Risks of Second Non-Breast Primaries Following Breast Cancer in Women

A Systematic Review and Meta-Analysis

Isaac Allen; Hend Hassan; Eleni Sofianopoulou; Diana Eccles; Clare Turnbull; Marc Tischkowitz; Paul Pharoah; Antonis C. Antoniou

Disclosures

Breast Cancer Res. 2023;25(18)

Abstract and Introduction

Abstract

Background: Second primary cancer incidence is rising among breast cancer survivors. We examined the risks of non-breast second primaries, in combination and at specific cancer sites, through a systematic review and meta-analysis.

Methods: We conducted a systematic search of PubMed, Embase, and Web of Science, seeking studies published by March 2022. We included studies that reported standardized incidence ratios (SIRs), with associated standard errors, assessing the combined risk of second non-breast primaries following breast cancer. We performed meta-analyses of combined second primary risks, stratifying by age, follow-up duration, and geographic region. We also assessed second primary risks at several specific sites, stratifying by age. The inverse variance method with DerSimonian–Laird estimators was used in all meta-analyses, assuming a random-effects model. Associated biases and study quality were evaluated using the Newcastle–Ottawa scale.

Results: One prospective and twenty-seven retrospective cohort studies were identified. SIRs for second non-breast primaries combined ranged from 0.84 to 1.84. The summary SIR estimate was 1.24 (95% CI 1.14–1.36, I ²: 99%). This varied by age: the estimate was 1.59 (95% CI 1.36–1.85) when breast cancer was diagnosed before age 50, which was significantly higher than in women first diagnosed at 50 or over (SIR: 1.13, 95% CI 1.01–1.36, p for difference: < 0.001). SPC risks were also significantly higher when based on Asian, rather than European, registries (Asia—SIR: 1.47, 95% CI 1.29–1.67. Europe—SIR: 1.16, 95% CI 1.04–1.28). There were significantly increased risks of second thyroid (SIR: 1.89, 95% CI 1.49–2.38), corpus uteri (SIR: 1.84, 95% CI 1.53–2.23), ovary (SIR: 1.53, 95% CI 1.35–1.73), kidney (SIR: 1.43, 95% CI 1.17–1.73), oesophagus (SIR: 1.39, 95% CI 1.26–1.55), skin (melanoma) (SIR: 1.34, 95% CI 1.18–1.52), blood (leukaemia) (SIR: 1.30, 95% CI 1.17–1.45), lung (SIR: 1.25, 95% CI 1.03–1.51), stomach (SIR: 1.23, 95% CI 1.12–1.36) and bladder (SIR: 1.15, 95% CI 1.05–1.26) primaries.

Conclusions: Breast cancer survivors are at significantly increased risk of second primaries at many sites. Risks are higher for those diagnosed with breast cancer before age 50 and in Asian breast cancer survivors compared to European breast cancer survivors. This study is limited by a lack of data on potentially confounding variables. The conclusions may inform clinical management decisions following breast cancer, although specific clinical recommendations lie outside the scope of this review.

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Breast Cancer Res. 2023;25(18) © 2023 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Study characteristics
Author and publication year	Period of first BC¹ dx² for cohort	Follow-up period	Study design	Country and centre of data derivation	Definition of cohort	Definition of second primary cancers
AIRTUM Working Group [1]	Dx: 1976–2010 (varied by registry)	Start: At BC dx End: At SPC dx, death, date of last known vital status, or end of last year of registration (dates varied by registry)	Retrospective cohort	Italy (Multiple cancer registries covering 48% of the population)	All patients dx with a first cancer, although melanoma skin cancer cases, cases based on death certificate only, cases based on autopsy only, and cases with follow-up time equal to zero were excluded. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR⁴ rules
Andersson [2]	Dx 1977–2001	Start: 1y after BC dx End: SPC dx, death, emigration, or study end (2002)	Retrospective cohort	Denmark (Danish Breast Cancer Cooperative Group)	Female BC patients with record of BC dx at under age 90 in both the Danish Breast Cancer Cooperative Group and the Danish Cancer Register, who survived at least 1y⁵ post-BC dx, with no prior cancer history other than non-melanoma skin cancer, treated and followed accorded to a Danish Breast Cancer Cooperative Group protocol	SPC⁶ coding rules unstated, but the Danish Breast Cancer Cooperative Group is linked to the Danish Cancer Register, which uses IARC/IACR rules
Brenner [3]	Dx 1968–1987	Start: 1y after BC dx End: study end given as 1987. No details of other censoring events provided	Retrospective cohort	Germany (Saarland Cancer Registry)	Women dx with a first BC (first 1y post dx excluded from analysis)	SPC coding rules unstated, but German registries use IARC/IACR rules. Secondary malignancies and tumours of unspecified location, the skin, the bone, the brain and nervous system, the lung and the liver were excluded
Brown [4]	Dx 1943–1999 (Denmark), 1953–2002 (Finland), 1953–2000 (Norway), 1958–2002 (Sweden)	Start: 1y after BC dx End: SPC dx, death, or study end (1999–2002, depending on registry)	Retrospective cohort	Denmark, Finland, Norway, Sweden (all national registries)	Women dx with a first BC, who survived for at least 1y (first 1y post dx excluded from analysis)	SPC coding rules unstated, but all participating registries use IARC/IACR rules. Non-haematological malignancies excluded
Chen [5]	Dx 1997–2010	Start: At BC dx End: SPC dx, death, emigration, or study end (2010)	Retrospective cohort	Germany (12 German cancer registries covering 33% of population). Data was also reported for Sweden, but is not included here due to fully overlapping with several larger studies	Patients aged 15y or over at dx of a first primary malignant tumour. Patients with only death certificate/autopsy information were excluded. Cohort was stratified by first cancer site, allowing analysis for first BC	According to IARC/IACR rules, not including non-melanoma skin cancer. All cancers must be discordant. 95% + of were cancers microscopically verified
Diab [6]	Dx 1973–2012	Start: At BC dx End: SPC dx, death, or study end (2015)	Retrospective cohort	The USA—9 SEER⁷ registries (Connecticut, Detroit, Atlanta, San Francisco (Oakland), Hawaii, Iowa, New Mexico, Seattle (Puget Sound), Utah)	Women dx with breast cancer. In situ malignancies, dx made without microscopic confirmation, and dx from death certificates and autopsy reports were not included	SEER rules
Evans [7]	Two cohorts pooled: Dx 1961–1970 and dx 1971–1995	Start: At BC dx End: SPC dx, death, loss to follow-up, 85th birthday, or study end (1982 for those dx 1961–70, 1996 for those dx 1971–1995)	Retrospective cohort	England (Thames Cancer Registry)	Women dx with first BC at under age 85	Second tumours at a separate anatomical site and of a distinct histological type to the first tumour, or stated as a new tumour by the treating clinician. Non-melanoma skin cancers, non-malignant cancers, second cancers occurring within 1y of the initial cancer at the same site with the same laterality and histology, or cancers in patients without residency information available at date of dx or a without given date of dx were all excluded
Gulhan [18]	1992–2006	Start: 1y after BC dx End: study end given as 2006. No details of other censoring events provided	Retrospective cohort	Turkey (Izmir Cancer Registry)	Women aged at least 20 with histologically confirmed invasive BC, with at least 1m⁸ of follow-up	IARC/IACR rules
Harvey [8]	1935–1982	Start: 2m after BC dx End: At SPC dx, death, date of last known vital status, or study end (1982)	Retrospective cohort	The USA (Connecticut Tumour Registry)	Individuals diagnosed with a first primary invasive BC when they were resident in Connecticut, that survived without a second cancer developing for at least 2 m after the diagnosis, who were observed for at least 2 m after the diagnosis, and whose cancer was not diagnosed only from an autopsy report or death certificate	Most of the data used in this study predates the publication of the SEER SPC coding rules, the most common rules applied in North America. However, SPC coding rules used in this study were very similar. Briefly, study defined SPCs as invasive cancers that developed at least 2 m after the first cancer, excluding in situ cancers or non-melanoma skin cancers. SPCs diagnosed only from autopsy reports or death certificates were included
Hung 2016 [19]	1997–2010	Start: At BC dx End: SPC dx, death, dropout from programme providing study data, or study end (2011)	Retrospective cohort	Taiwan (Registry of Catastrophic Illness)	Patients dx with a first BC	SPC coding rules unstated, but the registry histologically confirms cancer cases. Oncologists are required to give evidence of the diagnosis, including cytology reports, pathology reports, laboratory studies, and imaging studies, for review by commissioned expert panels
Jégu [9]	Dx 1989–2004	Start: 2 m (62 days) after BC dx End: At SPC dx, death, date of last known vital status, or study end (2007)	Retrospective cohort	France (10 registries covering the Bas-Rhin, Calvados, Doubs, Hérault, Isère, Manche, Somme and Tarn administrative regions)	Patients dx with a first cancer, who did not develop a SPC within 2 m (62 days) after their first cancer. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR rules
Jung [20]	Dx 1989–2014	Start: At BC dx End: At SPC dx, death, date of last known hospital visit, or study end (2014)	Retrospective cohort	Korea (3 medical centres in Soeul, Bucheon, and Choenan)	Women aged at least 20y dx with BC and with at least 1 visit to the Soeul, Bucheon, or Choenan centres within 2 m from dx and with treatment records, who contributed at least 2 m of follow-up time	SPC coding rules unspecified, but second cancers must be at discordant sites, dx at least 2 m after BC diagnosis, with each case "thoroughly reviewed, and misleading information from breast cancer metastasis excluded"
Lee [21]	Dx 1979–2003	Start: At BC dx End: At SPC dx, death, or study end (2003)	Retrospective cohort	Taiwan (National Cancer Registry)	Women dx with first BC, without missing dates of birth, follow-up dates or death statuses, and who survived without a second cancer for at least 1 m post-BC dx	According to IARC/IACR rules. Second cancers reported within 1 m of BC dx excluded
Levi [10]	Dx 1974–1998	Start: At BC dx End: At SPC dx, death, emigration, or study end (1998)	Retrospective cohort	Switzerland (Swiss Cancer Registries of Vaud and Neuchâtel)	Women dx with a first BC with at least 1 m of follow-up	SPC rules unstated, but the Vaud and Neuchâtel registries use IARC/IACR rules. Second cancers diagnosed at autopsy, death, by death certification alone, or within 1 m of first BC were excluded. Second cancers must be morphologically different or at different anatomical sites
Mellemkjaer [33]	Australia, New South Wales: 1972–1997, Canada, British Colombia: 1970–1998, Canada, Manitoba: 1970–1998, Canada, Saskatchewan: 1967–1998, Denmark: 1943–1997, Finland: 1953–1998, Iceland: 1955–2000, Norway: 1953–1999, Singapore: 1968–1992, Slovenia: 1961–1998, Spain, Zaragoza: 1978–1998, Sweden: 1961–1998, UK, Scotland: 1960–1996	Start: At BC dx End: At SPC dx, death, emigration, or study end (between 1992 and 2000, depending on registry)	Retrospective cohort	13 large cancer registries. Canada (British Columbia, Manitoba and Saskatchewan), Singapore, Slovenia, Norway, Denmark, Scotland, Australia (New South Wales), Sweden, Finland, Iceland, Spain (Zaragoza)	Women dx with a first BC	IARC/IACR rules. Tumours identified by following the recording practices of the included registries
Molina-Montes [11]	Dx 1985–2007	Start: At BC dx End: At SPC dx, death, or study end (2007)	Retrospective cohort	Spain (Granada Cancer Registry)	Women dx with a first BC, aged 15y or over at BC dx	According to IARC/IACR rules. Second cancers only included if they occurred at least 3 m after the BC dx
Murakami [22]	Dx 1965–1982	Start: Unstated, but less than 1y after BC dx End: At SPC dx, death, or study end (1983)	Retrospective cohort	Japan (Osaka Cancer Registry)	Women dx with a first BC who survived at least 3 m after the BC dx	SPC rules unspecified but Osaka Cancer Registry follows IARC/IACR rules. Second cancers only included if they occurred at least 3 m after the BC dx
Odani [23]	2000–2014	Start: 3 m after BC dx End: At SPC dx, death, 10y after BC dx, or study end (2015)	Retrospective cohort	Japan (Osaka Cancer Registry)	Dx with first primary invasive cancer, aged 15–79 years and resident in Osaka at dx. Dx with death certificate only were excluded. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR rules
Ricceri [12]	Individuals recruited to cohort of generally healthy individuals between 1992 and 1998. The subset of these that developed a first primary BC during 11y of follow-up was taken as the cohort of BC survivors in this study	Start: At BC dx End: at SPC dx, death, or end of study (year of study end unstated)	Prospective cohort	EPIC⁹ cohort is drawn from generally healthy individuals aged 35–70 from 23 centres from Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and the UK. Follow-up for cancer was based on population cancer registries except in France, Germany and Greece, where a combination of methods including health insurance records, cancer and pathology registries and active follow-up were used	Female subset of EPIC cohort that developed a first BC after recruitment into study, or that developed a BC as their second cancer after a first non-melanoma skin cancer. Cases identified using death certificate only were excluded	IARC/IACR rules. Second cancers dx on same date as initial BC or identified using death certificate only were excluded
Rubino [13]	1954–1984	Start: 1973, for those dx with BC 1954–1971. 1y after BC dx, for those dx with BC 1972–1984 End: At SPC dx, death, loss to follow-up, or study end (1992)	Retrospective cohort	France (Institut Gustave Roussy)	Women dx with first BC, born and living in France, with at least 1y of follow-up since BC dx	SPC rules unspecified. All second malignancies were histologically confirmed. Second bilateral BCs and non-melanoma skin cancers were excluded
Schaapveld [14]	Groningen and Amsterdam: 1989–2003 Eindhoven: 1989–2002	Start: At BC dx End: at SPC dx, death, or end of study (Groningen and Amsterdam: 2005. Eindhoven: 2004)	Retrospective cohort	The Netherlands (Comprehensive cancer centres of Groningen, Amsterdam, and Eindhoven)	Women dx with first BC with no prior cancer history, or a first BC following non-melanoma skin cancer	According to IARC/IACR coding rules. All unknown primary adenocarcinomas, meningiomas, myelodysplastic syndromes, polycythemia veras, and non-melanoma skin cancers were excluded as second cancers. A cancer occurring after a non-melanoma skin cancer that followed the BC was classed as the second cancer rather than the non-melanoma skin cancer
Schottenfeld [15]	Treatment (rather than dx) of breast, endometrial, ovarian, vagina, vulva, or cervix uteri cancers at Memorial Sloan Kettering Cancer Centre between 1949 and 1962	Start: Unstated End: Unstated. Study ended in 1962	Retrospective cohort	The USA (Memorial Sloan Kettering Cancer Centre)	Patients with cancer of the breast, endometrium, ovary, vagina, vulva, or cervix uteri treated at the Memorial Sloan Kettering Cancer Centre between 1949 and 1962. Cohort was stratified by first cancer site, allowing analysis for first BC	The study predates the publication of the SEER SPC coding rules, the most common rules applied in North America. However, medical records were reviewed to validate the pathologic findings (where presumably recurrences and metastases were ruled out) whenever SPC incidence "increased significantly"
Silverman [24]	1990–2006	Start: At BC dx. Also provided results for a start of follow-up at 6 m after BC dx End: at SPC dx, death, or end of study (2011)	Retrospective cohort	Israel—Israel National Cancer Registry	Women with first BC, excluding breast lymphomas	SPC coding rules unstated, but Israel National Cancer Registry uses IARC/IACR rules with the following optional rules: 1: Two tumours of different laterality, but of the same morphology, diagnosed in paired organs (e.g. breast) are registered separately unless stated to have originated from a single primary 2: Cancers that occur in any 4th character subcategory of colon (C18) and skin (C44) are registered as multiple primary cancers
Tabuchi [25]	Dx 1985–2004	Start: 3 m after BC dx End: At SPC dx, death, 10y after BC dx, 80th birthday, or study end (2005)	Retrospective cohort	Japan (Osaka Cancer Registry)	All individuals aged 0–79 dx with a first primary cancer who survived at least 3 m. Cohort was stratified by first cancer site, allowing analysis for first BC	According to IARC/IACR rules. Only discordant second cancers included
Trama [16]	Dx at and followed up until various periods starting from 1976, respectively, according to the establishment dates of and the most recent incidence data entry dates of the registries in study	Start: At BC dx End: At SPC dx, death, emigration, or end of last year of data entry into registry records (dates varied by registry)	Retrospective cohort	Italy—34 cancer registries covering 43% of Italian population as of 2019	Individuals diagnosed with a first primary cancer (invasive or of uncertain behaviour), aged 15–39 at the first cancer diagnosis, who survived at least 5y after the first diagnosis. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR rules
Tsukuma [26]	1966–86, but information on standardized incidence ratios for SPCs following BC only available for those dx 1978–86	Start: At BC dx End: At SPC dx, death, 80th birthday, or study end (1989)	Retrospective cohort	Japan (Osaka Cancer Registry)	All individuals aged 0–79 dx with a first primary cancer, who survived at least 3 m after the first cancer dx. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR rules. Second cancers only included if they occurred at least 3 m after the BC dx
Utada [27]	1985–2007	Start: At BC dx End: At SPC dx, death, or study end (2008)	Retrospective cohort	Japan (Nagasaki Cancer Registry)	All individuals dx with a first primary cancer. Cohort was stratified by first cancer site, allowing analysis for first BC	IARC/IACR rules. Only discordant second cancers included
Zheng [17]	1958–2015	Start: At BC dx End: At SPC dx, death, emigration, or study end (2015)	Retrospective cohort	Sweden (FCD¹⁰)	The Swedish FCD is composed of two separate cohorts. 1: Swedish people born after 1931 ("offspring generation"), and 2: their parents ("parental generation"). This study examined the subset of the offspring generation dx with BC between 1958 and 2015	Swedish FCD data is linked to national registry, which uses IARC/IACR rules. All second cancers undergo "rigorous histological diagnostics". A request for separate and consistent tumour notifications from clinicians and pathologists is required

¹Breast Cancer
²Diagnosis/diagnoses/diagnosed
³Follow-up
⁴International Association of Cancer Registries/International Agency for Research on Cancer
⁵Year/years
⁶Second Primary Cancer
⁷Surveillance, Epidemiology, and End Results
⁸Month/months
⁹European Prospective Investigation into Cancer and nutrition
¹⁰Family Cancer Database

Table 2. Further study characteristics
Author and publication year	Total person years	FU¹ time since BC² dx³ strata	Age strata at BC dx	Specific SPC⁴s for which SIR⁵s reported	N⁶ first BC/N SPCs	SIR (95% CI⁷) for combined risk of non-breast SPCs
AIRTUM Working Group [1]	1,274,882	0–1 m⁸, 2–11 m, 12–59 m, 60–119 m, > = 120 m	0–19, 20–29, 30–39, 40–49, 50–69, > = 70	Oral cavity, Pharynx, Larynx, Oesophagus, Stomach, Colon, Rectum, Liver, Gallbladder, Pancreas, Lung, Skin melanoma, Mesothelioma, Kaposi sarcoma, Soft tissue, Bone, Corpus Uteri, Cervix Uteri, Ovary, Kidney and renal pelvis, Bladder and urinary tract, Brain and central nervous system, Thyroid, Hodgkin's lymphoma, Non-Hodgkin's lymphomas, Multiple myeloma, Leukaemias (Lymphoid leukaemia, Myeloid leukaemia, Other leukaemias), Other sites	215,809/10597	1.12 (1.10–1.14)
Andersson [2]	256,563	1–9 y⁹, 10–19 y, > = 20 y	< 50, 50–59, 60–69, 70–89	Lip, Tongue, Salivary glands, Mouth, Pharynx, Oesophagus, Stomach, Small intestine, Colon, Rectum, Liver, Gallbladder, Pancreas, Nose (sinuses), Larynx, Lung, Pleura, Cervix Uteri, Corpus Uteri, Uterus (other), Ovary (uterine adnexa), Other female genital organs, Kidney, Bladder (and other unspecified related sites), Melanoma of skin, Eye, Brain and nervous system, Thyroid, Bone, Soft tissues, Non-Hodgkin's Lymphoma, Hodgkin's disease, Multiple myeloma, Acute leukaemia, Other leukaemia	31,818/1993	1.04 (0.99–1.08)
Brenner [3]	43,642.25	Unreported	< 50, > = 50	Stomach, Colon, Rectum, Gallbladder and bile ducts, Pancreas, Corpus Uteri, Cervix Uteri, Ovaries, Urinary bladder, Kidneys, Lymphomas and leukaemias	9678/206	0.84 (0.73–0.96)
Brown [4]	2,990,587	1–9 y, 10–19 y, 20–29 y, > = 30 y	< 40, 40–49, 50–64, > 64	Salivary gland, Oesophagus, Lung, Pleura, Thyroid, Bone, Connective tissue, Uterine corpus, Lip, Tongue, Mouth, Pharynx, Stomach, Small intestine, Colon, Rectum/anus, Liver, Pancreas, Gallbladder, Nose/nasal cavity, Larynx, Cervix, Ovary, Kidney, Bladder, Malignant Melanoma, Eye, Brain and central nervous system	376,825/23158	1.15 (1.14–1.17)
Chen (Germany) [5]	Unreported	Unreported	Unreported	Unreported	234,863 (male and female combined)/3676	1.15 (1.13–1.17). 1.15 is the midpoint of the reported 95% CI—it was taken as an approximation for the SIR due to early rounding in the study
Diab [6]	Unreported	Unreported	< 50, > = 50	Oral cavity and pharynx, Digestive system, Colon, rectum, and anus, Pancreas, Peritoneum, omentum and mesentery, Respiratory system, Bones and joints, Soft tissue including heart, Skin excluding basal and squamous, Breast, Female genital system, Corpus and uterus (not otherwise specified), Ovary, Urinary system, Brain and other nervous system, Endocrine system, Lymphoma, Leukaemia	514,479/45509	1.03 (1.02–1.04)
Evans [7]	832,958.1	Unreported	< 50, > = 50	Tongue, Mouth, Oesophagus, Stomach, Colon, Rectum, Liver, Gallbladder, Pancreas, Larynx, Lung and bronchus, Bone, Connective tissue, Skin melanoma, Cervix Uteri, Corpus Uteri, Ovary, Bladder, Kidney, Brain and nervous system, Thyroid, Non-Hodgkin's Lymphoma, Multiple myeloma, Lymphoid Leukaemia, Myeloid Leukaemia	145,677/4470	0.89 (0.86–0.92)
Gulhan [18]	16,377	Unreported	Unreported	Endometrial, Ovary, Cervical	6356/88	1.76 (1.43–2.17)
Harvey [8]	271,524	< 1 y, 1–4 y, 5–9 y, > = 10 y	< 45, 45–54, > = 55	Lip, Tongue, Salivary gland, Gum and other mouth, Pharynx, Oesophagus, Stomach, Colon, Rectum, Liver (biliary), Pancreas, Nasal cavities and sinuses, Larynx, Trachea, bronchus, and lung, Cervix uteri, Corpus uteri, Uterus (not otherwise specified), Ovary and fallopian tubes, Kidney and renal pelvis and ureter, Bladder and other urinary, Skin (melanoma), Eye, Brain and central nervous system, Thyroid gland, Bone, Connective tissue, Non-Hodgkin's lymphoma, Hodgkin's disease, Multiple myeloma, Leukaemias, Chronic lymphocytic leukaemia, Acute nonlymphocytic leukaemia	41,109/2057	1.15 (1.10–1.20)
Hung [19]	527,009	< 1 y, 1–4 y, > = 5 y	20–29, 30–39, 40–49, 50–59, 60–69, 70–79, > = 80	Head and neck, Oesophagus, Stomach, Colon and rectum and anus, Liver and biliary tract, Liver, Lung and mediastinum, Bone and soft tissue, Skin, Cervix, Uterus, Ovary, Bladder, Kidney, Thyroid, Hematologic malignancies, All others	100,915/3,080	1.50 (1.44–1.55)
Jégu [9]	351,434	Unreported	Unreported	Corpus Uteri	Unreported/2476	1.31 (1.26–1.36)
Jung [20]	13,433.5	Unreported	30–39, 40–49, 50–59, 60–69, > = 70	Oesophagus, Stomach, Colon and rectum, Anus, Liver, Gallbladder and common bile duct, Lung, Cervix, Endometrium, Ovary, Kidney, Bladder, Thyroid, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Acute myeloid leukaemia, Skin, Muscle	3344/93	1.56 (1.27–1.91)
Lee [21]	290,966	< = 5 y, 6–10 y, > 10 y	< 50, > = 50	Bone, Corpus uteri, Ovary, Non-melanoma skin, Thyroid, Head and neck, Nasopharynx and nasal cavity, Oesophagus, Stomach, Small intestine, Colon and rectum, Liver, Biliary system, Pancreas, Lung, Thymus, Sarcoma, Cervix uteri, Urinary bladder, Kidney and other urinary organs, Brain, Leukaemia or lymphoma, Others	53,783/1085	1.09 (1.03–1.16)
Levi [10]	61,834	< 5 y, > = 5 y	Unreported	Mouth and pharynx, Oesophagus, Stomach, Colorectum, Gallbladder, Pancreas, Lung, Soft tissue, Skin melanoma, Cervix Uteri, Corpus Uteri, Ovary, Other female genital organs, Bladder, Kidney, Thyroid, Non-Hodgkin's lymphomas, Multiple myelomas, Leukaemias, Other and unknown sites	9729/443	1.14 (1.04–1.25)
Mellemkjaer [33]	3,784,660	< 1 y, 1–9 y, > = 10y	< = 45, 46–55, > = 56	Oral cavity and pharynx, Oesophagus, Stomach, Small intestine, Colorectal, Liver, Pancreas, Larynx, Lung, Bone, Soft tissue sarcoma (of thorax and upper lim inc. shoulder), Melanoma, Non-melanoma skin cancer, Corpus Uteri, Ovary, Bladder, Kidney, Brain and nervous system, Thyroid gland, Non-Hodgkin's lymphoma, Leukaemia, Myeloid leukaemia	525,527/31399	1.25 (1.24–1.26)
Molina-Montes [11]	37,605	< 5 y, > = 5 y	< 50, > = 50	Endometrium, Colon and rectum, Stomach, Ovary, Thyroid gland, Non-melanoma skin, Kidney, Bladder, Hematologic malignancies (lymphoid leukaemia, myeloid leukaemia, and multiple myeloma)	5897/314	1.39 (1.24–1.55)
Murakami [22]	53,738	< 1 y, 1–4 y, 5–9 y, > = 10 y	< 45, 45–54, > = 55	Buccal cavity, Stomach, Oesophagus, Colon, Rectum, Liver, Pancreas, Lung, Cervix Uteri, Corpus Uteri, Ovary, Urinary bladder, Thyroid gland, Leukaemia	9503/254	1.34 (1.18–1.52)
Odani [23]	266,685	3 m–1 y, 1–5 y, 5–10 y	Unreported	Oral cavity/pharynx, Stomach, Colorectum, Liver, Gallbladder, Pancreas, Lung, Uterus, Ovary, Kidney/urinary tract/bladder, Thyroid, Blood	47,622/1843	1.84 (1.76–1.92)
Ricceri [12]	56,496	Unreported	Unreported	Colorectum, Lung, Pancreas, Melanoma, Endometrium, Ovary, Kidney, Thyroid gland, Lymphomas	10,045/352	1.30 (1.18–1.42)
Rubino [13]	33,044	1–10 y, > = 10 y	< 50, > = 50	Oral cavity, Oesophagus, Stomach, Colon and rectum, Liver and gallbladder, Pancreas, Larynx, Lung and bronchus, Uterus, Ovaries, Bladder, Kidney, Melanoma, Nervous system, Thyroid, Other endocrine, Bone, Soft tissue, Undefined sites, Myeloma, Lymphoma, Leukaemia	4416/193	1.40 (1.21–1.62)
Schaapveld [14]	362,470	Not reported in a fashion that allows accurate extraction of age-stratified SIRs and corresponding 95% standard errors	< 50, > = 50	Head and neck, Thyroid, Oesophagus, Stomach, Pancreas, Gallbladder/extrahepatic bile ducts, Colon, Rectum and Anus, Lung, Soft tissue sarcomas, Melanoma of skin, Ovary, Cervix, Uterus, Vulva, Kidney, Bladder, Brain, Acute myeloid leukaemia, Other Leukaemia, Non-Hodgkin's lymphoma, Multiple myeloma	58,068/2578	1.22 (1.17–1.27)
Schottenfeld [15]	Unreported	Unreported	Unreported	Ovary, Corpus Uteri, Cervix Uteri, Vulva and vagina, Buccal cavity and Pharynx, Oesophagus, Stomach, Colon, Rectum, Pancreas, Liver and bile ducts, Larynx, Lung, Kidney, Bladder, Lymphoma and leukaemia, Salivary glands, Thyroid, Soft-part sarcomas, Bone sarcomas	9792/231	1.01 (0.9–1.1)
Silverman [24]	363,333	Unreported	< 50, > = 50	Colorectum, Uterus, Lung, Ovary, Non-Hodgkin's Lymphoma, Brain, Melanoma (invasive), Thyroid, Leukaemia, Uterine Cervix	43,794/3866	1.26 (1.23–1.30)
Tabuchi [25]	197,571	< 1 y, 1–5 y, 5–10 y	Unreported	Mouth/pharynx, Stomach, Oesophagus, Colorectal, Liver, Gallbladder, Pancreas, Lung, Uterus, Ovary, Thyroid, Kidney/urinary tract/bladder, Blood	Unreported/1007	1.48 (1.39–1.57)
Trama [16]	102,629	< 5 y, 5–10 y, 10–15 y, 15–20 y, 20–25 y, > 25 y	Unreported	Soft tissue sarcomas, Colorectal, Stomach, Pancreatic, Liver, Bladder, Kidney, Cervical, Ovarian, Corpus Uteri, Central nervous system, Germ cell	11,328/299	1.13 (1.0–1.3)
Tsukuma [26]	Unreported	< 1 y, 1–4 y, 5–9 y	Unreported	Stomach, Colon, Lung, Thyroid	Unreported/226	1.42 (1.25–1.62)
Utada [27]	Unreported	Not reported in a fashion that allows accurate extraction of age-stratified SIRs and corresponding 95% standard errors	Unreported	Lung, Uterus, Ovary, Thyroid	Unreported/727	1.16 (1.08–1.25)
Zheng [17]	Unreported	Unreported	Unreported	Upper aerodigestive tract, Oesophagus, Stomach, Small intestine, Colorectum, Anus, Liver, Nose, Pancreas, Lung, Cervix, Endometrium, Uterus, Ovary, Other female genitals, Kidney, Bladder, Melanoma, Skin (squamous cell carcinoma), Eye, Nervous system, Thyroid gland, Endocrine gland, Bone, Connective Tissue, Non-Hodgkin's lymphoma, Hodgkin's lymphoma, Myeloma, Leukaemia, Cancer of unknown primary, Colon, Rectum	87,752/6299	1.43 (1.40–1.47)

¹Follow-up
²Diagnosis/Diagnoses/Diagnosed
³Breast Cancer
⁴Second Primary Cancer
⁵Standardized Incidence Ratio
⁶Number (of)
⁷Confidence Interval
⁸Month/Months
⁹Year/Years

Table 3. Risks of second primaries at specific sites
Cancer site	SIR (95% CI)—breast cancer diagnosed at any age	SIR (95% CI)—breast cancer diagnosed at under age 50	SIR (95% CI)—breast cancer diagnosed at age 50 or over	Number of studies in meta-analysis
Cancer site	SIR (95% CI)—breast cancer diagnosed at any age	SIR (95% CI)—breast cancer diagnosed at under age 50	SIR (95% CI)—breast cancer diagnosed at age 50 or over	Unstratified by age at BC dx	Aged under 50 at BC dx	Aged 50 or over at BC dx
Bladder¹	1.15 (1.05–1.26)	1.32 (1.17–1.48)	1.08 (0.89–1.30)	8	4	4
Blood (leukaemia)²	1.30 (1.17–1.45)	1.91 (1.77–2.05)	1.34 (0.99–1.81)	8	4	4
Blood (myeloma)³	0.83 (0.68–1.02)	1.01 (0.53–1.94)	0.63 (0.48–0.82)	4	1	1
Blood (non-Hodgkin's lymphoma)	1.04 (0.91–1.19)	1.17 (0.96–1.42)	0.93 (0.65–1.33)	7	2	2
Brain and central nervous system⁴	0.80 (0.71–0.91)	0.95 (0.81–1.11)	0.75 (0.69–0.81)	7	4	3
Cervix uteri⁵	0.88 (0.77–1.00)	0.65 (0.46–0.93)	0.57 (0.23–1.39)	10	2	2
Colorectum⁶	1.12 (0.99–1.27)	1.30 (0.91–1.86)	1.02 (0.87–1.19)	11	5	5
Corpus uteri⁷	1.84 (1.53–2.23)	1.40 (1.12–1.76)	1.75 (1.29–2.37)	16	5	5
Gallbladder⁸	1.13 (0.68–1.87)	0.49 (0.12–1.96)	0.86 (0.63–1.17)	7	1	1
Kidney⁹	1.43 (1.17–1.73)	1.29 (1.15–1.43)	1.35 (0.95–1.92)	11	4	4
Liver¹⁰	0.86 (0.60–1.24)	0.93 (0.71–1.21)	0.56 (0.33–0.96)	7	1	2
Lung¹¹	1.25 (1.03–1.51)	1.65 (1.49–1.82)	0.81 (0.55–1.20)	12	3	3
Oesophagus	1.39 (1.26–1.55)	2.21 (1.89–2.60)	1.20 (1.06–1.37)	9	3	3
Ovary	1.53 (1.35–1.73)	2.24 (1.59–3.13)	1.04 (0.93–1.16)	16	6	6
Pancreas	1.09 (0.93–1.27)	1.35 (1.16–1.57)	0.92 (0.81–1.04)	11	3	4
Skin (melanoma)	1.34 (1.18–1.52)	1.34 (1.23–1.45)	1.25 (1.17–1.35)	7	3	3
Stomach	1.23 (1.12–1.36)	1.90 (1.75–2.06)	1.10 (0.91–1.34)	13	4	4
Thyroid	1.89 (1.49–2.38)	2.06 (1.83–2.31)	1.17 (0.90–1.52)	14	4	3
Vulva¹²	0.92 (0.63–1.35)	–	–	2	0	0

¹Meta-analysis also includes data on cancer risks at the "urinary bladder"
²Meta-analysis includes data on combined lymphoid leukaemia and myeloid leukaemia risks
³Meta-analysis only includes data on "multiple myeloma(s)" risks
⁴Meta-analysis also includes data on cancer risks at the "brain and nervous system", brain only, and nervous system only
⁵Meta-analysis also includes data on "cervical", "cervix", and "uterine cervix" cancer risks
⁶Meta-analysis includes data on combined colon and rectum cancer risks
⁷Meta-analysis also includes data on cancer risks at the "uterus" and "endometrium"
⁸Meta-analysis also includes data on cancer risks at the "gallbladder and bile ducts", "gallbladder and common bile duct", and "gallbladder/extrahepatic bile ducts"
⁹Meta-analysis also includes data on cancer risks at the "kidney and renal pelvis"
¹⁰Meta-analysis also includes data at the "liver and biliary tract" and "liver and bile ducts"
¹¹Meta-analysis also includes data at the "lung and bronchus"
¹²Meta-analysis also includes data at the "vulva and vagina"