Increased risk of salivary gland cancer among women with a previous cancer diagnosis

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1 ORIGINAL ARTICLE Increased risk of salivary gland cancer among women with a previous cancer diagnosis Aaron D. Falchook, MD, 1 Jose P. Zevallos, MD, 2 Bhishamjit S. Chera, MD 1 * 1 Department of Radiation Oncology, University of North Carolina Hospitals, Chapel Hill, North Carolina, 2 Department of Otolaryngology, University of North Carolina Hospitals, Chapel Hill, North Carolina. Accepted 6 January 2015 Published online 14 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate salivary gland cancer incidence among patients with a previous cancer diagnosis and explore the potential relationship of salivary gland cancer among women with a previous diagnosis of breast cancer. Methods. We obtained information from the Surveillance, Epidemiology, and End Results (SEER) database for patients diagnosed between 1973 and Incidence, annual percent change (APC), and survival were examined. Results. Women were more likely than men to experience subsequent salivary gland cancer, female observed to expected (O/E) (95% confidence interval [CI], ) versus male O/E (95% CI, ). Index breast cancer does not confer greater risk of salivary gland cancer. Women demonstrate improved overall survival (OS) and cause-specific survival (CSS) compared with men for subsequent salivary gland cancer. Conclusion. Among patients with a previous cancer diagnosis, the risk of subsequent salivary gland cancer is greater among women than men. More research is needed to determine the relationship between index breast cancer and subsequent salivary gland cancer risk. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E446 E451, 2016 KEY WORDS: salivary gland cancer, breast cancer INTRODUCTION *Corresponding author: B. S. Chera, Department of Radiation Oncology, University of North Carolina Hospitals, CB #7512, Chapel Hill, NC bchera@med.unc.edu Malignant salivary gland tumors are rare and account for approximately 0.5% of all malignancies and 3% to 5% of all head and neck cancers. 1 The most common salivary gland cancer histologic subtypes include mucoepidermoid, adenoid cystic, acinic carcinomas, and adenocarcinomas. Less common salivary gland cancer histologies include lymphoma, myoepithelial, and mixed cell types. Overall, incidence of salivary gland cancer is higher among men compared to women at a 3:2 ratio. 2 Radiation exposure is a risk factor for development of salivary gland cancers, but other causative factors for these cancers remain unknown. 3 Analysis of cancer registries has shown that women diagnosed with breast cancer have increased incidence of subsequent salivary gland cancer. 4,5 There is currently no definitive explanation for this phenomenon. One possible mechanism of increased salivary gland cancer among breast cancer survivors is hormone receptor-mediated tumor biology. Breast cancer cells and salivary gland cancer cells may express estrogen receptors (ERs) and/or progesterone receptors (PRs). Medical literature regarding ER/PR expression in salivary gland cancers is mixed; some studies indicate that salivary gland cancers demonstrate ER/PR positivity, whereas other studies do not report these findings. 6 9 Furthermore, adenoid cystic, mucoepidermoid, and acinic cell carcinomas may arise de novo in the breast and these tumors exhibit immunohistochemical markers, which are similar to the intrinsic basallike subtype of breast cancer It is, thus, unclear what relationship, if any, exists between breast cancer and salivary gland cancer. The association between breast cancer and salivary gland cancer is potentially clinically relevant. Identification of biologic similarities between breast cancer and salivary gland cancer may lead to new screening, diagnostic, or treatment strategies for salivary gland cancer among women with a history of breast cancer. The purpose of this study was to evaluate the incidence of salivary gland cancer among patients with a history of cancer, and to explore the potential significance of index breast cancer on the subsequent risk of salivary gland cancer. MATERIALS AND METHODS Data source Incidence and survival data were obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The SEER 9 Registries were used to identify the patient population in this study. Cancer site for index and second cancers was classified using the SEER Site and Morphology Site recode B ICD-O-3/WHO 2008 variable. This study does E446 HEAD & NECK DOI /HED APRIL 2016

2 SALIVARY GLAND SECOND CANCER AFTER PREVIOUS CANCER TABLE 1. Patient race and tumor characteristics for overall primary and subsequent salivary gland cancers stratified by sex and breast versus nonbreast index cancer. Primary salivary gland cancers (N ) Subsequent salivary gland cancers (N ) Patient characteristics No. of patients (%) No. of patients (%) p value Race <.001 White 7538 (84) 1090 (89) Black 723 (8) 73 (6) Other 728 (8) 62 (5) Salivary cancer histology <.001 Acinar cell 1114 (13) 83 (7) Adenocarcinoma 1435 (16) 201 (16) Adenoid cystic 1222 (14) 75 (6) Carcinoma ex pleomorphic adenoma 204 (2) 22 (2) Ductal carcinoma 118 (1) 23 (2) Mucoepidermoid 2074 (23) 319 (26) Other 1081 (12) 161 (13) Squamous carcinoma 1361 (15) 302 (25) Unspecified 245 (3) 39 (3) Salivary cancer grade < (Well differentiated) 867 (10) 123 (10) 2 (Moderately differentiated) 1623 (18) 276 (23) 3 (Poorly differentiated) 1638 (18) 276 (23) 4 (Undifferentiated/anaplastic) 798 (9) 134 (11) Unknown 4063 (45) 416 (34) Salivary cancer site.499 Parotid 7042 (78) 979 (80) Submandibular 1423 (16) 174 (14) Sublingual 114 (1) 14 (1) Not specified 410 (5) 58 (5) not qualify as human subject research and received an exemption from the institutional review board. Study population Patients were diagnosed with cancer between 1973 and Nonmalignant cancers were excluded from all analyses. Patients with any index cancer were evaluated for subsequent salivary gland cancer, stratified by sex. Exploratory analyses excluded both patients with index head and neck cancer and index salivary gland cancer. Among female patients, index cancers were classified as breast cancer or nonbreast cancer. For female index breast cancers, hormone receptor status was assessed via the ER and PR Status Recode Breast Cancer variable (available only for patients diagnosed 1990 and later). Among female patients, the incidence of second breast cancer after an index salivary gland cancer was evaluated. Statistical analysis SEER*Stat version software was used to obtain case information and for statistical tests pertaining to expected cancers. Chi-square tests to compare characteristics of primary and subsequent salivary gland cancers and survival analysis were performed using SAS version 9.2 (Cary, NC). Multiple primary standardized incidence ratios were used to create an observed to expected (O/E) ratio of the observed secondary events. Excess personrisk per 10,000 and mean age of patients at the time of diagnosis for index cancer and second cancer is reported. SEER 9 registry data files were used to identify primary and subsequent cases, calculate expected values, and evaluate survival. Ninety-five percent confidence intervals (95% CIs) for O/E were calculated. Annual percent change (APC) for salivary gland cancer incidence was calculated from 1975 to Incident cases from the SEER 9 registry file from 1973 to 2002 (the most complete and recent SEER 9 file with survival data) were used in survival analysis. Overall survival (OS) and cause-specific survival (CSS) were estimated using Kaplan Meier analysis for patients with subsequent salivary gland cancers, stratified by sex. Log-rank p values are used to compare survival between men and women. Relative OS (observed survival divided by expected survival) for primary and subsequent salivary gland cancers is also reported, stratified by sex. RESULTS Patient race, salivary gland cancer histology, grade, and site are shown for both primary and subsequent salivary gland cancers in Table 1. Salivary gland tumor characteristics as well as index cancer sites are shown in Table 2, stratified by sex and breast versus nonbreast index cancer for women. Subsequent salivary gland cancers were highgrade more frequently than first primary salivary gland cancers (34% vs 27%), although 34% to 45% of patients had unknown tumor grade. Among all patients with a previous diagnosis of any index cancer, there were 1225 observed second salivary cancers and 850 expected HEAD & NECK DOI /HED APRIL 2016 E447

3 FALCHOOK ET AL. TABLE 2. Patient race and tumor characteristics for subsequent salivary gland cancers stratified by sex and breast versus nonbreast index cancer. Men (any index, N 5 748) Women (breast index, N 5 194) Women (nonbreast index, N 5 279) Patient characteristics No. of patients (%) No. of patients (%) No. of patients (%) p value Race.044 White 678 (91) 166 (85) 242 (87) Black 40 (5) 11 (9) 22 (8) Other 30 (4) 17 (6) 15 (5) Index cancer CNS/eye 19 (3) ( ) 9 (3) Gastrointestinal 83 (11) ( ) 44 (16) Female breast ( ) 194 (100) ( ) Gynecologic ( ) ( ) 48 (17) Head and neck (nonsalivary) 82 (11) ( ) 31 (11) Leukemia/lymphoma 100 (13) ( ) 44 (16) Lung and bronchus 33 (4) ( ) 13 (5) Skin melanoma 51 (7) ( ) 22 (8) Other 40 (5) ( ) 10 (4) Prostate 248 (33) ( ) ( ) Renal/urinary 65 (9) ( ) 14 (5) Salivary gland 13 (2) ( ) 18 (6) Thyroid 14 (2) ( ) 26 (9) Subsequent salivary cancer histology <.001 Acinar cell 34 (5) 20 (10) 29 (10) Adenocarcinoma 123 (16) 36 (18) 42 (15) Adenoid cystic 33 (4) 11 (6) 31 (11) Carcinoma ex pleomorphic adenoma 12 (2) 5 (3) 5 (2) Ductal carcinoma 14 (2) 3 (2) 6 (2) Mucoepidermoid 155 (21) 77 (39) 87 (31) Other 108 (14) 22 (11) 31 (11) Squamous carcinoma 244 (33) 18 (9) 40 (14) Unspecified 27 (4) 4 (2) 8 (3) Subsequent salivary cancer grade < (Well differentiated) 57 (8) 31 (16) 35 (13) 2 (Moderately differentiated) 144 (19) 56 (29) 76 (27) 3 (Poorly differentiated) 213 (28) 24 (12) 39 (14) 4 (Undifferentiated/anaplastic) 103 (14) 12 (6) 19 (7) Unknown 233 (31) 73 (37) 110 (39) Subsequent salivary cancer site.534 Parotid 606 (81) 154 (79) 219 (78) Submandibular 101 (13) 30 (15) 43 (15) Sublingual 7 (1) 1 (1) 6 (2) Not specified 36 (5) 11 (6) 11 (4) Abbreviation: CNS, central nervous system. cancers (Table 3). The O/E for women with any index cancer was 1.63, which was statistically significantly greater than the O/E of 1.34 for men with any index cancer. When index salivary gland cancer and index head and neck cancers were excluded, the statistically significant increase of second salivary gland cancer among women versus men persisted. There was no significant difference in salivary gland O/E for white versus black patients. Among women, there was no difference in the O/E salivary gland cancer incidence for patients with index breast TABLE 3. Incidence of subsequent salivary gland cancer among patients with a previous cancer diagnosis. Sex Index cancer Salivary cancers observed Salivary cancers expected O/E 95% CI Excess risk per 10,000 Mean age of index cancer, y Mean age of salivary cancer, y Any Any ( ) Male Any ( ) Female Any ( ) Female Breast ( ) Female Nonbreast ( ) Abbreviations: O/E, observed/expected; 95% CI, 95% confidence interval. E448 HEAD & NECK DOI /HED APRIL 2016

4 SALIVARY GLAND SECOND CANCER AFTER PREVIOUS CANCER TABLE 4. Incidence of salivary gland cancer diagnosis among women with breast cancer diagnosis, stratified by hormone receptor status of index breast cancer (for women diagnosed with breast cancer 1990 or later). ER PR Cases observed Cases expected O/E 95% CI Excess risk per 10,000 Mean age of index cancer, y Mean age of salivary gland cancer, y Positive Positive ( ) Negative Negative ( ) Positive Any ( ) Any Positive ( ) Abbreviations: ER, estrogen receptor; PR, progesterone receptor; O/E, observed/expected; 95% CI, 95% confidence interval. cancer versus nonbreast cancer (Table 3). An exploratory analysis that included women diagnosed with ductal carcinoma in situ, did not significantly change these results. Stratification by race did not reveal a statistically significant risk differential for second salivary gland cancer between white and black women for both breast and nonbreast index cancers. Examination of index breast cancer by ER and PR status did not identify a subset of patients with a statistically increased O/E for salivary gland cancer compared to the baseline female cohort (Table 4). When women with index salivary gland cancers were evaluated, there was no excess incidence of second breast cancers, O/E (95% CI ). There was no significant change in incidence of primary salivary gland cancers between 1975 and The APC for subsequent salivary gland cancer after any index cancer was 3.19 (95% CI, ). This is significantly increased compared to the APC for subsequent nonsalivary gland cancers, 2.28 (95% CI, ; see Figure 1). Stratification by sex did not reveal a significantly different APC for men versus women for either primary or subsequent salivary gland cancers. Kaplan Meier survival estimates for OS and CSS are shown in Figure 2. Five-year OS was 57% for women and 28% for men (log-rank p <.0001). Five-year CSS was 87% for women and 75% for men (log-rank p ). Relative survival at 5 years was 69% (95% CI, 62 75) for women and 40% (95% CI, 34 46) for men. FIGURE 1. Age adjusted salivary gland cancer rates, 1975 to APC, annual percent change; CI, confidence interval. DISCUSSION We observed an increasing incidence (APC ) from 1975 to 2011 of subsequent salivary gland cancer in patients with a prior index cancer (see Figure 1). For all subsequent salivary cancers, change in grade over time was evaluated and no trend for increased diagnosis of low-grade subsequent salivary gland cancers was identified. As demonstrated in Table 1, there was a slight increase in the diagnosis of higher grade subsequent salivary gland cancers compared with primary cancers. However, these findings should be interpreted in the context of unknown tumor grade recorded in 34% to 45% of cases in this dataset. The incidence of index salivary gland cancers during this time was stable. It is known that the incidence of index salivary gland cancers is higher in men than women. 2 However, we observed a reversal in this statistic for subsequent salivary gland cancer, with women having a higher incidence (Table 3). Women with subsequent salivary gland cancers had a better survival than men (see Figure 2). Women with an index breast cancer did not have a higher risk of subsequent salivary gland cancer as compared with women with no prior diagnoses of cancer (Table 3). Further stratification by hormone receptor status in women with index breast cancer did not show a cohort with a higher incidence. Retrospective studies have demonstrated increased incidence of second primary breast cancer among women with a history of salivary gland cancer. 13,14 Those findings were not confirmed in this study, as no excess incidence of breast cancer was observed among women with a history of salivary gland cancer in this SEER cohort. Among female patients, the mean interval between index cancer and salivary gland cancer is 7.6 years for index breast cancer and 2.6 years for nonbreast index cancer. Because of the fact that subsequent salivary cancer histology and grade are similar between these 2 groups, this finding may be related to increased detection during surveillance imaging for nonbreast index cancers, as breast cancer surveillance imaging (mammography) would be unlikely to detect salivary gland cancers. Radioisotope therapy was used for 15 of the 40 patients with index thyroid carcinoma in this dataset. It is possible that the use of radioactive iodine may increase the risk of subsequent salivary gland carcinoma for these patients. Decreased OS seen in men may be partly attributable to the difference in age at onset of subsequent salivary gland cancer (72.2 years for men, 66.8 years for women). HEAD & NECK DOI /HED APRIL 2016 E449

5 FALCHOOK ET AL. FIGURE 2. (A) Overall survival for subsequent salivary gland cancer, stratified by sex. (B) Cause-specific survival for subsequent salivary gland cancer, stratified by sex. However, improved survival was observed among women even when corrected for age and race (relative survival), and CSS was superior for women as well. Given the age and comorbidity associated with previous cancer diagnoses, it should be noted that competing risks of death for patients in this study is likely to be high. Furthermore, ascertainment of cause of death may be difficult for patients with multiple cancers and this may impact the accuracy of estimates of CSS for patients. Because of the observed clinical, biological (ie, receptors), and histopathological similarities of breast cancer and salivary gland cancer, an association between these cancers has been proposed. 14 It has been suggested that hormonal signaling may play a role in the development of salivary gland cancer. 15 If salivary gland carcinogenesis is mediated by hormone signaling pathways, women with hormone receptor-positive breast cancers may demonstrate a decreased risk of subsequent salivary gland cancers, because these women would presumably receive adjuvant hormonal therapy as part of their breast cancer treatment. This hypothesis was not supported by the finding that women with index breast cancer were not less likely to develop subsequent salivary gland cancer compared with women with index nonbreast cancer. Furthermore, when analysis was restricted to women with index hormone receptor-positive breast cancer, there was still no decrease in the incidence of subsequent salivary gland cancer. An alternate theory is that the use of adjuvant endocrine therapy after breast cancer may increase the risk of subsequent salivary gland cancer. This could potentially explain the reversal of sex predilection for salivary gland cancer in patients among those patients with index breast cancer. This hypothesis was not supported by the results of our analysis, which demonstrated that women with hormone receptor-negative index breast cancer (who presumably did not receive adjuvant endocrine therapy) did not have decreased risk of subsequent salivary gland cancer. Because there were only 19 cases of subsequent salivary gland cancer among women with hormone receptornegative breast cancer, this study may be underpowered to detect such a difference. Another explanation for the increased risk of salivary gland cancer among women with a history of breast cancer is that radiotherapy treatment of the breast cancer causes secondary malignancy. Analysis of the SEER database revealed that women with breast cancer treated with radiotherapy were not more likely than those not treated with radiotherapy to develop salivary gland cancer. 2 Furthermore, the salivary glands of the head and neck should receive minimal dose from breast radiotherapy. This remains true even for patients who receive comprehensive regional lymph node irradiation, as the superior border of the supraclavicular lymph node radiotherapy field is typically at the level of the cricoid cartilage, inferior to salivary gland tissues. The relationship between salivary gland cancer and breast cancer may be explained by genetic familial syndromes. A study of 153 Swedish men diagnosed with breast cancer from 1965 to 1989 revealed a significant excess risk of parotid gland cancer among female firstdegree relatives (standardized morbidity ratio 5.58). 16 Because of the limitations of the SEER database, we were unable to examine familial patterns of salivary gland cancer incidence to further investigate this question. Salivary duct carcinoma and mucoepidermoid carcinoma have been shown to overexpress the HER-2/neu gene, and this pathologic finding has been correlated with poor prognosis A case report details the use of trastuzumabbased chemotherapy in the treatment of metastatic carcinoma ex pleomorphic adenoma of the salivary gland with resultant durable complete response for over 1 year. 20 The relationship between the HER-2/neu gene overexpression and salivary gland cancer presents another potential link between salivary gland cancer and breast cancer biology. A possible explanation for the increased incidence of subsequent salivary gland cancers may be that, in more recent years, patients with index cancers experience improved cure rates compared with previous years. This increased survival translates into a longer follow-up time during which subsequent malignancies can develop. Despite the increased follow-up time, the APC for subsequent salivary gland cancer is greater than subsequent nonsalivary gland cancer, suggesting that other factors may E450 HEAD & NECK DOI /HED APRIL 2016

6 SALIVARY GLAND SECOND CANCER AFTER PREVIOUS CANCER contribute to the risk of subsequent salivary gland cancer. The issue of subsequent cancer diagnosis and treatment remains an important aspect of cancer survivorship. This study had several limitations. Because salivary gland cancer is so rare, this study may have been underpowered to detect clinically meaningful differences in patterns of incidence. There was insufficient data in the SEER database regarding HER-2/neu gene expression of index breast cancers to perform subset analysis of subsequent salivary gland cancer risk. Future studies based on the salivary gland cancer subtype could yield additional information regarding the relationship between salivary gland cancer and previous malignancies. Salivary gland cancer cases with squamous cell histology in the SEER database may represent cutaneous metastases, rather than primary squamous cell salivary gland cancers (which are rare). It is not possible to exclude this specific histology from the O/E reported in Tables 3 and 4 nor is it possible to identify patients with index squamous cell carcinoma of the skin in the SEER database to further evaluate this issue. However, because subsequent squamous histology salivary cancer is more common among men than women (33% vs 12%), exclusion of patients with reported squamous histology would increase the magnitude of our reported findings of increased salivary gland cancers among women. The correlation between increased incidence of salivary gland carcinoma and previous diagnosis of cancer does not imply causality, and this finding may not be the result of a clinically meaningful biologic mechanism. Additional study of tumor biology is required to better understand these issues. In summary, we evaluated the SEER database and report an excess incidence of salivary gland cancer among patients with a previous cancer diagnosis. 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