Background:

Subsequent malignant neoplasms (SMN; new cancers that arise after an original diagnosis) contribute to premature mortality among adolescent and young adult (AYA) cancer survivors. Because of the high population prevalence of human papillomavirus (HPV) infection, we identify demographic and clinical risk factors for HPV-associated SMNs (HPV-SMN) among AYA cancer survivors in the SEER-9 registries diagnosed from 1976 to 2015.

Methods:

Outcomes included any HPV-SMN, oropharyngeal-SMN, and cervical-SMN. Follow-up started 2 months after their original diagnosis. Standardized incidence ratios (SIR) compared risk between AYA survivors and general population. Age-period-cohort (APC) models examined trends over time. Fine and Gray's models identified therapy effects controlling for cancer and demographic confounders.

Results:

Of 374,408 survivors, 1,369 had an HPV-SMN, occurring on average 5 years after first cancer. Compared with the general population, AYA survivors had 70% increased risk for any HPV-SMN [95% confidence interval (CI), 1.61–1.79] and 117% for oropharyngeal-SMN (95% CI, 2.00–2.35); cervical-SMN risk was generally lower in survivors (SIR, 0.85; 95% CI, 0.76–0.95), but Hispanic AYA survivors had a 8.4 significant increase in cervical-SMN (SIR, 1.46; 95% CI, 1.01–2.06). AYAs first diagnosed with Kaposi sarcoma, leukemia, Hodgkin, and non-Hodgkin lymphoma had increased HPV-SMN risks compared with the general population. Oropharyngeal-SMN incidence declined over time in APC models. Chemotherapy and radiation were associated with any HPV-SMN among survivors with first HPV-related cancers, but not associated among survivors whose first cancers were not HPV-related.

Conclusions:

HPV-SMN in AYA survivors are driven by oropharyngeal cancers despite temporal declines in oropharyngeal-SMN. Hispanic survivors are at risk for cervical-SMN relative to the general population.

Impact:

Encouraging HPV vaccination and cervical and oral cancer screenings may reduce HPV-SMN burden among AYA survivors.

This article is featured in Highlights of This Issue, p. 583

Survivors of adolescent and young adult (AYA) cancers are at risk for mortality from subsequent malignant neoplasms (SMN), defined as new cancers that occur after the first primary diagnosis during adolescence or young adulthood (1–3). SMN may arise due to the original cancer (4), late treatment effects (5, 6), or cancer-causing agents including viruses (7, 8). Human papillomaviruses (HPV) cause 90% of cervical and anal, 70% of vaginal and vulvar, and 60% of penile cancers (9–11). In the United States (U.S.), prevalence of HPV infection is 42% in men and 39% in women (11). AYA cancer survivors may be at higher risk for HPV-associated SMNs (HPV-SMN) than the general public because of the immunologic impacts of their cancer therapy or the cancer itself (12, 13). Social determinants of health like low income, inadequate insurance, and debt from treatment may also impede AYAs from accessing preventive care that is necessary to prevent and detect HPV-SMN (14, 15). At the same time, AYA survivors receive the HPV vaccine at lower rates than the general public (16, 17), likely increasing their vulnerability to HPV-SMN compared with vaccinated persons.

Relative to persons without a cancer history, pediatric cancer survivors have up to 150% increased risk for HPV-SMN and are diagnosed with cervical-SMN an average of 7 years earlier than first cervical cancers in the general population (12, 13). Adult cancer survivors with first primary HPV-tumors also have a significant elevation in risk for HPV-SMN (18). The higher risk for both populations has been attributed to latent HPV infection as well as the immunosuppressive impact of cancer therapies like chemotherapy and radiation. However, research on the risk factors for HPV-SMN among AYAs is needed due to the different cancer diagnoses in this age group that do not fully overlap with pediatric or adult cancers. Breast, thyroid, lymphoma, testis, skin melanoma, leukemias, and lymphomas comprise 60% of AYA cancers. Survivors of these cancers have high risk for SMNs in general (4, 5, 19, 20), but the risk for HPV-SMN among these AYAs has not been examined separately from older adults (4, 5, 19).

At the same time, viral infections are also relevant to the etiology of certain AYA cancers and may impact one's future risk for HPV-SMNs (21). Cancer sites for which viral infection may be relevant to their development and later HPV-SMN risk include Kaposi sarcoma, lung, and colorectal cancers (22–24). Thus, there is a pressing need to identify the risk for HPV-SMN among AYA survivors in general, and to understand whether HPV-SMN risks are greater among AYAs whose cancers may be related to viral infection, who experience barriers to care based on sociodemographic factors, and treatment factors such as radiotherapy for their original cancers.

Using Surveillance Epidemiology and End Results (SEER) program data from 1976 to 2015, we used multiple methods to address unexamined questions about risk factors for HPV-SMNs among AYAs. Our first set of analyses calculate standardized incidence ratios (SIR) to identify survivors at risk for HPV-SMN relative to the general population from 1976 to 2015. The baseline risk for HPV-SMN among persons diagnosed with their first cancer in the 2000s may differ greatly from risk among survivors diagnosed in the 1970s because of changes in public understanding of HPV, recommendations for cervical cancer screening, and the introduction of HPV vaccination (25). We extend the science by identifying changes in the temporal patterns of incident HPV-SMN among AYAs using age-period-cohort (APC) models (12, 13, 18, 26).

Finally, we explored differences in risk for HPV-SMN among AYA survivors according to the first primary cancer site and treatment for the first primary cancer. In prior studies, radiation treatment for the first tumor was identified as a risk factor for HPV-SMN among young survivors with HPV-related first tumors (12, 13); however, it is unknown if the reported effect is a result of radiation treatment to the pelvis or latent HPV infection. Because of this potential correlation between the site of radiation treatment and HPV infection, we examined the association between treatment and HPV-SMN in a SEER-based cohort of AYAs. We also determined the association of treatment and HPV-SMN based the first cancer site's relationship to HPV infection.

Supported by the National Cancer Institute (NCI), SEER provides information on cancer diagnoses, treatment, and survival aggregated from 22 cancer registries across the nation. Of these, 9 registries have data starting from 1973. Our observational cohort used data from the SEER 9 registries on cancers diagnosed between age 15 and 44 years from 1976 to 2015. While the NCI's definition of AYA cancer is 15 to 39 at diagnosis, the APC analysis necessitates this extended age grouping as the subjects must be divided into groups with equally spaced age and diagnosis year intervals (26); 10-year intervals (rather than 5-year) were necessary to ensure sufficient power as HPV-SMNs are generally rare. Subjects were followed from 2 months after their initial diagnosis, which ensured we did not capture multiple primary tumors. Subjects were followed until death, December 31, 2016, or loss-to-follow-up. We exported deidentified individual data for use in the APC analysis and time-to-event analysis.

First primary cancers, HPV-related cancers, and HPV-SMN

We identified risk for HPV-SMN according to site of the first primary tumor. We chose sites that were previously identified has having the highest risk for SMN (4): bladder; bones and joints; brain and other nervous system; female breast; cervix; colon and rectum; oral cavity and pharynx; leukemia; lung, bronchus, and trachea; Hodgkin lymphoma; non-Hodgkin lymphoma; skin melanoma; other female genital system (vagina, vulva, uterus); other male genital system; ovary; soft tissue including heart; testis; and thyroid. Kaposi sarcoma was separated from other sarcomas because of its relationship with human immunodeficiency virus (HIV).

We defined HPV-related first primary cancers and HPV-SMN as oropharyngeal, cervical, vaginal, vulvar, penile, anal, tongue, and tonsil cancers (19). While SEER*Stat did not allow us to define HPV-SMN with confirmed HPV infection as an outcome, the HPV-SMN outcomes in this study have strong prior evidence of relationship with HPV (27, 28).

Demographic information

Sex, race, ethnicity, age, and other demographic variables were reported by SEER. Race (American Indian/Alaska Native, Asian or Pacific Islander, Black, White) was provided in mutually exclusive categorical variables (29). Hispanic ethnicity, diagnosis age, and birth year were reported by SEER. Health insurance was available for survivors diagnosed in 2007 onwards only (uninsured, any Medicaid, insured). In the APC, we used 10-year bins to group diagnosis age (15–24, 25–34, 35–44 years) and diagnosis year (1976–1985, 1986–1995, 1996–2005, 2006–2015).

Cancer stage and therapy

We categorized stage as localized (reference), regional, distant (excluding leukemia), and unstaged. SEER provided cancer treatment for the first primary cancer. This included chemotherapy (Yes, No/Unknown) and type of radiotherapy: beam, combination of beam and other type, isotope implants and radioisotopes, recommended but not received or refused, and none/unknown. We used these data to create the variable “cancer therapy” defined as having been treated with chemotherapy and radiation, radiation only, chemotherapy only, no chemo and no radiation (reference).

Statistical methods

We computed descriptive statistics, SIRs and their 95% confidence intervals (CI), and excess risk per 10,000 persons using the MP-SIR function in SEER*Stat (30). Our outcomes were any HPV-SMN, oropharyngeal-SMN (oropharynx, tongue, tonsil), and female cervical-SMN; small numbers prohibited separate examination of other sites. Observed counts were counts of HPV-SMN over follow-up. Multiple HPV-SMNs occurring within the same persons were included in the observed counts for the SIR analysis. Expected counts were derived from first HPV-related tumors in persons without a cancer history (general population), adjusted for age, diagnosis year, and follow-up time. We computed SIRs by sex, race, Hispanic ethnicity, stage, first primary HPV-related cancer, and first cancer site.

We used NCI's web-based APC analysis tool to identify patterns in the incidence of any HPV-SMN, oropharyngeal-SMN, and cervical-SMN over the study period (26). Age was defined as the age at first diagnosis; period refers to the year of first diagnosis; cohort is the year of birth. To use the tool, we computed event counts and person-years by 10-year bins of age and diagnosis year.

We compared the median time from the first primary diagnosis to HPV-SMN with the Wilcoxon two-sample test. We used Fine and Gray's proportional hazards model to compute hazards ratios while accounting for the competing risk for death. For this analysis, we included only the first HPV-SMN as an event. We computed risk for any HPV-SMN according to cancer therapy while controlling for race, ethnicity, age at diagnosis, year of birth, stage at diagnosis, and HPV-related first primary tumor. We included results from the Wald test to determine the overall significance of cancer therapy while holding these factors constant. We also computed risk for cancer therapy stratified by first primary HPV-related cancer (Yes/No), then within first primary oropharyngeal and cervical cancers.

The 374,408 AYA survivors were largely female (60.7%), diagnosed between age 35 and 44 (61.2%), White (80.7%), and non-Hispanic (91.9%; Table 1). The most common first cancers were female breast (20.3%), skin melanomas (10.2%), thyroid (9.2%), testis (5.7%), and non-Hodgkin lymphoma (5.6%). A total of 1,447 HPV-SMN occurred in 1,369 (0.4%) of survivors with no differences by sex. Cervical-SMN (TumorN = 308, 21.2%) and oropharyngeal-SMN (TumorN = 603, 41.7%) were the most common HPV-SMN. HPV-SMN were diagnosed a mean of 5.12 years after the first cancer, with no difference by sex (Femalemean = 5.04; Malesmean = 5.26) or if the first cancer was HPV-related (HPV-relatedmean = 4.87 years, Not HPV-relatedmean = 5.20, Wilcoxontwo-sidedP = 0.08). The average age of HPV-SMN diagnosis was 55 years overall, 53 years for cervical-SMN, and 57 years for oropharyngeal-SMN.

Table 1.

Demographics of survivors of adolescent and adult cancer in the SEER 9 registries, 1976–2015.

N%
Total 374,408  
Sex 
 Male 147,143 39.3 
 Female 227,265 60.7 
Diagnosis age 
 15–24 years 39,579 10.6 
 25–34 years 105,617 28.2 
 35–44 years 229,212 61.2 
Diagnosis year 
 1976–1985 67,852 18.1 
 1986–1995 96,808 25.9 
 1996–2005 103,350 27.6 
 2006–2015 106,398 28.4 
Race 
 White 302,126 80.7 
 Black 40,351 10.8 
 American Indian/Alaska Native 3,244 0.9 
 Asian or Pacific Islander 28,687 7.7 
Hispanic ethnicity 
 Non-Hispanic 344,205 91.9 
 Hispanic 30,203 8.1 
Stagea 
 Localized 167,000 44.6 
 Regional 80,376 21.5 
 Distant 33,210 8.9 
 Unstaged 75,512 20.2 
Cancer siteb 
 Anus, anal canal, and anorectum 1,184 0.3 
 Bladder 5,562 1.5 
 Bones and Joints 3,410 0.9 
 Brain and other nervous system 13,581 3.6 
 Breast, female 75,988 20.3 
 Cervical, female 17,665 4.7 
 Colon and rectum 19,335 5.2 
 Oral cavity and pharynx 9,189 2.5 
 Kaposi sarcoma 10,151 2.7 
 Leukemia, any type 12,528 3.3 
  Leukemia, Lymphoid 2,797 0.8 
  Leukemia, Myeloid 4,566 1.2 
 Lung and bronchus, trachea 12,396 3.3 
 Lymphoma, Hodgkin 17,256 4.6 
 Lymphoma, non-Hodgkin 20,813 5.6 
 Melanoma of the Skin 38,024 10.2 
 Other female genital system 10,704 2.9 
 Other male genital system 2,624 0.7 
 Ovary 8,485 2.3 
 Soft tissue including heart 6,270 1.7 
 Testis 21,393 5.7 
 Thyroid 34,534 9.2 
First primary HPV-related cancerc 
 Yes 22,270 5.9 
 No 352,138 94.1 
N%
Total 374,408  
Sex 
 Male 147,143 39.3 
 Female 227,265 60.7 
Diagnosis age 
 15–24 years 39,579 10.6 
 25–34 years 105,617 28.2 
 35–44 years 229,212 61.2 
Diagnosis year 
 1976–1985 67,852 18.1 
 1986–1995 96,808 25.9 
 1996–2005 103,350 27.6 
 2006–2015 106,398 28.4 
Race 
 White 302,126 80.7 
 Black 40,351 10.8 
 American Indian/Alaska Native 3,244 0.9 
 Asian or Pacific Islander 28,687 7.7 
Hispanic ethnicity 
 Non-Hispanic 344,205 91.9 
 Hispanic 30,203 8.1 
Stagea 
 Localized 167,000 44.6 
 Regional 80,376 21.5 
 Distant 33,210 8.9 
 Unstaged 75,512 20.2 
Cancer siteb 
 Anus, anal canal, and anorectum 1,184 0.3 
 Bladder 5,562 1.5 
 Bones and Joints 3,410 0.9 
 Brain and other nervous system 13,581 3.6 
 Breast, female 75,988 20.3 
 Cervical, female 17,665 4.7 
 Colon and rectum 19,335 5.2 
 Oral cavity and pharynx 9,189 2.5 
 Kaposi sarcoma 10,151 2.7 
 Leukemia, any type 12,528 3.3 
  Leukemia, Lymphoid 2,797 0.8 
  Leukemia, Myeloid 4,566 1.2 
 Lung and bronchus, trachea 12,396 3.3 
 Lymphoma, Hodgkin 17,256 4.6 
 Lymphoma, non-Hodgkin 20,813 5.6 
 Melanoma of the Skin 38,024 10.2 
 Other female genital system 10,704 2.9 
 Other male genital system 2,624 0.7 
 Ovary 8,485 2.3 
 Soft tissue including heart 6,270 1.7 
 Testis 21,393 5.7 
 Thyroid 34,534 9.2 
First primary HPV-related cancerc 
 Yes 22,270 5.9 
 No 352,138 94.1 

aLocal stage includes localized/regional prostate cancers; distant stage tumors exclude leukemias.

bOther female genital includes vagina, vulva, corpus and uterus, and other female genital sites; other male genital includes prostate, penis, other male genital sites.

cOropharyngeal, cervical, vaginal, vulvar, penile, anal, tongue, and tonsil cancers.

Survivors in nearly every demographic group had elevated risk for any HPV-SMN or oropharyngeal-SMN relative to the general population (Table 2). SIRs for any HPV-SMN and oropharyngeal-SMN in male and female AYAs were significantly greater than males and females in the general population (Males: HPV-SMN, 2.44; CI, 2.24–2.66; Oropharyngeal-SMN, 2.10; CI, 1.89–2.33; Females: HPV-SMN, 1.44; CI, 1.35–1.54; Oropharyngeal-SMN, 2.30; CI, 2.01–2.61). Relative to the general population, SIRs for any HPV-SMN or oropharyngeal-SMN were elevated in every diagnosis age, diagnosis year, and racial and ethnic group. Increases in any HPV-SMN were highest among American Indian/Alaska Native survivors relative to the American Indian/Alaska Native general population (SIR, 2.66; CI, 1.33–4.75). Asian/Pacific Islander survivors had the highest risk for oropharyngeal-SMNs relative to Asian/Pacific Islander general population (SIR, 4.21; CI, 2.91–5.88). AYAs who were uninsured at the time of diagnosis or who were on Medicaid had significant increases in their risk for any HPV-SMN relative to persons in the general populations with the same insurance status (Uninsured SIR, 5.23; CI, 2.26–10.31; Medicaid SIR, 5.95; CI, 4.07–8.40). AYAs who were on Medicaid or insured at diagnosis had higher risk for oropharyngeal-SMN than members of the general population with the same insurance status (Medicaid SIR, 6.09; CI, 2.24–13.26; Insured SIR, 3.34; CI, 2.16–4.93).

Table 2.

SIRs for the risk of HPV-SMNs among AYA cancer survivors compared with the general population in the SEER 9 database, stratified by demographic and clinical factors.

Any HPV-SMNOropharyngeal-SMNaCervical-SMN
ObsbO/Eb95% CIbERbObsbO/Eb95% CIbERbObsbO/Eb95% CIbERb
All survivors 1,447 1.70* 1.61–1.79 1.28 603 2.17* 2.00–2.35   
Sex 
 Male 528 2.44* 2.24–2.66 1.88 374 2.10* 1.89–2.33 1.18  
 Female 919 1.44* 1.35–1.54 0.94 229 2.30* 2.01–2.61 0.43 308 0.85* 0.76–0.95 −0.18 
Race 
 White 1,153 1.58* 1.49–1.68 1.07 505 2.02* 1.85–2.20 0.65 234 0.80* 0.70–0.91 −0.23 
 Black 207 2.61* 2.27–2.99 3.36 63 3.36* 2.58–4.29 1.16 48 1.17 0.86–1.55 0.26 
 American Indian/Alaska Native 11 2.66* 1.33–4.75 2.06 1.26 0.03–7.03 0.06 2.11 0.78–4.60 −0.16 
 Asian or Pacific Islander 76 1.89* 1.49–2.37 1.2 34 4.21* 2.91–5.88 0.87 20 0.74 0.45–1.15 
Hispanic ethnicity 
 Non-Hispanic 1,356 1.69* 1.60–1.78 1.26 578 2.19* 2.02–2.38 0.72 275 0.81* 0.72–0.91 −0.23 
 Hispanic 91 1.86* 1.50–2.29 1.45 25 1.77* 1.15–2.62 0.38 33 1.46* 1.01–2.06 0.53 
Health insurance 
 Uninsured 5.23* 2.26–10.31 4.03 2.74 0.07–15.28 0.4 3.49 0.72–10.19 2.61 
 Any Medicaid 32 5.95* 4.07–8.40 5.3 6.09* 2.24–13.26 10 2.94* 1.41–5.40 1.97 
 Insured 79 2.28* 1.80–2.84 1.54 25 3.34* 2.16–4.93 0.61 23 1.12 0.71–1.67 0.13 
Stagec 
 Localized 687 1.35* 1.25–1.45 0.68 293 1.81* 1.61–2.03 0.5 146 0.67* 0.57–0.79 −0.4 
 Regional 335 1.88* 1.68–2.09 1.68 138 2.72* 2.29–3.22 0.94 83 1.01 0.80–1.25 0.01 
 Distant 47 1.73* 1.27–2.30 1.38 45 3.14* 1.86–4.23 1.14 0.49 0.18–1.07 −0.25 
 Unstaged 332 2.83* 2.53–3.15 2.63 116 2.42* 2.00–2.91 0.84 64 1.47* 1.13–1.88 0.53 
First primary HPV-related cancer 
 Yes 383 5.42* 4.89–5.99 9.5 178 13.19* 11.33–15.28 57 1.48* 1.12–1.92 0.6 
 No 1,062 1.36* 1.28–1.44 0.65 425 1.61* 1.46–1.77 0.37 249 0.77* 0.68–0.87 −0.27 
Any HPV-SMNOropharyngeal-SMNaCervical-SMN
ObsbO/Eb95% CIbERbObsbO/Eb95% CIbERbObsbO/Eb95% CIbERb
All survivors 1,447 1.70* 1.61–1.79 1.28 603 2.17* 2.00–2.35   
Sex 
 Male 528 2.44* 2.24–2.66 1.88 374 2.10* 1.89–2.33 1.18  
 Female 919 1.44* 1.35–1.54 0.94 229 2.30* 2.01–2.61 0.43 308 0.85* 0.76–0.95 −0.18 
Race 
 White 1,153 1.58* 1.49–1.68 1.07 505 2.02* 1.85–2.20 0.65 234 0.80* 0.70–0.91 −0.23 
 Black 207 2.61* 2.27–2.99 3.36 63 3.36* 2.58–4.29 1.16 48 1.17 0.86–1.55 0.26 
 American Indian/Alaska Native 11 2.66* 1.33–4.75 2.06 1.26 0.03–7.03 0.06 2.11 0.78–4.60 −0.16 
 Asian or Pacific Islander 76 1.89* 1.49–2.37 1.2 34 4.21* 2.91–5.88 0.87 20 0.74 0.45–1.15 
Hispanic ethnicity 
 Non-Hispanic 1,356 1.69* 1.60–1.78 1.26 578 2.19* 2.02–2.38 0.72 275 0.81* 0.72–0.91 −0.23 
 Hispanic 91 1.86* 1.50–2.29 1.45 25 1.77* 1.15–2.62 0.38 33 1.46* 1.01–2.06 0.53 
Health insurance 
 Uninsured 5.23* 2.26–10.31 4.03 2.74 0.07–15.28 0.4 3.49 0.72–10.19 2.61 
 Any Medicaid 32 5.95* 4.07–8.40 5.3 6.09* 2.24–13.26 10 2.94* 1.41–5.40 1.97 
 Insured 79 2.28* 1.80–2.84 1.54 25 3.34* 2.16–4.93 0.61 23 1.12 0.71–1.67 0.13 
Stagec 
 Localized 687 1.35* 1.25–1.45 0.68 293 1.81* 1.61–2.03 0.5 146 0.67* 0.57–0.79 −0.4 
 Regional 335 1.88* 1.68–2.09 1.68 138 2.72* 2.29–3.22 0.94 83 1.01 0.80–1.25 0.01 
 Distant 47 1.73* 1.27–2.30 1.38 45 3.14* 1.86–4.23 1.14 0.49 0.18–1.07 −0.25 
 Unstaged 332 2.83* 2.53–3.15 2.63 116 2.42* 2.00–2.91 0.84 64 1.47* 1.13–1.88 0.53 
First primary HPV-related cancer 
 Yes 383 5.42* 4.89–5.99 9.5 178 13.19* 11.33–15.28 57 1.48* 1.12–1.92 0.6 
 No 1,062 1.36* 1.28–1.44 0.65 425 1.61* 1.46–1.77 0.37 249 0.77* 0.68–0.87 −0.27 

aOropharyngeal cancers include cancers of the oropharynx, tongue, and tonsil.

bObs = observed SMN; O/E = The observed count divided by the expected count; ER = Excess risk per 10,000 person-years.

cDistant stage tumors exclude leukemias.

*Significant at P < 0.05.

Health insurance is only available for patients diagnosed 2007 onwards.

When examined by stage, SIRs for any HPV-SMN were highest among AYAs whose first primary tumor was unstaged relative to the general population (SIR, 2.83; CI, 2.53–3.15). AYAs with distant stage tumors had the highest SIR for oropharyngeal-SMN compared with the general population (SIR, 3.14; CI, 1.86–4.23). AYAs whose first tumor was related to HPV had the highest SIRs for any HPV-SMN and oropharyngeal-SMN (Any HPV-SMN SIR, 5.42; CI, 4.89–5.99; Oropharyngeal-SMN SIR, 13.19; CI, 11.33–15.28) relative to the general population. In a subset of AYAs with HPV-related first primary tumors, 52% had an HPV-SMN of the same site. Among AYAs whose first primary cancer was related to HPV, the median time to an HPV-SMN of the same site as the first primary HPV tumor was 10 years.

In contrast, cervical-SMN SIRs were lower in female AYAs relative to the female general population (SIR, 0.85; CI, 0.76–0.95). We saw significant decreases among women diagnosed with a first primary tumor between age 35 to 44 years relative to the general population of the same age (SIR, 0.81; 95% CI, 0.70–0.94). However, AYAs with increased risk for cervical-SMN included women diagnosed with their first primary cancer between 2006 and 2015 (SIR, 1.37; CI, 1.02–1.81), Hispanic women (SIR, 1.46; CI, 1.01–2.06), and women with unstaged tumors (SIR, 1.47; CI, 1.13–1.88), women on Medicaid (SIR, 2.94; CI, 1.41–5.40), or who had a first HPV-related tumors (SIR, 1.48; CI, 1.12–1.92) relative to the general population.

SIRs for first primary cancers with the highest risk for any HPV-SMN relative to the general population are shown in Fig. 1. This included Kaposi sarcoma (SIR, 16.19; CI, 12.39–20.80), oropharyngeal (SIR, 11.73; CI, 10.26–13.35), and anal cancers (SIR, 13.34; CI = 8.86–19.28). AYAs whose first primaries are unrelated to HPV also had elevated SIRs: lung and bronchus (SIR, 1.84; CI, 1.13–2.85), Hodgkin lymphoma (SIR, 2.70; CI, 2.18–3.31), non-Hodgkin lymphoma (SIR, 3.07; CI, 2.51–3.72), and leukemia (SIR, 2.39; CI, 1.61–3.41).

Figure 1.

SIRs for HPV-SMNs according to cancer site among AYA cancer survivors relative to the general population.

Figure 1.

SIRs for HPV-SMNs according to cancer site among AYA cancer survivors relative to the general population.

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In the APC analysis (Fig. 2), we found little evidence of anomalous age, period, or cohort deviations, indicating that incidence of HPV-SMN did not change across these measures from 1976 to 2015. The one exception was the incidence of HPV-SMN shown in the fitted temporal trend. This trend showed that the incidence of HPV-SMN generally decreased over time and incidence of oropharyngeal-SMN had a steeper decline than expected based on the overall temporal trend (P = 0.05).

Figure 2.

APC analysis of HPV-SMNs among AYA cancer survivors.

Figure 2.

APC analysis of HPV-SMNs among AYA cancer survivors.

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In our analysis of the AYA cohort, the overall effect of chemotherapy and/or radiotherapy on risk for any HPV-SMN was significant (Wald P value = 0.02, Table 3). Survivors treated with chemotherapy (HR, 1.19; 95% CI, 1.00–1.42) and radiotherapy (HR, 1.20; 95% CI, 1.04–1.38) had increased risk for any HPV-SMN relative to survivors treated with no chemotherapy and no radiotherapy. In survivors with non–HPV-related first primary tumors, treatment with chemotherapy only increased risk for any HPV-SMN (HR, 1.20; 95% CI = 1.00–1.44). In this group of survivors, cancer therapy was not significant overall after accounting for other demographic and cancer variables (Wald P value = 0.16).

Table 3.

Association of cancer therapy with HPV-SMNs.

ModelHRb95% CIbWald P valueb
1 Chemotherapy and/or radiationa 
No chemo and no radiation Ref   
Chemo and radiation 0.98 0.82–1.18 0.02 
Chemo only 1.19* 1.00–1.42  
Radiation only 1.20* 1.04–1.38  
2 Combination therapy in strata of first cancer typea 
Not HPV-related 
 No chemo and no radiation Ref   
 Chemo and radiation 1.04 0.85–1.29 0.16 
 Chemo only 1.20* 1.00–1.44  
 Radiation only 1.13 0.95–1.35  
HPV-related 
 No chemo and no radiation   <0.0001 
 Chemo and radiation 0.59* 0.41–0.85  
 Chemo only 0.42 0.13–1.36  
 Radiation only 1.35* 1.03–1.77  
3 Combination therapy in strata of first HPV-related cancer sitea 
First Oropharyngeal 
 No chemo and no radiation Ref  0.17 
 Chemo and radiation 0.56* 0.31–0.98  
 Chemo only 0.32 0.04–2.33  
 Radiation only 0.83 0.57–1.23  
First Cervical 
 No chemo and no radiation Ref  0.07 
 Chemo and radiation 0.86 0.43–1.71  
 Chemo only 0.49 0.06–3.94  
 Radiation only 1.59* 1.07–2.37  
ModelHRb95% CIbWald P valueb
1 Chemotherapy and/or radiationa 
No chemo and no radiation Ref   
Chemo and radiation 0.98 0.82–1.18 0.02 
Chemo only 1.19* 1.00–1.42  
Radiation only 1.20* 1.04–1.38  
2 Combination therapy in strata of first cancer typea 
Not HPV-related 
 No chemo and no radiation Ref   
 Chemo and radiation 1.04 0.85–1.29 0.16 
 Chemo only 1.20* 1.00–1.44  
 Radiation only 1.13 0.95–1.35  
HPV-related 
 No chemo and no radiation   <0.0001 
 Chemo and radiation 0.59* 0.41–0.85  
 Chemo only 0.42 0.13–1.36  
 Radiation only 1.35* 1.03–1.77  
3 Combination therapy in strata of first HPV-related cancer sitea 
First Oropharyngeal 
 No chemo and no radiation Ref  0.17 
 Chemo and radiation 0.56* 0.31–0.98  
 Chemo only 0.32 0.04–2.33  
 Radiation only 0.83 0.57–1.23  
First Cervical 
 No chemo and no radiation Ref  0.07 
 Chemo and radiation 0.86 0.43–1.71  
 Chemo only 0.49 0.06–3.94  
 Radiation only 1.59* 1.07–2.37  

aModels 1–3 are Fine and Gray models. Model 1 control for race, ethnicity, age at diagnosis, year of birth, stage at diagnosis, and HPV-related first primary tumor. Models 2–3 control for ethnicity, age at diagnosis, year of birth, and stage at diagnosis.

bHR = Hazard ratio, Wald test from Type 3 test of global significance.

*Significant at P < 0.05.

Among survivors with HPV-related first primary tumors, the overall effect of cancer therapy was significant in the model after controlling for confounders (Wald P value < 0.001). Survivors treated with chemotherapy and radiation (HR, 0.59; 95% CI, 0.41–0.85) had decreased risk for any HPV-SMN relative to survivors treated without chemotherapy or radiation. Survivors treated with radiation only had increased risk for HPV-SMN relative to the same reference group (HR, 1.35; 95% CI, 1.03–1.77). In survivors with first oropharyngeal cancers and first cervical cancers, cancer therapy was not significant in the model overall. Radiotherapy treatment in survivors with first cervical cancers had a significant association with any HPV-SMN compared with survivors treated without chemotherapy or radiotherapy (HR, 1.59; 95% CI, 1.07–2.37).

In this study, we found that the incidence of HPV-SMN declined over the study period and the overall incidence of HPV-SMN among AYA cancer survivors was low, affecting only 0.4% of survivors. Yet, AYA cancer survivors had a higher risk for any HPV-SMN than the general population. This appears to originate from increased risk for oropharyngeal-SMN, which reflects the current national trend of increasing incidence of oropharyngeal cancers (31). Unlike pediatric cancer survivors, the age at diagnosis of cervical-SMN and oropharyngeal-SMN among AYA cancer survivors did not differ from the national average ages of 50 years for first primary cervical and 60 years for oropharyngeal cancers (32, 33). We found decreased risk for cervical-SMN among White AYA survivors compared with the general population, but there were elevated risks for cervical-SMN among Hispanic survivors, survivors on Medicaid, and survivors with unstaged tumors relative to the general population.

Our results largely support continued efforts to promote cancer screenings and HPV vaccination among AYA cancer survivors, with particular focus on addressing disparities in cancer prevention. AYA survivors should receive cervical cancer screening and oral exams while on therapy (and continuing after) as the median years from first cancer diagnosis to HPV-SMN is 5 years for AYAs in general. At the same time, HPV vaccination remains severely underutilized among young cancer survivors (16, 17), but vaccination is the primary way to reduce risk for oropharyngeal-SMN (34) as there are no FDA-approved screenings for oropharyngeal cancers and oral exams can miss oral cancers and precancers (34). As such, oncologists and primary care providers should communicate with each other to ensure that HPV vaccine or catch-up vaccines are being recommended to their AYA survivors, and to ensure that survivors begin and finish the series when age eligible (35–37). CDC guidelines recommend that individuals ages 9 to 26 with certain immunocompromising conditions, such as cancer, receive three doses of the HPV vaccine (rather than two doses that are now recommended for the general population; ref. 38), meaning that educational efforts may be needed to inform providers of these guidelines. In addition, as survivors aged 26 and older may have been exposed to HPV before their first cancer and are not typically vaccine-eligible, cervical and oral cancer screenings should be emphasized in this group.

Multiple barriers, however, exist to improving control of HPV-SMN among AYAs. Cancer screening and other healthcare services are often missed due to financial concerns and insurance issues (14). Primary care providers may not be aware of AYAs’ needs for cancer screenings and catch-up HPV vaccines (37). Survivors are also less likely to uptake the HPV vaccine than the general population unless they specifically have recommendations from oncologists (16, 17). In some studies, AYA survivors are more likely to receive Pap smears than the general population, but access to preventive care and health insurance is necessary to facilitate the receipt of Pap smears (1). Coupled with the rise in oropharyngeal cancers, these systematic barriers to screening and vaccination may explain why incidence of oropharyngeal-SMN and cervical-SMN increased in certain racial or ethnic groups and underinsured AYA survivors.

Our results suggest that disparities in cervical-SMN cannot be easily overcome by expanding insurance coverage alone; differences in use of the healthcare system by ethnicity and other sociodemographic factors also need to be considered. Hispanics have the highest cervical cancer incidence in the U.S. relative to other ethnic groups (39). This may be due to structural barriers to receiving healthcare (40–42) as Hispanics report the highest rates of forgone healthcare due to cost (15). Unstaged tumors may also indicate persons with limited healthcare access that impacts participation in cancer screenings. Survivors with unstaged tumors are often of Black or Hispanic ethnicity, have low educational attainment, and are uninsured (43). Because female survivors had a mean of 13 years of follow-up, premature mortality is not likely a reason for these patterns. Rather, these patterns highlight the importance of developing culturally tailored interventions and promoting ethical healthcare access to reducing risk for HPV-SMN among AYA cancer survivors.

Radiotherapy, therapy-related immune dysfunction, and persistent HPV infection have been proposed as the main mechanisms by which HPV-SMN manifests in survivors (12, 13). Our results add to these hypotheses by identifying the differential impact of cancer therapy based on the etiology of the first primary cancer. Among survivors with first primary HPV-related tumors, radiotherapy coupled with potentially persistent HPV-infection (or new HPV infection) appear to increase risk for HPV-SMN, and the effect of therapy is significant overall. In contrast, among survivors whose first tumors were not HPV-related, the effect of cancer therapy alone on risk for HPV-SMN was not significant, suggesting that the viral infection alone increases risk for HPV-SMN. Additional screenings may be needed for AYAs with first primary HPV cancers and HPV vaccination should be emphasized in AYAs whose first primary tumors are not related to HPV.

In the SIR analysis, we found that lymphoma, leukemia, and Kaposi sarcoma survivors had elevated risks for HPV-SMN relative to the general population. Survivors of leukemia and lymphoma may have immunosuppression resulting from their primary diagnosis, and Kaposi sarcoma survivors may also have immunosuppression from HIV infection that is associated with the etiology of Kaposi sarcoma (44–46). This implies that survivors whose first primary cancers involve the immune system or whose first cancer developed as a result of viral infection may have increased susceptibility to HPV-SMN. Thus, the first tumor's relationship to the immune system and viral infection may need to be considered as risk factors for HPV-SMN.

We detected significant increases in risk for HPV-SMN among lung cancer survivors, driven by oropharyngeal-SMN. Lung cancers are suspected to be linked to HPV infection and have a strong association with smoking (23, 47). AYA colorectal cancer survivors displayed a marginally nonsignificant increased risk for any HPV-SMN, which was largely driven by cervical-SMN. Further investigation of whether HPV infection impacts the first diagnosis of lung and colorectal cancer and whether HPV infection among AYA survivors of lung and colorectal cancers may impact HPV-SMN are needed. Of special interest is the potential interaction between smoking and HPV infection on HPV-SMN among AYA survivors.

Strengths and limitations

Strengths of the study include long follow-up from SEER 9 which allows for observation of HPV-SMN in AYA survivors. SEER only reports new cancers, so it is unlikely that HPV-SMN are relapses or recurrence of the original tumor. Additional strengths of SEER beyond include that it is comprised of population-based cancer registries that cover approximately half of the US population and that ongoing surveillance of patient vital status allows accounting for death as a competing risk in analyses.

Limitations of SEER include that patients may move out of the registry catchment areas and contribute to loss to follow-up. For patients diagnosed in 2015, follow-up only lasted until the end of 2016 providing less follow-up than for survivors diagnosed in prior time periods. SEER also has limited clinical data, including no information on HPV infection status to classify HPV-related first tumors or HPV-SMN, nor do we have data about HIV status that may play a key role in the development of Kaposi sarcoma. SEER treatment data also has limitations; unknown forms of cancer therapy are classified as "None," there is no cancer therapy information on surgical resection that may decrease risk of SMN in the same organ, and there is no information use of other hormonal or immune-modulating therapies that may also impact future risk of SMN.

We do not have data about smoking and alcohol consumption that are known to increase risk for oropharyngeal and cervical cancers. In addition to being independent risk factors, smoking and alcohol consumption may work in tandem with HPV infection to increase risk for HPV-SMN, but the cumulative impact of these exposures cannot be examined in this study. AYA survivors are distinct from the general population due to their cancer history, patterns of healthcare access, and other behavioral reasons that may not be accounted for with the SIR method but are touched on with the Fine and Gray method. The SIRs reported by SEER*Stat did not provide the exact P values for the survivor and general population comparisons, which does not allow us to account for potentially spurious results due to multiple testing.

Conclusion

HPV-SMNs are preventable through screenings and vaccination. Recommending preventative care from diagnosis onwards among AYA survivors is of great importance, particularly among survivors who are Hispanic, uninsured or are low income, or have unstaged tumors. Survivors with first HPV-related tumors, or who were first diagnosed with lymphoma, leukemia, and Kaposi sarcoma survivors should also be recommended for HPV vaccination and cancer screening.

J.Y. Ou reports grants from Huntsman Cancer Institute during the conduct of the study. K. Parker reports grants from NCI Cancer Center during the conduct of the study. D. Kepka reports grants from American Cancer Society/Merck outside the submitted work. J.M. Ramsay reports grants from P30CA042014 during the conduct of the study. A.C. Kirchhoff reports grants from Huntsman Cancer Institute during the conduct of the study. No disclosures were reported by the other authors.

This manuscript has been authored by UT-Battelle, LLC, under contract DE-AC05–00OR22725 with the US Department of Energy (DOE). The US government retains and the publisher, by accepting the article for publication, acknowledges that the US government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).

J.Y. Ou: Conceptualization, formal analysis, supervision, methodology, writing–original draft, writing–review and editing. N. Bennion: Data curation, writing–review and editing. K. Parker: Conceptualization, writing–review and editing. D. Fair: Conceptualization, writing–review and editing. H.A. Hanson: Methodology, writing–review and editing. D. Kepka: Writing–review and editing. E.L. Warner: Writing–review and editing. J.M. Ramsay: Conceptualization, writing–review and editing. H.K. Kaddas: Writing–original draft, writing–review and editing. A.C. Kirchhoff: Conceptualization, funding acquisition, writing–original draft, writing–review and editing.

Support was provided to the research team (A.C. Kirchhoff, J.Y. Ou, H.K. Kaddas, D. Kepka, and J.M. Ramsay) under the Cancer Center Support grant 5P30CA042014 awarded to Dr. Cornelia Ulrich. The authors declare no conflict of interest.

NCI grant 5P30CA042014 (PI: Cornelia Ulrich)

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

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