patients.