Development Of Second Primary Malignancies Research Articles

Androgen Deprivation Therapy for Treatment of Localized Prostate Cancer and Risk of Second Primary Malignancies

Background:While androgen deprivation therapy (ADT) is a common treatment for prostate cancer, little is known regarding its long term health effects, particularly as it relates to the development of second primary malignancies. Therefore, the goal of this study was to assess the association between ADT use and second primary malignancies among men diagnosed with localized prostate cancer. Methods:We assessed whether use of ADT (specifically, gonadotropin-releasing hormone agonists) was associated with the development of second primary malignancies in a retrospective cohort of 24,038 men ages >18 years who were diagnosed with localized prostate cancer between 1998 and 2007, and followed through 2009. We used proportional hazards regression to estimate the risk of developing a second primary cancer among men who were treated with ADT compared to men who were not. Results:Men who were treated with ADT were not more likely to develop any second primary malignancy compared to those who were not treated with ADT after adjustment for age, race, date of diagnosis, utilization, clinical stage, Gleason score and radiation therapy (HR: 1.10, 95%CI: 0.98, 1.22). Radiation therapy, diabetes and obesity did not modify the association between ADT use and second primary cancer risk. Conclusions: Our results suggest among men with localized prostate cancer, androgen deprivation therapy is not associated with an increased risk of second primary malignancies. Impact:When evaluating the risks and benefits of using ADT as a treatment for localized prostate cancer, considering the risk of second primary malignancies may not be clinically important.

Risk factors for development of second primary malignancies (SPM) after autologous stem cell transplant (ASCT) for multiple myeloma.

8038 Background: Studies from the CALGB and IFM have suggested an increased incidence of SPM post ASCT in patients on lenalidomide maintenance. Patients with MM as well as patients post ASCT are inherently at higher risk of SPM. Therefore, assessment of risk factors associated with SPM would be useful in therapeutic decisions re preASCT therapy and post ASCTmaintenance. Methods: We conducted a retrospective cohort study of 841 consecutive MM patients who underwent at least one ASCT at City of Hope from 1989 to 2009. Sixty cases with 70 SPMs were identified. A nested case-control study was also conducted to understand the role of therapeutic exposures associated with SPMs. Controls were MM patients post ASCT matched by year of HCT (±5 years). Results: The median length of follow up was 3.3 yrs. (range 0.3-19.9). Median age at ASCT was 56 yrs (range 18-77). 62% had received a single autologous HCT, 27% tandem autologous HCT, 11% had received multiple HCTs (72 had a second allogeneic HCT)). The overall cumulative incidence of any SPM was 7.4% at 5 years and 15.9% at 10 years; the cumulative incidence of SPMs for patients >55 years approached 21.9% at 10 years. The cumulative incidence of MDS/AML was 1.8% and of solid tumors was 13.0%. Factors examined included age, race, sex, number and individual therapeutic exposures ( pre-ASCT, conditioning, and post-ASCT), disease status at ASCT. Multivariate Cox regression analysis revealed non-Hispanic whites (RR=2.4, 95% CI, 1.2-4.6, p=0.01) and older age (>55) at diagnosis of MM (RR=2.3, 95% CI, 1.3-4.1, p=0.004) to be associated with an increased risk of developing SPMs. Only cumulative thalidomide exposure (both pre-ASCT and post-ASCT) demonstrated a trend toward a positive association (OR=3.5, 95% CI, 0.6-19.4, p=0.15). Six patients (3 cases and 3 controls) were exposed to lenalidomide prior to development of SPM (OR=1.0, 95% CI, 0.14-7.10). Conclusions: This single institution analysis identified non-hispanic whites and older age to be associated with increased risk of developing SPM in pts post ASCT for MM. The trend towards increased risk with thalidomide exposure may be suggestive of a class effect from IMIDs that is not restricted to lenalidomide alone.

A Novel Molecular Signature Identified by Systems Genetics Approach Predicts Prognosis in Oral Squamous Cell Carcinoma

Molecular methods for predicting prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are urgently needed, considering its high recurrence rate and tendency for metastasis. The present study investigated the genetic basis of variations in gene expression associated with poor prognosis in OSCC using Affymetrix SNP 6.0 and Affymetrix GeneChip Human Gene 1.0 ST arrays. We identified recurrent DNA amplifications scattered from 8q22.2 to 8q24.3 in 112 OSCC specimens. These amplicons demonstrated significant associations with increased incidence of extracapsular spread, development of second primary malignancies, and poor survival. Fluorescence in situ hybridization, in a validation panel consisting of 295 cases, confirmed these associations. Assessment of the effects of copy number variations (CNVs) on genome-wide variations in gene expression identified a total of 85 CNV-associated transcripts enriched in the MYC-centered regulatory network. Twenty-four transcripts associated with increased risk of second primary malignancies, tumor relapse, and poor survival. Besides MYC itself, a novel dysregulated MYC module plays a key role in OSCC carcinogenesis. This study identified a candidate molecular signature associated with poor prognosis in OSCC patients, which may ultimately facilitate patient-tailored selection of therapeutic strategies.

Genetic variants of the p53 and p73 genes jointly increase risk of second primary malignancies in patients after index squamous cell carcinoma of the head and neck

Because of the structural and biochemical similarities between the antitumor p53 and p73 proteins, the authors hypothesized that individuals who carry high-risk genotypes of p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms have a higher risk of developing second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). A cohort of 1269 patients with index cases of SCCHN was recruited between May 1995 and January 2007 at The University of Texas MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms. A log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk among different risk groups with the combined risk genotypes of the 2 polymorphisms. The data demonstrated that patients with p53 WP + PP and p73 GC/GC genotypes had a worse SPM-free survival and an increased SPM risk compared with the corresponding p53 WW and p73 GC/AT + AT/AT genotypes. After combining the 2 polymorphisms, a borderline significantly or significantly reduced SPM-free survival and increased SPM risk were observed in the medium-risk group (p53 WW and p73 GC/GC or p53 P carriers and p73 AT carriers) and high-risk group (p53 P carriers and p73 GC/GC) compared with low-risk group (p53 WW and p73 AT carriers), respectively. The results suggest an increased risk of SPM after index SCCHN with both p53 and p73 polymorphisms individually and in combination.

Site-specific relative risks of second primary malignancies among patients with Waldenstrom macroglobulinemia.

e18566 Background: Waldenstrom Macroglobulinemia (WM) is a rare and indolent B-cell malignancy characterized by overproduction of monoclonal immunoglobulin M protein. The long duration of survival for most patients with WM and the use of potentially carcinogenic agents during therapy raise concerns about the development of second primary malignancies. However, the relative risks of second primary malignancies among patients with WM are not well-documented. Therefore, we investigated site-specific relative risks of second primary malignancies among patients with primary WM. Methods: Data from 9 population-based registries of the Surveillance, Epidemiology, and End Results program were used to identify patients diagnosed with primary WM between 1973 and 2007 for whom follow-up data were available. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CIs) of site-specific second primary malignancies were estimated by dividing the number of observed cases of second primary malignancies for the specific site within the WM cohort by the number of expected cases (standardized by age, sex, race/ethnicity, and calendar-year) of secondary primary malignancies for the specific site in the general United States population. Results: The WM cohort (n=1,521) yielded 226 second primary malignancies during 6,958 person-years of follow-up (incidence density = 3,248 cases/100,000 person-years of follow-up). Potentially durable estimates of higher site-specific relative risks were observed for colon (SIR=2.3, 95% CI: 1.6, 3.3), lung (SIR=1.7, 95% CI: 1.2, 2.4), non-Hodgkin lymphoma (SIR=4.9, 95% CI: 3.2, 7.1), myeloma (SIR=4.9, 95% CI: 2.2, 9.2), and acute myeloid leukemia (SIR=5.9, 95% CI: 2.2, 12.8) compared to the general US population. Conclusions: Our results indicate that patients with WM have a higher relative risk of second primary malignancies for several sites. Although the higher relative risks of second primary hematologic malignancies may be treatment- or immunologically-related, the modestly higher relative risks of second primary solid tumors may be the result of detection bias or risk factors shared between WM and the specific solid tumors.

Incidence of second primary malignancies (SPM) after 6-years follow-up of continuous lenalidomide in first-line treatment of multiple myeloma (MM).

8008 Background: Lenalidomide (Rev) has markedly improved survival in patients (pts) with MM. As we gain insight into the long-term effects of this agent, concern has arisen for the possibility of SPM including MDS/AML. Clarithromycin (Biaxin), lenalidomide and dexamethasone (BiRD) was shown to be an effective regimen in symptomatic, newly diagnosed MM. Of 72 patients enrolled, 90.3% had an objective response, 38.9% a complete response (sCR/CR), and 73.6% at least a very good partial response (VGPR). This experience has been compounded by the observation of deepening responses to prolongation of Rev-based therapy beyond induction. All pts have continued to be followed. Methods: Review of all pts charts from the original study with focus on overall survival, progression of disease, time to progression, and development of SPM was completed. Pts were maintained on BiRD until progression of disease, stem cell transplant, or development of intolerable side effects. Results: Long-term follow up demonstrates an overall survival of 82.2% (95% CI 70.7, 89.5) after 4 years. Eleven pts remain on study, while 47 have received second line therapy. Evaluation of SPM in the 68 evaluable pts revealed 11 new diagnoses (incidence of 16%) after an average of 31 cycles (range 3-68) of lenalidomide (BiRd). Six were skin cancers (4 BCC, 2 SCC), 2 colon, 1 prostate, 1 pancreas and 1 metastatic melanoma. Notably, none developed MDS/AML. Mean time to SPM diagnosis was 35 months (range 5-64). Only 7/11 subjects were still on active lenalidomide therapy. Conclusions: BiRD is a highly effective regimen in newly diagnosed MM. In these treatment-naïve pts, no cases of secondary MDS/AML were seen, in contrast to reports in relapse/refractory pts who received Rev as third or fourth line therapy (Reece, Goswami ) or as post-transplant maintenance (Attal , McCarthy). Frequency of SPM is similar to 2010 SEER data for non-MM individuals of similar age. As survival in pts with MM continues to improve, so will our understanding of the long-term effects of novel agents. Design of regular cancer screening programs (derm and GI) of MM pts should be regularly implemented.

Association of p53 codon 72 polymorphism with risk of second primary malignancy in patients with squamous cell carcinoma of the head and neck

p53 plays a critical role in cellular anticancer mechanisms, and has been correlated with second primary malignancy (SPM) development. A common polymorphism in codon 72 of p53 results in an amino acid substitution and could influence p53 function. The authors hypothesized that p53 codon 72 polymorphism may be associated with risk of SPMs and SPM-free survival among patients with squamous cell carcinoma of the head and neck (SCCHN). A total of 1271 patients, who were diagnosed with incident SCCHN between May 1995 and January 2007, were genotyped and observed for SPM development. Log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk between the different genotype groups. The authors found significantly reduced SPM-free survival for patients with variant proline (Pro) 72 allele compared with patients with arginine (Arg) 72 homozygous genotype (log-rank test, P = .005). Compared with SCCHN patients with the p53 72Arg/Arg genotype, there was a significantly greater risk of SPM associated with the p53 72Arg/Pro genotype (hazard ratio [HR], 1.75; 95% confidence interval [CI], 1.17-2.61) and combined p53 72Arg/Pro + Pro/Pro (HR, 1.58; 95% CI, 1.07-2.34). Furthermore, stratification analyses showed that the risk of SPM associated with p53 variant genotypes (Arg/Pro + Pro/Pro) was more pronounced in several subgroups. p53 codon 72 polymorphism could be a risk marker for genetic susceptibility to SPM in patients with primary SCCHN.

P73 G4C14‐to‐A4T14 polymorphism and risk of second primary malignancy after index squamous cell carcinoma of head and neck

P73 plays an important role in modulating cell-cycle control, inducing apoptosis, and inhibiting cell growth. A novel noncoding p73 G4C14-to-A4T14 exon 2 polymorphism was associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that p73 G4C14-to-A4T14 polymorphism modulates risk of second primary malignancies (SPM) in patients after index SCCHN. We followed a cohort of 1,384 patients diagnosed with incident SCCHN between May 1995 and January 2007 for SPM development. Log-rank test and Cox proportional hazard models were used to compare SPM-free survival and SPM risk between the different genotype groups. Our results showed that patients carrying the p73 variant AT allele were less likely to develop SPM compared with the patients with p73 GC/GC genotype (Log-rank test, p = 0.013). Compared with the p73 GC/GC genotype, there was a significantly reduced risk of SPM associated with the p73 GC/AT genotype (HR, 0.61, 95% CI, 0.40-0.93) and the combined p73 GC/AT+AT/AT genotypes (HR, 0.59, 95% CI, 0.39-0.89), but a nonsignificantly reduced risk for p73 AT/AT genotype (HR, 0.44, 95% CI, 0.14-1.41). The p73 AT allele was significantly associated with risk of SPM in an allele dose-response manner (p = 0.011 for trend). The risk of SPM associated with p73 variant genotypes (GC/AT+AT/AT) was more pronounced in several subgroups (e.g., older patients, men, minorities, ever smokers, and ever drinkers). Our results support that this p73 polymorphism may be a marker for risk of SPM among patients with an incident SCCHN.

Glutathione S-Transferase Polymorphisms and Risk of Second Primary Malignancy after Index Squamous Cell Carcinoma of the Head and Neck

Glutathione S-transferases (GST) detoxify carcinogens in tobacco smoke, which plays a major role in development of not only squamous cell carcinoma of the head and neck (SCCHN) but also second primary malignancy (SPM) after index SCCHN. We hypothesized that GSTM1 null, GSTT1 null, GSTP1 Ile(105)Val, and GSTP1 Ala(114)Val polymorphisms would individually and, more likely, collectively show an association with risk of SPM after index SCCHN. One thousand three hundred seventy-six incident SCCHN patients were prospectively recruited between May 1996 and December 2006, genotyped, and followed for SPM development. One hundred ten patients (8%) developed SPM: 43 (39%) second SCCHN, 38 (35%) other tobacco-associated sites, and 29 (26%) other non-tobacco-associated sites. Patients with GSTP1 Ile(105)Val polymorphism had a statistically significant association with risk of SPM development (adjusted hazard ratio, 1.7; 95% confidence interval, 1.1-2.5). However, no statistically significant associations were observed with GSTM1, GSTT1, or GSTP1 Ala(114)Val polymorphisms. After combining risk genotypes for all four polymorphisms, rates of SPM development with 0 to 1, 2, 3, and 4 risk genotypes were 6.4%, 8.4%, 10.9%, and 15.1%, respectively, and a stepwise increase in SPM risk was observed with increasing number of risk genotypes (P = 0.004 for trend). Patients with 3 to 4 risk genotypes had a 1.7-fold increased risk for SPM compared with patients with 0 to 2 risk genotypes (hazard ratio, 1.70; 95% confidence interval, 1.2-2.5). This large prospective cohort study supports a modestly increased risk of SPM after index SCCHN with GSTP1 Ile(105)Val polymorphism and an even greater risk of SPM with multiple combined GST risk genotypes.

Nucleotide excision repair core gene polymorphisms and risk of second primary malignancy in patients with index squamous cell carcinoma of the head and neck

The nucleotide excision repair (NER) pathway is central in response to damage induced by environmental carcinogens. Efficiency of this pathway, probably genetically determined, may modulate individual risk of developing squamous cell carcinoma of the head and neck (SCCHN) as well as second primary malignancy (SPM) after the index tumor. We hypothesized that common non-synonymous and regulatory single-nucleotide polymorphisms (SNPs) in the NER core genes individually, and more probably collectively, associated with the risk of SPM. We genotyped for seven selected SNPs in 1376 incident SCCHN patients who were prospectively recruited between 1995 and 2006 and followed for SPM development. We found that 110 patients (8%) developed SPM: 43 (39%) second SCCHN; 38 (35%) other tobacco-associated sites and 29 (26%) other non-tobacco-associated sites. The associations of these SNPs with SPM risk were assessed assuming a recessive genetic model. We did not find any significant associations of each or in combination of the seven SNPs with SPM risk in the recessive models. However, when we explored the combined effect based on an alternatively dominant genetic model, we found that the number of observed risk genotypes was associated with a significantly increased SPM risk in a dose-response manner (P = 0.005) and patients with five to seven risk genotypes had a significantly 2.4-fold increased SPM risk compared with patients with zero to two risk genotypes. These findings suggest that a profile of NER core gene polymorphisms might collectively contribute to risk of SPM not in a recessive model but in a dominant model among patients with an index primary SCCHN. These findings need to be validated in future studies with larger sample sizes and longer follow-up time.

Whole abdomen irradiation in epithelial ovarian cancer: A single institution study

Background: The examination of the use of whole abdomen irradiation open field technique in optimally debulked patients with no residual disease with epithelial ovarian cancer (OC). Methods: Between 1993 and 2007, 20 patients with optimally cytoreduced epithelial OC were treated with WAI. The stage distribution was stage I in 15 patients, stage II in 1, and stage III in 4. The grade distribution was grade 1 in 10 patients, grade 2 in 4, and grade 3 in 6. WAI consisted of 30 Gy, delivered in daily fractions, mainly of 1.5 Gy (95%), 5 days/weekly, in 14 patients. After abdominal irradiation, in 75% of the patients a pelvic boost, and in 7 a boost to other risk sites was given to reach 45 - 50 Gy. Nine patients received platinum based chemotherapy (CT). Median follow-up was 7.96 years. Results: The overall survival (OS) rate was 82% and 70% at 5 and 10 years. A tendency to better survival was found in patients with age ? 40 than in those with > 40 years (100%:100% vs. 68%:51%; p=0.03). Patients with grade 1-2 tumors had significantly better 5- and 10-year survival rate than those with grade 3 tumors (100%:100% vs. 40%:20%; p<0.00). The 5- and 10-year OS for the patients 'with' and 'without' a pelvic boost turned to be in favor of the patients 'with' the boost (91%:91% vs. 60%:40%; p=0.02). In 15 patients (75%) RT was transiently interrupted because of acute gastrointestinal and hematological toxicity. Neither grade 4 acute complications nor was mortality observed. Late gastrointestinal effect developed in 1 patient, presented with grade 4 complications. The development of second primary malignancy was not observed during the follow-up period. Conclusion: WAI achieves a quite favorable 5- and 10-year survival rate with an acceptable risk of acute and late side effects in properly selected patients with epithelial OC.

Second primary malignancies in patients with cancer of the head and neck

Clinical study of second primary malignancies (SPM) in patients with cancer of the head and neck (HNC). Study design and setting Retrospective study over 48 patients with SPMs culled from 636 with HNC seen in 122 months. The minimum follow-up was 18 months, and the setting for the study was the institutional referral center. There was association between the sites of first and second tumor. The SPMs were diagnosed with a constant rate throughout the period of study. Five year-survival rate was 29%. SPM in an advanced stage either outside of the head and neck or synchronous had poor survival. The SPMs are a growing problem with better survival after treatment of the first malignancy. Regular follow-up is necessary in HNC patients to improve their survival, giving special attention to the development of SPM.

Second primary malignancies in patients with cancer of the head and neck.

Clinical study of second primary malignancies (SPM) in patients with cancer of the head and neck (HNC). Study design and setting Retrospective study over 48 patients with SPMs culled from 636 with HNC seen in 122 months. The minimum follow-up was 18 months, and the setting for the study was the institutional referral center. There was association between the sites of first and second tumor. The SPMs were diagnosed with a constant rate throughout the period of study. Five year-survival rate was 29%. SPM in an advanced stage either outside of the head and neck or synchronous had poor survival. The SPMs are a growing problem with better survival after treatment of the first malignancy. Regular follow-up is necessary in HNC patients to improve their survival, giving special attention to the development of SPM.

Leiomyosarcoma as a Second Metachronous Malignant Neoplasm Following Colon Adenocarcinoma. A Case Report and Review of the Literature

Long-term cancer survivors are at increased risk for the development of second primary malignancies. This is usually associated with common genetic and etiologic factors and the treatment modality used for the primary cancer. In this paper we describe the case of a patient who developed a leiomyosarcoma in his left arm 5 years after he had a colon adenocarcinoma resected. Both primary tumours were treated successfully with surgical resection alone. The literature regarding second primary neoplasms, specifically focused on sarcomas, is briefly reviewed.