Subsequent Primary Cancer Risk Among 5-Year Survivors of Adolescent and Young Adult Cancers

Hyuna Sung; Rebecca L Siegel; Noorie Hyun; Kimberly D Miller; K Robin Yabroff; Ahmedin Jemal

doi:10.1093/jnci/djac091

. 2022 May 4;114(8):1095–1108. doi: 10.1093/jnci/djac091

Subsequent Primary Cancer Risk Among 5-Year Survivors of Adolescent and Young Adult Cancers

Hyuna Sung ^1,^✉, Rebecca L Siegel ², Noorie Hyun ³, Kimberly D Miller ⁴, K Robin Yabroff ⁵, Ahmedin Jemal ⁶

PMCID: PMC9360462 PMID: 35511931

Abstract

Background

A comprehensive examination of the incidence and mortality of subsequent primary cancers (SPCs) among adolescent and young adult (AYA) cancer survivors in the United States is lacking.

Methods

Cancer incidence and mortality among 170 404 cancer survivors of 5 or more years who were aged 15-39 years at first primary cancer diagnosis during 1975-2013 in 9 Surveillance, Epidemiology, and End Results registries were compared with those in the general population using standardized incidence ratio (SIR), absolute excess incidence (AEI), standardized mortality ratio (SMR), and absolute excess mortality (AEM).

Results

During a mean follow-up of 14.6 years, 13 420 SPC cases and 5008 SPC deaths occurred among survivors (excluding the same site as index cancer), corresponding to 25% higher incidence (95% confidence interval [CI] = 1.23 to 1.27, AEI = 10.8 per 10 000) and 84% higher mortality (95% CI = 1.79 to 1.89, AEM = 9.2 per 10 000) than that in the general population. Overall, SPC risk was statistically significantly higher for 20 of 29 index cancers for incidence and 26 for mortality, with the highest SIR among female Hodgkin lymphoma survivors (SIR = 3.05, 95% CI = 2.88 to 3.24, AEI = 73.0 per 10 000) and the highest SMR among small intestine cancer survivors (SMR = 6.97, 95% CI = 4.80 to 9.79, AEM = 64.1 per 10 000). Type-specific SPC risks varied substantially by index cancers; however, SPCs of the female breast, lung, and colorectum combined constituted 36% of all SPC cases and 39% of all SPC deaths, with lung cancer alone representing 11% and 24% of all cases and deaths, respectively.

Conclusion

AYA cancer survivors are almost twice as likely to die from a new primary cancer as the general population, highlighting the need for primary care clinicians to prioritize cancer prevention and targeted surveillance strategies in these individuals.

The number of survivors of adolescent and young adult (AYA) cancer continues to increase in the United States, reflecting improved survival, growth of the population, and increasing incidence of several cancers (1-3). AYA cancer survivors are at higher risk of long-term adverse health outcomes (4), including new malignancies, as late effects of cancer treatment (5-7). Despite unique medical challenges and opportunities for risk reduction and early detection (8), few studies have comprehensively examined the risk of subsequent primary cancer (SPC) diagnosis and death among AYA cancer survivors. Previous studies mainly focused on survivors of a specific type of AYA cancer (6,7,9-17) or on a specific type of SPC (16,18-22). Recent reports have been more expansive but only investigated incidence of SPC and did not examine mortality (23-25). One study of survivors of AYA cancer in southern California reported that those who developed SPC had more than sevenfold higher all-cause mortality than survivors who did not develop SPC, although cause-specific mortality was not considered (5). A comprehensive and concurrent examination of SPC incidence and mortality across wide-ranging survivor groups is essential to establish an integrated strategy for quality surveillance and care for AYA cancer survivors. Herein, we follow up on a previous study of subsequent malignancies among adult-onset cancer survivors (26) by exploring young-onset cancer survivors in detail. Specifically, we estimate the overall and type-specific risk of developing and dying from SPC after diagnosis of 29 AYA cancers in the United States.

Method

Study Participants

We used population-based cancer incidence (27) and mortality (28) data from 9 Surveillance, Epidemiology, and End Results Program (SEER) registries. We identified cancer survivors of 5 or more years whose first primary (index) malignant cancer was diagnosed at ages 15-39 years during 1975-2013. We included 29 index cancers (Supplementary Table 1, available online), coded per the International Classification of Diseases for Oncology (ICD), 3rd edition, and then categorized according to SEER Site Recode International Classification of Diseases for Oncology (ICD), 3rd edition–World Health Organization 2008 definition (29), with 300 or more survivors to permit adequate numbers of events for type-specific risk assessment. We used a 5-year cut-off to provide risk estimates among long-term survivors, minimize bias from heightened medical surveillance and incidental finding, and permit comparison of findings with published results (23-25,30).

SPC Ascertainment

Follow-up began 5 years from initial cancer diagnosis and continued until censoring at death, loss to follow-up, or December 31, 2018, whichever came first. SPCs that occurred at the same site of index cancers (Supplementary Table 2, available online) were excluded to minimize bias from potential misclassification of recurrence, as was nonmelanoma skin cancer. Ascertainment of SPC death was based on the SEER cause-specific death classification (31). SPC death calculations excluded deaths from nonmelanoma skin cancer, same-type SPC, and miscellaneous malignant cancer. Second and higher-order cancers were counted for comparability between the observed and expected numbers of SPCs because the expected numbers, based on population-based cancer registrations in SEER, count multiple primary cancers in an individual.

Statistical Analysis

Cumulative incidence and cumulative mortality of SPCs were calculated at 35 years after index cancer diagnosis with deaths from any cause and non-SPC deaths treated as competing risks, respectively (Supplementary Methods, available online). The excess risk of developing SPCs among survivors beyond that expected from the general population was quantified using standardized incidence ratio (SIR) and absolute excess incidence (AEI) (32). SIRs were calculated as the observed divided by the expected number of SPCs, and AEIs were calculated as the observed minus the expected number of SPCs, divided by person-years of follow-up and expressed per 10 000 person-years. The expected number of SPCs was computed by multiplying age-, sex-, race-, and year-specific incidence rates in the 9 SEER registries by stratum-specific follow-up years. Similarly, the excess risk of dying from SPC among survivors beyond that expected in the general population was estimated using standardized mortality ratio (SMR) and absolute excess mortality (AEM).

For each index cancer, risks of developing or dying from any SPCs (overall risk) were calculated with and without stratification by time since initial diagnosis (5-9, 10-19, 20-29, ≥30 years). To further characterize type-specific risks of developing SPC, SIRs and AEIs for select SPCs were further stratified by stage at SPC diagnosis (localized, regional, distant, unstaged) (33), treatment era (1975-1986, 1987-1999, 2000-2013), and the first course of treatment (radiotherapy alone, chemotherapy alone, both radiotherapy and chemotherapy, neither [no or unknown radiotherapy or chemotherapy]) (Supplementary Methods, available online). Sex-combined analyses were used to provide more stable risk estimates, except Hodgkin lymphoma (HL) (because of known sex differences in the risk) (24), female breast (breast hereafter), and male Kaposi sarcoma. Analyses were performed using SEER*Stat 8.3.9, Stata 13, and SAS 9.4. A 2-sided P value of less than .05 was considered statistically significant.

Results

Among 170 404 survivors, 62.6% were females and 64.3% were in their 30s at first cancer diagnosis (Table 1). The most prevalent AYA cancer diagnoses were breast, followed by melanoma of the skin, thyroid, and testicular cancers (Table 2). During a mean follow-up of 14.6 years, 13 420 SPC (53.8 per 10 000) cases and 5008 (20.4 per 10 000) SPC deaths occurred (excluding the same site as index cancer), with a 35-year cumulative incidence of 13.7% and cumulative mortality of 6.2%. Breast cancer accounted for 17.8% of SPCs, followed by lung (10.8%), colorectum (7.6%), and prostate (7.1%) (Figure 1, A). Lung cancer was the leading cause of SPC death (23.7%), followed by breast (8.6%), colorectal (6.9%), and pancreatic (6.8%) cancers (Figure 1, B).

Table 1.

Characteristics of survivors of 5 or more years of adolescent and young adult (AYA) cancer with first cancer diagnoses in 1975-2013 in 9 registries of the Surveillance, Epidemiology, and End Results Program (SEER)

Characteristics	No. (%)	Total follow-up years (beginning 5 years after index cancer diagnosis)	Mean follow-up years (beginning 5 years after index cancer diagnosis)
Total	170 404 (100.0)	2 492 830	14.6
Sex
Female	106 622 (62.6)	1 565 914	14.7
Male	63 782 (37.4)	926 916	14.5
Age at index cancer diagnosis, y
15-19	10 775 (6.3)	169 424	15.7
20-24	18 722 (11.0)	292 356	15.6
25-29	31 255 (18.3)	480 099	15.4
30-34	45 437 (26.7)	668 032	14.7
35-39	64 215 (37.7)	882 919	13.7
Calendar year of index cancer diagnosis
1975-1986	39 725 (23.3)	1 011 451	25.5
1987-1999	58 366 (34.3)	1 020 898	17.5
2000-2013	72 313 (42.4)	460 482	6.4
Total follow-up time since index cancer diagnosis, y
5-9	170 404 (100)	749 459	4.4
10-19	131 778 (77.3)	1 021 438	7.8
20-29	75 376 (44.2)	530 849	7.0
≥30	33 041 (19.4)	191 084	5.8
Race
Black	14 134 (8.3)	180 071	12.7
Other (American Indian, Asian, or Pacific Islander)	12 993 (7.6)	158 462	12.2
White	141 142 (82.8)	2 127 072	15.1
Unknown^a	2135 (1.3)	27 225	12.8
Registry
Seattle	27 435 (16.1)	391 281	14.3
San Francisco-Oakland	26 558 (15.6)	402 178	15.1
Detroit	25 405 (14.9)	381 972	15.0
Connecticut	22 755 (13.4)	342 379	15.0
Iowa	18 628 (10.9)	287 024	15.4
Atlanta	18 019 (10.6)	248 822	13.8
Utah	14 317 (8.4)	187 910	13.1
New Mexico	9543 (5.6)	138 261	14.5
Hawaii	7744 (4.5)	113 003	14.6
Stage of index cancers^b
Localized	90 894 (63.5)	1 414 807	15.6
Regional	32 558 (22.7)	438 266	13.5
Distant	5668 (4.0)	74 410	13.1
Unstaged	13 309 (9.3)	177 202	13.3
Blank(s)^c	770 (0.5)	12 457	16.2
Reasons for the exit of the study
End of study	125 484 (73.6)	—	—
Death	29 851 (17.5)	—	—
Lost to follow-up	15 069 (8.8)	—	—
Number of subsequent primary cancers per survivor^d
0	158 609 (93.1)	—	—
1	10 411 (6.1)	—	—
2	1178 (0.7)	—	—
≥3	206 (0.1)	—	—

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^{^a}

Because populations are not available for unknown race, these cases were grouped with Whites when calculating risks. — = Not calculated.

Restricted to solid cancers and classified based on by SEER historic stage A. Hematologic cancer cases accounted for 16.0% (n = 27 205) of all cases, accruing 375 689 (mean = 13.8 ) follow-up years.

Cases with certain site and/or year combinations that were not covered by SEER historic stage A are coded as “blank(s),” including 451 lung cancer cases from 1975 to 1987; 302 head and neck cancer cases for certain subsites from 1975 to 1982 and 2004 to 2013; and 17 vaginal cancer cases from 2004 to 2013. Refer to the SEER Variable and Recode Definitions for details (https://seer.cancer.gov/seerstat/variables/seer/yr1973_2009/lrd_stage/index.html).

Includes second and later primaries and encompasses all cancer sites that were diagnosed 5 or more years since the first primary cancer diagnosis, except for nonmelanoma skin and same-type cancer as the index AYA cancer.

Table 2.

Risks of developing or dying from subsequent primary cancers (SPCs)^a by first primary index cancer types among 5 or more years AYA cancer survivors with first cancer diagnosis in 1975-2013 in 9 SEER registries

First AYA cancer	Survivors, n (%)	Person-years, total (mean)	SPC cases				SPC death				Mean age
First AYA cancer	Survivors, n (%)	Person-years, total (mean)	35-year cumulative incidence, % (95% CI)	Observed/Expected^b	SIR (95% CI)^c	AEI per 10 000^d	35-year cumulative mortality, % (95% CI)	Observed/Expected^b	SMR (95% CI)^c	AEM per 10 000^d	First cancer	SPC diagnosis	SPC death
Total^e	170 404 (100)	2 492 830 (14.6)	13.7 (13.4 to 14.0)	13 420/10 721	1.25 (1.23 to 1.27)	10.8	6.2 (6.0 to 6.5)	5008/2719	1.84 (1.79 to 1.89)	9.2	31.6	53.5	54.7
Breast (F)^f	27 176 (15.9)	369 017 (13.6)	10.8 (10.2 to 11.5)	1821/1394	1.31 (1.25 to 1.37)	11.6	5.9 (5.5 to 6.5)	768/430	1.79 (1.66 to 1.92)	9.2	35.4	54.9	57.7
Melanoma of the skin	24 000 (14.1)	375 984 (15.7)	11.6 (10.9 to 12.3)	1594/1826	0.87 (0.83 to 0.92)	−6.2	4.0 (3.6 to 4.5)	427/461	0.93 (0.84 to 1.02)	−0.9	31.7	54.9	56.5
Thyroid	23 408 (13.7)	336 131 (14.4)	13.0 (12.2 to 13.8)	1514/1513	1 (0.95 to 1.05)	0	3.7 (3.3 to 4.2)	365/361	1.01 (0.91 to 1.12)	0.1	31	53.3	55.5
Testis	16 501 (9.7)	263 825 (16)	15.1 (14.1 to 16.1)	1280/1061	1.21 (1.14 to 1.27)	8.3	7.2 (6.5 to 8.0)	484/278	1.74 (1.59 to 1.9)	7.8	29.6	55.1	56.7
Cervix uteri	10 314 (6.1)	184 623 (17.9)	13.4 (12.5 to 14.5)	950/904	1.05 (0.99 to 1.12)	2.5	6.1 (5.4 to 6.9)	369/220	1.68 (1.51 to 1.86)	8.1	32.8	55.5	57.2
Non-Hodgkin lymphoma^g	9474 (5.6)	122 395 (12.9)	17.9 (16.3 to 19.5)	803/490	1.64 (1.53 to 1.76)	25.6	7.5 (6.48 to 8.71)	291/120	2.43 (2.16 to 2.72)	14	31.2	53.1	52.5
Hodgkin lymphoma (M)	6854 (4.0)	104 855 (15.3)	18.8 (17.3 to 20.3)	769/343	2.24 (2.09 to 2.41)	40.6	12.3 (11.0 to 13.6)	422/87	4.84 (4.39 to 5.32)	31.9	27.4	51.8	51.9
Hodgkin lymphoma (F)	6550 (3.8)	102 533 (15.7)	25.9 (24.2 to 27.6)	1113/365	3.05 (2.88 to 3.24)	73	13.0 (11.6 to 14.5)	399/72	5.54 (5.01 to 6.11)	31.9	26.7	47.8	50.4
Brain and other nervous system cancer	6499 (3.8)	73 731 (11.3)	6.56 (5.57 to 7.65)	250/226	1.11 (0.97 to 1.25)	3.3	2.8 (2.17 to 3.5)	100/48	2.08 (1.69 to 2.53)	7	28.5	48.6	47.5
Colon and rectum	5843 (3.4)	77 069 (13.2)	15.8 (14.2 to 17.5)	536/394	1.36 (1.25 to 1.48)	18.5	6.9 (5.75 to 8.2)	178/101	1.76 (1.51 to 2.04)	10	33.9	54.6	54.2
Head and neck	4683 (2.7)	70 464 (15)	13.6 (12.1 to 15.1)	412/348	1.18 (1.07 to 1.3)	9.1	7.2 (6.07 to 8.4)	181/90	2.01 (1.73 to 2.32)	12.9	32.1	54	53.7
Ovary	4066 (2.4)	69 792 (17.2)	12.2 (10.8 to 13.8)	357/299	1.19 (1.07 to 1.33)	8.3	4.5 (3.6 to 5.6)	115/70	1.65 (1.36 to 1.98)	6.5	30.3	53.2	56.1
Corpus uteri (including not otherwise specified)	3608 (2.1)	53 474 (14.8)	15.4 (13.5 to 17.5)	332/278	1.19 (1.07 to 1.33)	10.1	6.6 (5.3 to 8.1)	118/68	1.73 (1.43 to 2.07)	9.3	34.8	55.7	57.2
Soft tissue including heart	3207 (1.9)	47 565 (14.8)	14.0 (12.0 to 16.1)	257/204	1.26 (1.11 to 1.43)	11.2	6.8 (5.5 to 8.3)	134/50	2.69 (2.25 to 3.18)	17.7	29	51.6	46.3
Kidney and renal pelvis	2916 (1.7)	33 780 (11.6)	16.4 (13.6 to 19.4)	205/162	1.26 (1.1 to 1.45)	12.6	6.9 (5.1 to 9.1)	70/41	1.72 (1.34 to 2.18)	8.7	34	53.6	54.4
Urinary bladder	2709 (1.6)	50 379 (18.6)	16.5 (14.4 to 18.7)	296/300	0.99 (0.88 to 1.1)	−0.9	6.6 (5.3 to 8.1)	102/83	1.23 (1 to 1.49)	3.7	33.3	58	59.1
Bones and joints	1978 (1.2)	29 386 (14.9)	11.5 (9.3 to 13.9)	146/98	1.48 (1.25 to 1.74)	16.2	8.5 (6.5 to 10.8)	85/23	3.73 (2.98 to 4.61)	21.2	25.6	48	45.9
Kaposi sarcoma (M)^f	1561 (0.9)	15 256 (9.8)	13.7 (11.1 to 16.7)	145/56	2.58 (2.18 to 3.03)	58.2	5.1 (3.4 to 7.3)	42/14	2.96 (2.14 to 4.01)	18.2	33.5	47.6	48.9
Acute myeloid leukemia	1477 (0.9)	17 141 (11.6)	16.8 (12.6 to 21.6)	93/55	1.68 (1.36 to 2.06)	22	5.7 (3.3 to 9.1)	27/12	2.28 (1.51 to 3.32)	8.9	28.6	49.7	47.6
Lung and bronchus	1456 (0.9)	20 821 (14.3)	10.4 (8.2 to 12.9)	105/99	1.06 (0.87 to 1.28)	2.9	6.9 (5.1 to 9.1)	50/20	2.52 (1.87 to 3.32)	14.5	32.7	54.2	51.9
Chronic myeloid leukemia	1259 (0.7)	11 184 (8.9)	13.2 (9.3 to 17.7)	59/36	1.65 (1.26 to 2.13)	20.8	5.9 (3.3 to 9.5)	29/8	3.78 (2.53 to 5.43)	19.1	31	48.8	45.7
Vagina and vulva	1123 (0.7)	19 471 (17.3)	10.7 (8.3 to 14.0)	102/94	1.09 (0.89 to 1.32)	4.2	8.2 (6.1 to 10.7)	56/22	2.57 (1.94 to 3.34)	17.6	30.7	53.2	51.7
Acute lymphocytic leukemia	1113 (0.7)	13 750 (12.4)	8.1 (5.6 to 11.1)	55/31	1.77 (1.33 to 2.3)	17.4	5.3 (3.1 to 8.3)	23/6	3.65 (2.31 to 5.47)	12.1	23.4	41.8	39.6
Stomach	566 (0.3)	6829 (12.1)	10.0 (6.5 to 14.5)	45/34	1.34 (0.98 to 1.79)	16.7	8.6 (4.9 to 13.6)	24/8	2.89 (1.85 to 4.3)	23	33.9	51.6	52.1
Eye and orbit	562 (0.3)	8143 (14.5)	11.1 (7.7 to 15.1)	48/41	1.16 (0.85 to 1.54)	8	17.6 (13.4 to 22.3)^h	67/10	6.53 (5.06 to 8.29)^h	69.7^h	31.7	53	46.8
Myeloma	478 (0.3)	3832 (8)	14.5 (9.1 to 21.1)	32/16	1.95 (1.34 to 2.76)	40.8	4.7 (2.1 to 8.8)	44504	2.67 (1.33 to 4.77)	18	35.1	52.1	48.3
Small intestine	390 (0.2)	4408 (11.3)	17.7 (9.3 to 28.3)	33/20	1.67 (1.15 to 2.35)	30	11.2 (7.0 to 16.5)	33/5	6.97 (4.8 to 9.79)	64.1	33.5	52.4	48.1
Pancreas	333 (0.2)	3230 (9.7)	13.4 (8.0 to 20.2)	28/14	2.04 (1.35 to 2.94)	44.1	4.5 (3.6 to 5.6)	9/3	2.81 (1.28 to 5.33)	17.9	31.8	47.8	47.9
Anus	300 (0.2)	3766 (12.6)	20.2 (13.0 to 28.5)	40/19	2.14 (1.53 to 2.91)	56.5	22.8 (13.8 to 33.1)ⁱ	29/5	6.34 (4.25 to 9.11)ⁱ	64.9ⁱ	35.1	54.7	53.5

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^{^a}

Includes second and later primaries and encompasses all cancer sites, except for nonmelanoma skin and same-type cancer as the index AYA cancer. Refer to Supplementary Table 2 (available online) for the definition of same-type cancer. AEI = absolute excess incidence; AEM = absolute excess mortality; AYA = adolescent and young adult; CI = confidence interval; F = female; ICD = International Classification of Diseases for Oncology; M = male; SEER = Surveillance, Epidemiology, and End Results Program; SIR = standardized incidence ratio; SMR = standardized mortality ratio; SPC = subsequent primary cancers.

The expected number of SPC cases and deaths from subsequent primary cancers were extrapolated from the incidence and mortality rates of 9 SEER areas, respectively, with a comparable distribution of race, sex, age, and calendar year. The expected risk of SPC deaths can be interpreted as the risk of dying from newly diagnosed cancer if survivors experienced the same cancer death rates as persons in the general reference population.

Calculated as the observed divided by the expected. The SIR and SMR are generally considered a measure of the strength of an association between the first and subsequent primary cancers.

Calculated as the observed minus the expected, divided by the total person-years of follow-up, and multiplied by 10 000. The modest or small relative excess risk (SIR or SMR) can result in high absolute excess risk (AEI or AEM) when the cancer rates in the general population are high.

Sum of 29 types of index AYA cancers.

Male breast cancer survivors were excluded because they accounted for only 0.2% (n = 60) of breast cancer survivors, as were female Kaposi sarcoma survivors because they accounted for only 1.6% (n = 25) of all Kaposi sarcoma survivors. For all other excluded cancers, refer to Supplementary Table 1 (available online).

Includes chronic lymphocytic leukemia (ICD-O-3 histology 9823 and site codes C420, C421, C424) and acute lymphoblastic lymphoma (ICD-O-3 histology codes 9811-9818, 9837 and all site codes except C024, C098-C099, C111, C142, C379, C420-C422, C424, C770-C779).

When excluding death from subsequent melanoma (n = 53), 35-year cumulative mortality, SMR (95% CI) and AEM were 3.7% (1.7-6.8) and 1.40 (0.77-2.35), and 4.9 per 10 000, respectively.

ⁱ

When excluding death from subsequent colorectal cancer (n = 11), 35-year cumulative mortality, SMR (95% CI) and AEM were 17.8% (9.5- 28.2) and 4.37 (2.59- 6.90), and 36.9 per 10 000, respectively.

Figure 1. — Perce ntage contribution of each first primary (index) cancer and subsequent primary cancer (SPC) combination to the total number of subsequent primary cancer cases **(A)** and deaths **(B)** among AYA cancer survivors of 5 or more years. Calculated by dividing the observed number of SPC cases or deaths of each cell by the total number of observed SPC cases or deaths. The percentages on the bottom row indicate proportions of all SPCs that are accounted for by each type of SPC and add up 100%, and the percentages on the far-right column indicate proportions of all SPCs that are contributed by each first primary cancer survivor group and add up 100%. **Gray cells** indicate zero events. AYA = adolescent and young adult; F = female; M = male; NOS = not otherwise specified; ONS = other nervous system.

Survivors overall had a 25% higher risk of developing SPCs and an 84% higher risk of dying from SPCs than the expected risks in the general population, corresponding to 10.8 excess cases and 9.2 excess deaths per 10 000, respectively (Table 2). The overall SPC incidence was statistically significantly higher for 20 of 29 index cancers, with the highest SIRs after female HL (SIR = 3.05, AEI = 73.0 per 10 000), male Kaposi sarcoma (SIR = 2.58, AEI = 58.2 per 10 000), and male HL (SIR = 2.24, AEI = 40.6 per 10 000), with a 35-year cumulative incidence of 25.9%, 13.7%, and 18.8%, respectively. The mortality from any SPC was statistically significantly higher for 26 index cancers, with the highest SMRs after small intestine (SMR = 6.97, AEM = 64.1 per 10 000), eye (SMR = 6.53, AEM = 69.7 per 10 000), and anal (SMR = 6.34, AEM = 64.9 per 10 000) cancers. Although SIRs and SMRs generally attenuated with a longer-term follow-up, the elevated risk remained statistically significant 20 or more years postdiagnosis for 9 index cancers for incidence and 20 for mortality (Supplementary Figure 1, available online) and 35 or more years postdiagnosis for lymphomas and testicular cancer for both incidence and mortality (Figure 2), with corresponding AEIs and AEMs increasing over time (Figure 3).

Figure 2. — Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) for overall risk of subsequent primary cancers among AYA cancer survivors of 5 or more years by time since index cancer diagnosis. Estimates are not shown for tests based on less than 5 observed events. AYA = adolescent and young adult; F = female; M = male. ^aA different scale from the other graphs in figure is used.

Figure 3. — Absolute excess incidences (AEIs) and absolute excess mortalities (AEMs) for overall risk of subsequent primary cancers among AYA cancer survivors of 5 or more years by time since index cancer diagnosis. Estimates are not shown for tests based on less than 5 observed events. AYA = adolescent and young adult; F = female; M = male. ^aA different scale from the other graphs in figure is used.

As for the 4 most common index cancers among survivors, the risk of developing SPCs compared with the general population was statistically significantly elevated among breast (SIR = 1.31, AEI = 12.1 per 10 000) and testicular (SIR = 1.21, AEI = 7.9 per 10 000) cancer survivors, not different among thyroid cancer survivors, and statistically significantly lower among melanoma survivors (SIR = 0.87, AEI = -6.2 per 10 000) (Table 2). Generally similar to incidence, the risks of dying from SPCs were statistically significantly elevated among breast (SMR = 1.79, AEM = 9.2 per 10 000) and testicular (SMR = 1.74, AEM = 7.8 per 10 000) cancer survivors and were not different among thyroid cancer and melanoma survivors.

Figure 4 presents higher-than-expected SIRs and SMRs for type-specific SPC risks, with corresponding AEIs and AEMs shown in Figure 5 (Supplementary Table 3, available online for point estimates and 95% confidence intervals [CIs]). Among 689 eligible tests for incidence, the risk was statistically significantly higher than expected for 134 tests with the highest SIR for anal cancer following male Kaposi sarcoma (SIR = 81.2, 95% CI = 55.5 to 114.6) and the highest AEI for breast cancer following HL (AEI = 31.8 per 10 000, 95% CI = 27.8 to 36.2). Of the 523 tests for mortality, the risk was statistically significantly higher for 115 tests, with the highest SMR for soft tissue sarcoma following small intestine cancer (SMR = 235.3, 95% CI = 125.3 to 402.3) and the highest AEM for melanoma following eye cancer (AEM = 64.8 per 10 000, 95% CI = 48.4 to 84.8).

Despite considerable variation in type-specific SPC risks, subsequent breast cancer constituted 12.1% of total excess cases among all survivors, followed by lung (11.6%), thyroid (7.7%), colorectal (5.5%), and head and neck (5.4%) cancers, whereas lung cancer constituted 17.5% of all excess deaths, followed by soft tissue sarcoma (6.8%), non-HL (6.7%), and pancreatic cancer (6.6%) (“All first AYA cancers” column in Figure 5 for AEIs and AEMs; Supplementary Figure 2, available online for percentages). Stratifications by stage at SPC diagnosis revealed that statistically significant excess incidences among survivors were confined to localized- and regional-stage cancers of the thyroid, colorectum, and head and neck (Table 3). For breast and lung cancers, however, the risk was also statistically significantly elevated for distant-stage disease.

Table 3.

Risks of developing stage-specific subsequent primary cancers (SPCs) among 5 year or more AYA cancer survivors^a

Subsequent primary cancer, stage	Observed, No. (%)	Expected, No. (%)	Standardized incidence ratio (95% CI)	Absolute excess incidence (95% CI) per 10 000 person-years	Survivors, No.^b	Mean person-years at risk
Female breast cancer
Localized	1206 (62.6)	1098.9 (61.3)	1.10 (1.04 to 1.16)	0.89 (0.33 to 1.48)	79 554^c	15.1
Regional	565 (29.3)	562.6 (31.4)	1.00 (0.92 to 1.09)	0.02 (−0.36 to 0.43)	79 554^c	15.1
Distant	128 (6.6)	105.7 (5.9)	1.21 (1.01 to 1.44)	0.19 (0.01 to 0.39)	79 554^c	15.1
Unstaged	27 (1.4)	25.0 (1.4)	1.08 (0.71 to 1.57)	0.02 (−0.06 to 0.12)	79 554^c	15.1
Colon and rectum
Localized	371 (44.0)	281.4 (40.5)	1.32 (1.19 to 1.46)	0.37 (0.22 to 0.53)	165 011	14.7
Regional	298 (35.3)	241.2 (34.7)	1.24 (1.1 to 1.38)	0.24 (0.1 to 0.38)	165 011	14.7
Distant	153 (18.1)	149.7 (21.6)	1.02 (0.87 to 1.2)	0.01 (−0.08 to 0.12)	165 011	14.7
Unstaged	21 (2.5)	22.1 (3.2)	0.95 (0.59 to 1.45)	−0.01 (−0.04 to 0.04)	165 011	14.7
Lung and bronchus
Localized	231 (20.6)	158.4 (18.8)	1.46 (1.28 to 1.66)	0.29 (0.18 to 0.42)	169 398	14.6
Regional	271 (24.2)	202.4 (24.0)	1.34 (1.18 to 1.51)	0.28 (0.15 to 0.42)	169 398	14.6
Distant	578 (51.5)	452.3 (53.6)	1.28 (1.18 to 1.39)	0.51 (0.32 to 0.71)	169 398	14.6
Unstaged	42 (3.7)	31.1 (3.7)	1.35 (0.97 to 1.83)	0.04 (0 to 0.1)	169 398	14.6
Thyroid
Localized	336 (62.1)	227.3 (65.2)	1.48 (1.32 to 1.65)	0.5 (0.34 to 0.68)	147 446	14.7
Regional	186 (34.4)	106.4 (30.5)	1.75 (1.51 to 2.02)	0.37 (0.25 to 0.5)	147 446	14.7
Distant	6 (1.1)	8.7 (2.5)	0.69 (0.25 to 1.5)	−0.01 (−0.03 to 0.02)	147 446	14.7
Unstaged	13 (2.4)	5.9 (1.7)	2.20 (1.17 to 3.76)	0.03 (0 to 0.08)	147 446	14.7
Head and neck
Localized	196 (47.9)	91.0 (34.7)	2.15 (1.86 to 2.48)	0.43 (0.32 to 0.55)	166 171	14.6
Regional	153 (37.4)	127.0 (48.4)	1.20 (1.02 to 1.41)	0.11 (0.01 to 0.22)	166 171	14.6
Distant	45 (11.0)	33.9 (12.9)	1.33 (0.97 to 1.78)	0.05 (0 to 0.11)	166 171	14.6
Unstaged	15 (3.7)	10.5 (4.0)	1.43 (0.8 to 2.36)	0.02 (−0.01 to 0.06)	166 171	14.6

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Top 5 most common subsequent primary cancers that accounted for the highest proportions of all excess cases among all survivors combined. AYA = adolescent and young adult; CI = confidence interval.

All survivors excluding those whose index cancer was diagnosed at the same site as SPC in question.

All female survivors excluding breast cancer survivors.

Concerning the top 5 SPCs representing the largest proportions of the excess cases, the risks of developing and dying from lung cancer were statistically significantly elevated following lymphomas and cancers of the breast, anus, vagina or vulva, head and neck, urinary bladder, and cervix, with the greatest excess risks among survivors of anal cancer (SIR = 5.40, 95% CI = 2.47 to 10.24; SMR = 6.34, 95% CI = 2.74 to 12.49), male HL (SIR = 4.69, 95% CI = 3.96 to 5.52; SMR = 4.92, 95% CI = 4.10 to 5.85), and female HL (SIR = 4.32, 95% CI = 3.52 to 5.24; SMR = 5.08, 95% CI = 4.04 to 6.31) (Figure 4). The risks of developing and dying from breast cancer were statistically significantly higher among survivors of lymphomas and sarcomas, with the greatest excess risk following HL (SIR = 3.34, 95% CI = 3.04 to 3.66; SMR = 5.87, 95% CI = 4.79 to 7.13). The risk of developing colorectal cancer was statistically significantly higher among small intestine, corpus uteri, cervix, testis, ovary, and HL cancer survivors, with excess mortality statistically significant for all but ovarian cancer and female HL. The incidence of head and neck cancers was statistically significantly higher following leukemias, lymphomas, myeloma, sarcomas, and cancers of the brain, breast, and thyroid, with the greatest excess risk after chronic myeloid leukemia; however, no statistically significant excess death was observed. Similarly, thyroid cancer incidence was elevated following 10 index cancers, but the excess mortality was not statistically significant for any AYA cancer survivors.

We found that SIRs differed statistically significantly by treatment group for lung cancer among survivors of HL and breast cancer with greater SIRs following radiotherapy alone and in combination with chemotherapy and among testicular cancer survivors following chemotherapy alone (Supplementary Table 4, available online). Additionally, SIRs also varied by treatment group for breast cancer following HL and colorectal cancer following uterine corpus and cervical cancers. For these associations, statistically significant declines in the SIRs across treatment eras from 1975-1986 to 2000-2013 were observed only among HL survivors, from 4.80 (95% CI = 4.11 to 5.58) to 2.53 (95% CI = 0.82 to 5.90) for lung cancer and from 3.81 (95% CI = 3.36 to 4.30) to 1.99 (95% CI = 1.31 to 2.89) for breast cancer (Supplementary Figure 3, available online).

Discussion

In this large population-based cohort, AYA cancer survivors had a 25% higher risk of developing cancer and an 84% higher risk of dying from a new primary cancer compared with the expected risks in the general population. The overall risk of developing or dying from SPC was statistically significantly higher for 20 and 26 of 29 index cancers, respectively, and remained elevated for 20 or more years postdiagnosis for 9 cancers for incidence and 20 cancers for mortality. Leading sites of SPCs were lung, breast, and colorectum, comprising 36% of all SPC cases and 39% of all SPC deaths, highlighting prevention priorities through intensifying health promotion and effective surveillance as part of routine survivorship care (34).

Many studies have examined the risks of developing SPCs among AYA cancer survivors (5-7,9-25), however, there is a paucity of data on the risks of SPC deaths, with prior studies investigating mainly overall (5) or subsequent breast cancer death (20,35-37). To our knowledge, this is the first study to present the overall and type-specific risks of incidence and mortality among AYA cancer survivors concurrently. Although the leading causes of SPC deaths among AYA cancer survivors were the same as those in the general population, AYA cancer survivors were almost twice as likely to die from new cancer than the general population, reflecting both higher incidence and lower survival. The overall relative risk of dying from SPCs was substantially smaller than the risk reported for survivors of childhood (12- to 15-fold) (30,38) or early adolescent and young adult (15-20 years at diagnosis; eightfold) cancer (30); however, the absolute risks were comparable (20 per 10 000 vs 17-27 per 10 000) likely because of higher baseline cancer rates among the AYA population, underscoring the importance of age-appropriate and risk-based follow-up and surveillance care. Studies have shown that SPCs are independently associated with poorer outcomes than first primary cancers after accounting for age, stage at diagnosis (20,35,36,39), and treatment (36) and that this disadvantage is more pronounced among AYA cancer survivors vs those first diagnosed at a younger or older age (39). Limited therapeutic options, multiple comorbidities (40,41), and concerns regarding additional treatment exposures may contribute to poor outcomes among individuals with a history of cancer, although factors specific to the disproportionate influence on AYA cancer survivors require further investigation. Additional research on tumor characteristics (42) and treatment patterns of SPCs occurring among AYA cancer survivors may provide insight into the outcomes of SPCs.

Lung cancer alone constituted approximately 1 in 4 SPC deaths. The elevated risks following diagnoses of smoking-related cancers (head and neck, cervix, urinary bladder, anus) point to smoking as a shared etiology (43,44), whereas the varying degrees of lung cancer risk by treatment group found among breast, male HL, and testicular cancer survivors support the well-documented late-effect of chest radiotherapy and chemotherapy as a contributing factor (32,45-47). Our study was unable to examine the contribution of smoking, alone or in combination with treatment, to lung cancer risk, and contributions of individual risk factors are unknown. Nevertheless, given the known synergistic effect of smoking with cytotoxic cancer therapy (48-50), the benefits of smoking cessation after a cancer diagnosis (51,52) and higher smoking prevalence among AYA cancer survivors than their general population counterparts (26% vs 16% in 2014-2018) (53), interventions for smoking cessation should be an integral part of survivorship care (54,55). Findings of the excess lung cancer risk following multiple major AYA cancers underscore the importance of future analytical studies to identify risk factors specific to the survivor cohort. Additionally, studies on the effectiveness of lung cancer screening among cancer survivors may merit a comprehensive examination of survivors at increased risk beyond survivors of HL and head and neck cancers (56-58).

Breast cancer was the most commonly diagnosed SPC (18%) and ranked second in SPC deaths (9%) excluding subsequent breast cancers among breast cancer survivors. The elevated risk following treatment of HL was greatest for those treated with radiotherapy alone, consistent with previous findings (59). We were not able to evaluate the effects of specific chemotherapeutic agents because of lack of data; however, the increasingly common use of anthracyclines, with or without chest radiotherapy, has been shown to increase breast cancer risk and may partly explain the elevated risks among survivors of lymphomas and sarcomas (60,61). Contrary to other major SPCs, the magnitude of SIR was slightly greater for distant- than earlier-stage disease for subsequent breast cancer (1.21 vs 1.00-1.10), which is counterintuitive given the increased contact with a health-care system expected among cancer survivors (62). Together with the excess breast cancer mortality among survivors, this finding underscores the importance of early detection to mitigate the excess deaths from subsequent breast cancer among AYA cancer survivors (63,64).

Colorectal cancer was the third most common SPC (8%) and the third cause of SPC deaths (7%) with the highest risks following small intestine, uterine corpus, and ovarian cancers. Among colorectal cancer survivors, risks of these cancers were also increased, suggesting a role of shared behavioral risk factors and genetic factors, such as Lynch syndrome (65), for which clinician referral of high-risk survivors to genetic risk assessment may allow opportunities for early detection and prevention of SPCs (66). Shared lifestyle factors relevant to observed associations include obesity and metabolic factors (ovary, uterine corpus, small intestine), alcohol consumption (small intestine), and smoking (small intestine, stomach, cervix) (67,68), warranting future analytical studies on the associations of these factors with the risk of subsequent colorectal cancer. Further, evidence suggests that abdominopelvic radiotherapy and possibly alkylating-based chemotherapy increase colorectal cancer risk (7,69-71), which may partly explain the increased risk observed among survivors of the uterine corpus, cervical, testicular cancers, and male HL with treatment history.

Increased risks of developing head and neck cancers were seen following 12 index cancers. Human papillomavirus (HPV) infectious status, an important risk factor, was not available in SEER, however, the increased risks following hematologic cancers are consistent with prior studies (21,32) and may relate to the increased risk of HPV infection because of prolonged immunosuppression among survivors who receive bone marrow transplantation, a curative treatment for a variety of hematologic disorders (72,73). Reasons remain unclear for the elevated risk after breast, thyroid, and brain cancers and soft tissue sarcoma, although the late effect of treatment and heightened medical scrutiny have been suspected (32). A study of childhood cancer survivors linked exposure to head and neck radiotherapy or platinum chemotherapy to a borderline increase in oropharyngeal cancer risk (74); however, studies are limited among AYA cancer survivors. Prevention efforts should continue to increase the uptake of HPV vaccination to mitigate increased risk for HPV-related cancers in AYA cancer survivors (21,75,76), given the substantially lower uptake among young cancer survivors vs the general population (23.8% vs 40.5% for at least 1 dose, ages 15-26 years) (77).

This study has several limitations. Even with long-term follow-up, events were rare, if any, for some SPCs, as reflected in the lack of estimates or wide confidence intervals. Restricting the analysis to SPCs that occurred 5 or more years after the initial diagnosis likely underestimated the risk for some SPCs, particularly treatment-related acute myeloid leukemia or myelodysplastic syndromes, which typically arise after a short-term latency (78). Additionally, underestimation is also possible because of outmigration from the 9 SEER areas of persons diagnosed with SPC (79) and exclusion of same-site SPCs that may include multicentric or multifocal tumors, new primaries at the other side of paired organs, and those with different histology and because the referent group general population includes persons with a history of cancer. Conversely, excess deaths from some SPCs may result from misclassified SPCs (eg, melanoma death after eye cancer and colorectal cancer death after small intestine and anal cancers) as the accuracy of cancer mortality data among individuals with multiple primary cancers remains to be determined (80). We caution overinterpretation of the presence or lack of treatment association with SPC risk because of limitations inherent in SEER treatment data—underascertainment, lack of detailed treatment regimen, no distinction between “no” and “unknown” indicated for chemotherapy or radiotherapy receipt, and lack of information beyond the first course of treatment (81)—that likely result in misclassification and residual confounding. Further, the lack of genetic and lifestyle risk factors, such as smoking and HPV infection, precluded the investigation of their role in SPC occurrence but was discussed as potentially contributing factors based on previous studies. Cancer classification was primarily based on topography code and did not use the classification scheme developed for AYA cancers (82) to maintain consistency between index and SPCs, which may have concealed heterogeneous risk patterns by tumor subtypes. Finally, some statistically significant associations may have occurred spuriously because of multiple tests, thus results should be interpreted based on biological and clinical plausibility.

In summary, using population-based data with a long-term follow-up, this study provides the risks of developing and dying from SPCs for a comprehensive list of AYA cancers. AYA cancer survivors are almost twice as likely to die from a new primary cancer as the general population, underscoring the critical role of primary care providers in the provision of high-quality posttreatment survivorship care to reduce the risks of developing SPCs or facilitate early detection of disease for successful treatment. Consolidated surveillance guidelines by the International Guideline Harmonization Group exist for subsequent breast (63) and thyroid (83) cancers and are under development for colorectal cancer (84,85), based on evidence primarily generated from studies of pediatric oncology and AYA survivors of HL and testicular cancer (16,47,86-89). Our findings highlight the need to expand the emphasis on SPC surveillance to include AYA as well as childhood cancer survivors and to develop age-specific and risk-appropriate surveillance strategies for SPCs in this growing population of survivors.

Funding

This work was supported by the Surveillance and Health Equity Science Department of the American Cancer Society (HS, RLS, KRY, KDM, AJ) and Institutional Research Grant from the American Cancer Society and the Medical College of Wisconsin Cancer Center (IRG #16-183-31, NH).

Notes

Role of the funder: The American Cancer Society had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Disclosures: KRY serves on the Flatiron Health Equity Advisory Board. The other authors declare no competing interests. KRY, who is a JNCI Associate Editor and coauthor on this article, was not involved in the editorial review or decision to publish the manuscript.

Author contributions: Conceptualization: HS, AJ; Data curation: HS; Methodology: HS and NH; Formal analysis: HS and NH; Writing—original draft: HS; Writing—review & editing: All authors; Supervision: AJ.

Prior presentations: This manuscript was published in abstract form (general poster session) at the 2021 American Society of Clinical Oncology Annual Meeting.

Data Availability

The database is publicly available and can be obtained upon user authentication from the Surveillance, Epidemiology, and End Results (SEER) Program in National Cancer Institute (https://seer.cancer.gov/data/).

Supplementary Material

djac091_Supplementary_Data

Click here for additional data file.^{(1.6MB, pdf)}

Contributor Information

Hyuna Sung, Surveillance and Health Equity Science, American Cancer Society, Kennesaw, GA, USA.

Rebecca L Siegel, Surveillance and Health Equity Science, American Cancer Society, Kennesaw, GA, USA.

Noorie Hyun, Division of Biostatistics, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.

Kimberly D Miller, Surveillance and Health Equity Science, American Cancer Society, Kennesaw, GA, USA.

K Robin Yabroff, Surveillance and Health Equity Science, American Cancer Society, Kennesaw, GA, USA.

Ahmedin Jemal, Surveillance and Health Equity Science, American Cancer Society, Kennesaw, GA, USA.

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Data Availability Statement

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PERMALINK

Subsequent Primary Cancer Risk Among 5-Year Survivors of Adolescent and Young Adult Cancers

Hyuna Sung, PhD

Rebecca L Siegel, MPH

Noorie Hyun, PhD

Kimberly D Miller, MPH

K Robin Yabroff, PhD

Ahmedin Jemal, DVM, PhD

Abstract

Background

Methods

Results

Conclusion

Method

Study Participants

SPC Ascertainment

Statistical Analysis

Results

Table 1.

Table 2.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Table 3.

Discussion

Funding

Notes

Data Availability

Supplementary Material

Contributor Information

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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