Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group

Abstract

PURPOSE

As new evidence is available, the International Late Effects of Childhood Cancer Guideline Harmonization Group has updated breast cancer surveillance recommendations for female survivors of childhood, adolescent, and young adult cancer.

METHODS

We used evidence-based methods to apply new knowledge in refining the international harmonized recommendations developed in 2013. The guideline panel updated the systematic literature review, developed evidence summaries, appraised the evidence, and updated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance interventions while attaining flexibility in implementation across different health care systems. The GRADE Evidence-to-Decision framework was used to translate evidence to recommendations. A survivor information form was developed to counsel survivors about the potential harms and benefits of surveillance.

RESULTS

The literature update identified new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), radiation dose-volume, anthracyclines and alkylating agents in non–chest irradiated survivors, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the performance metrics of mammography and magnetic resonance imaging among survivors of Hodgkin lymphoma. Modified recommendations include the performance of mammography and breast magnetic resonance imaging for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with any type of anthracyclines in the absence of chest radiation.

CONCLUSION

The newly identified evidence prompted significant change to the recommendations formulated in 2013 related to moderate-dose chest radiation and anthracycline exposure as well as breast cancer surveillance modality.

INTRODUCTION

Female survivors of childhood, adolescent, and young adult (CAYA) cancer treated with radiation to fields that expose breast tissue—hereafter referred to as chest radiation—are at increased risk of developing breast cancer at a young age.¹ The cumulative breast cancer incidence ranges from 13% to 20% by age 40 to 45 years in survivors of childhood cancer^2-4 and is as high as 35% by age 50 years in survivors of Hodgkin lymphoma,⁵ comparable to that observed among BRCA gene mutation carriers.^4,5 Moreover, mortality after breast cancer is higher in survivors of CAYA cancer than in women with primary breast cancer.⁶ In view of the high breast cancer risk, tailored long-term breast surveillance has been recommended for female survivors of CAYA cancer treated with chest radiation.^7-9

CONTEXT

• Key Objective

• To evaluate newly published evidence related to breast cancer surveillance for survivors of childhood, adolescent, and young adult cancer and update surveillance recommendations.

• Knowledge Generated

• New data prompted significant changes to the recommendations formulated in 2013 regarding breast cancer surveillance for survivors treated with 10 Gy or greater chest radiation, upper abdominal field radiation exposing breast tissue at a young age, and anthracyclines in the absence of chest radiation; the upper age limit for breast cancer surveillance; and the surveillance modality.

• Relevance

• This International Late Effects of Childhood Cancer Guideline Harmonization Group breast cancer surveillance guideline aims to improve health outcomes by facilitating consistent long-term follow-up care for female survivors of childhood, adolescent, and young adult cancer and to promote strategically planned future research that will inform future guideline updates.

In 2013, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) harmonized evidence-based breast cancer surveillance recommendations for female survivors of CAYA cancer.⁷ We present the updated recommendations after consideration of new data regarding breast cancer risk associated with low-dose chest radiation as well as chemotherapy exposure. In addition, we evaluate potential harms and benefits of surveillance. A survivor information form summarizing the benefits and harms associated with surveillance is provided to facilitate counseling and informed decision making.

METHODS

Guideline Development Panel

Guideline representatives from the North American Children’s Oncology Group, the Dutch Childhood Oncology Group, Scottish Intercollegiate Guidelines Network, United Kingdom Children’s Cancer and Leukaemia Group, and other international pediatric oncology societies and institutions developed a working group of 18 experts from North America and Europe. Panelists were selected for their expertise in the fields of pediatric, radiation, and medical oncology; survivorship; cancer prevention; primary care; diagnostic imaging; epidemiology; and guideline methodology.

Scope and Definitions

This guideline aims to provide health care providers and female survivors of CAYA cancer with tailored recommendations for breast cancer surveillance. The target population is females diagnosed with cancer at younger than 30 years of age and 2 or more years after the completion of treatment. Chest radiation exposing breast tissue includes the following treatment fields: thorax, whole (or partial) lung, mediastinal, axilla, mantle, mini-mantle, (sub)total lymphoid, upper abdominal radiation likely exposing breast tissue, and total body irradiation (TBI).

Systematic Literature Review

IGHG’s methodology has been previously published.^7,10 Experts devised clinical questions for breast cancer surveillance evaluating the following issues: who needs surveillance, at what age should surveillance be initiated, at what frequency should surveillance be performed, at what age should surveillance be stopped, and what surveillance modality should be used (Data Supplement). An update of the systematic literature search was performed from August 2011 to June 2019. We searched MEDLINE (through PubMed) using the search terms breast cancer, secondary tumor, and survivor(detailed search strategy is provided in the Data Supplement). We also contacted experts to determine if additional evidence was available. The inclusion criteria are reported in the Data Supplement.

Evidence summaries were generated using standardized data extraction forms to answer clinical questions. The quality of the evidence was graded according to evidence-based methods (Data Supplement).

Translating Evidence Into Recommendations

The GRADE Evidence-to-Decision framework, a systematic and transparent approach to formulate recommendations, was used.¹¹ Recommendations were based on the consideration of the evidence, clinical judgements, decisions about thresholds, costs, and the benefits versus harms of surveillance and need for flexibility of implementation across different health care systems. Decisions were made through group consensus. The strength of each recommendation was graded according to published evidence-based methods (Data Supplement).^12,13

Survivors of CAYA cancer who have a relative breast cancer risk that is four times higher or greater than the risk in survivors not exposed to a specific treatment were considered high risk, a risk two to four times higher as moderate risk, and two times higher or less as low risk. A strong recommendation was formulated when there was consistent, high-quality evidence of a high breast cancer risk after a certain exposure.

To promote informed decision making, we developed a survivor information form to facilitate the discussion of potential benefits and harms of surveillance between the patient and health care provider.

The updated recommendations and survivor information form were critically appraised by three independent external experts (C.v.G., I.D.D., and E.M.) and three patient representatives (A.B., L.G., and K.W.).

RESULTS

New data prompted significant change to the recommendations formulated in 2013. Modified recommendations include the performance of mammography and breast magnetic resonance imaging (MRI) for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with anthracyclines in the absence of chest radiation (Table 1 and Fig 1). These modifications were based on new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), the joint effects of radiation dose and radiation volume, the effects of anthracyclines and alkylating agents in the absence of chest radiation, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the diagnostic accuracy of mammography and MRI among survivors of Hodgkin lymphoma (Fig 2). The Data Supplement includes studies from the updated literature search, evidence summaries, and conclusions of evidence tables.

TABLE 1.

Modifications to the Breast Cancer Surveillance Recommendations Formulated in 2013 Versus 2019

FIG 1.

Updated harmonized recommendations for breast cancer surveillance for female survivors of childhood, adolescent and young adult cancer. Green represents a strong recommendation with a low degree of uncertainty. Yellow represents a moderate recommendation with a higher degree of uncertainty. (1) Recommended breast cancer surveillance beyond the national breast cancer screening program. (2) Patient age, family history, menopausal status, other previous cancer treatment. (3) Testing for genetic cancer predisposition syndromes, like Li-Fraumeni syndrome, can be considered for survivors of leukemia, CNS tumor, and non-Ewing sarcoma who have been treated with high-dose anthracyclines to determine if the breast cancer risk is additionally increased. NOTE. Breast cancer surveillance recommendations for female survivors of childhood, adolescent and young adult cancer with a genetic predisposition to breast cancer are outside the scope of this paper. For that purpose, we refer to the country-specific recommendations. CAYA, childhood, adolescent, and young adult; MRI, magnetic resonance imaging.

FIG 2.

Conclusions of evidence from the systematic literature search for breast cancer surveillance for female survivors of childhood, adolescent, and young adult (CAYA) cancer in 2013 versus 2019. MRI, magnetic resonance imaging; TBI, total body irradiation.

Risk After Chest Radiation, TBI, and Upper Abdominal Radiation Exposing Breast Tissue

Women treated before age 30 years with therapeutic radiation volumes exposing breast tissue are at increased risk of breast cancer at a young age. Risk was previously recognized as especially high for women with a high delivered dose of chest radiation (≥ 20 Gy; level A).^1,5,14-18 There is now evidence that women who are exposed to moderate doses of chest radiation (10-19 Gy) have a substantially elevated risk of breast cancer compared with women not exposed to chest radiation (level A).^5,18-24 The relatively small number of women exposed to doses of 1 to 9 Gy prohibits a precise determination of risk (level B).^{15,18-22,25,26} Evidence suggests an increased risk in survivors of CAYA cancer treated with TBI versus no TBI,^5,16,20,27 but it is unclear if a prescribed TBI dose less than 10 Gy increases breast cancer risk. Evidence is lacking about the effects of single-dose TBI versus fractionated-dose TBI. New evidence, primarily from young children treated for Wilms tumor, also showed that radiation to a high abdominal field that extends above the diaphragm—an approximate anatomic location of the prepubertal nipple—was associated with an increased risk (level B).^5,20,23,24

The irradiated volume of the breast is also an important factor to consider as this may vary substantially at similar prescribed or calculated dose levels. Women treated with whole-lung irradiation receive lower doses of radiation but to a larger volume of breast tissue than women treated with a mantle or mediastinal field in which lungs are largely shielded. Moskowitz et al⁵ reported a standardized incidence ratio of 43.6 (95% CI, 27.1 to 70.1) for breast cancer in women who received whole-lung irradiation (median delivered dose of 14 Gy) compared with 24.2 (95% CI, 20.7 to 28.3) among women treated with a mantle field (median delivered dose of 40 Gy) and 13.0 (95% CI, 8.4 to 20.2) for those treated with a mediastinal field that excludes the axilla (median delivered dose of 30 Gy). In addition, other studies observed reduced breast cancer risks among women treated with a mediastinal field that limited the volume of irradiated breast tissue by omitting the axillary nodes in the field.^15,17,28 Of note, studies vary in the method of estimation of breast radiation exposure, with some using retrospective dose reconstruction that reflects the absorbed dose at the site of the breast tumor, whereas other studies used prescribed radiation dose to the breast area. As these are different concepts, radiation dose-specific risk estimates cannot be directly compared across studies using prescribed dose and studies using dose to the affected site of the breast.

Risk After Radiation to Ovaries and Alkylating Agents

There is evidence that radiation to volumes exposing the ovaries to doses greater than 5 Gy will predispose individuals, in a dose-response manner, to develop premature ovarian insufficiency (POI).²⁹ POI seems to reduce the carcinogenic effects of breast irradiation (level A),^{3,5,14,15,18,21,22,26,28,30-33} most likely by reducing exposure of radiation-damaged breast cells to the stimulating effect of ovarian hormones. Data are insufficient to define the potential risk-reducing effects of pelvic radiation in patients treated with low to moderate doses of chest radiation.

Alkylating agent chemotherapy may also affect ovarian function in survivors. Studies among survivors of cancer treated at older ages (21-49 years) with chest radiation and alkylating agents demonstrated a lower risk of breast cancer compared with those not exposed to alkylating agents (level A).^{15,17,26,28,30,32,34} However, low-level evidence indicates a significant protective effect in survivors treated with high doses of alkylating agents (≥ 14,000 mg/m²) and chest radiation at younger ages (< 21 years),^{2,4,5,14,21,22,35} especially for survivors diagnosed with breast cancer at age 40 years or older.¹⁴ The variability in risk by age at radiotherapy and alkylating agent exposure may relate to the larger follicle pool in younger girls. Young adults treated with alkylating agents with a smaller number of immature oocytes are more likely to develop POI earlier than younger patients.^36,37 Data are insufficient to define the potential breast cancer risk-reducing effects of alkylating agents in survivors treated with low- to moderate-dose chest radiation (< 20 Gy).

Risk After Early Menopause and Treatment of Early Menopause

More direct evidence from study groups that measured menopausal age/status reported a protective effect of early menopause on breast cancer risk in survivors of CAYA cancer treated with chest radiation (level A).^{14,15,28,32,38} In addition, survivors of CAYA cancer with a shorter duration of intact ovarian function after chest radiation have a decreased risk compared with females with a longer duration of intact ovarian function after chest radiation (level A).^{14,15,28,32,38} Some women with POI receive hormonal treatment, which may counterbalance the reduced risk of radiation-induced breast cancer associated with early menopause. To date, empirical evidence does not show a significant effect of such hormonal treatment on breast cancer risk in survivors of CAYA cancer (level B).^14,15,32

Risk After Chemotherapy Without Chest Radiation

Recent studies demonstrate that survivors of CAYA cancer treated with anthracyclines have a dose-related increased breast cancer risk (level A).^{16,18,21,39,40} Threshold doses for survivors who are at low, moderate, and high risk are difficult to determine with the current data. There is a suggestion that survivors of CAYA leukemia, non-Ewing sarcoma, and CNS tumor treated with high-dose anthracyclines but without chest radiation are at increased risk for breast cancer (level B).^16,18,39 These childhood cancer types may be associated with Li-Fraumeni(–like) syndromes. Despite a lack of individual data on genetic syndromes, findings in two independent cohort studies suggest that the effect may be related to a gene-anthracycline interaction.^18,41 Ehrhardt et al²¹ reported that high-dose anthracyclines (≥ 250 mg/m²) were associated with increased breast cancer risk in survivors who did not have pathogenic/likely pathogenic cancer-predisposing mutations and who did not receive chest radiation. In addition, there is a suggestion of an additive interaction between anthracyclines and chest radiation, as the risk associated with the combination of anthracyclines and chest radiation is higher than the sum of the individual risks.¹⁸

One study showed that survivors of CAYA cancer treated with higher doses of alkylating agents without chest radiation may also have an increased risk,³⁹ whereas four studies did not observe this effect (level C).^3,16,18,40

Breast Cancer Risk Over Time

The absolute excess risk of breast cancer strongly increases over time up to an attained age of 60 years (level A).^{5,17,21,30,35} Some evidence suggests that women with an attained age of 60 years and older still have an increased breast cancer risk (level C).^17,30 Data are not available to inform when surveillance should be stopped.

Potential Benefits of Breast Cancer Surveillance

There are no studies of survivors of CAYA cancer that investigated whether early detection by MRI or mammography results in better prognosis. Studies from the general population age 40 to 75 years have shown that mammography significantly reduces breast cancer mortality.^8,9 Modeling studies among women in the general population showed that, compared with no screening, mammography modestly increases quality-adjusted life years, although the magnitude varied by screening intervals and age at initiation and discontinuation of screening.^8,9

Recent prospective studies investigated the diagnostic value of breast cancer surveillance modalities in female survivors of CAYA cancer treated with chest radiation. Studies demonstrated moderate diagnostic accuracy of mammography (sensitivity, 54% to 73%; specificity, 93% to 99%) or breast MRI (sensitivity, 67% to 100%; specificity, 80% to 94%) for detecting breast cancer (number of breast cancers ranging from 10 to 33; levels A and B).^21,41-45 The diagnostic accuracy of the combination of breast MRI and mammography for detecting breast cancer is superior to either test alone (sensitivity, 86% to 100%; specificity, 89% to 99.7%; level B).^21,41,42

Despite limitations as a surveillance modality in women with dense breast tissue, mammography can detect breast cancer among young women with dense breast tissue, including survivors treated with chest radiation.^41-51 In addition, this modality is superior to MRI for detection of ductal carcinoma in situ (DCIS),^52,53 especially in survivors of CAYA cancer treated with chest radiation.^41,42 DCIS is common among survivors of CAYA cancer treated with chest radiation and is often multiquadrant.^41,42 In the general population, DCIS in younger women is associated with a substantially higher rate of recurrence and 10-year mortality compared with DCIS among older women.^54-56

In young premenopausal high-risk women, MRI is superior to mammography in detecting breast cancer in women with dense breast tissue, has a higher sensitivity in detecting invasive breast cancer than mammography, and identifies cancer at earlier stages.^{9,52,53,57-62} Although previous studies among women with hereditary breast cancer also demonstrated that the combination of MRI and mammography is superior to either test alone,^57,63,64 recent studies suggest that annual mammography may not be of additional benefit to (bi)annual MRI in women younger than age 40 years in this high-risk population.^65-67

It is unclear what percentage of women with dense breast tissue, affecting approximately 60% of survivors of CAYA cancer, will have largely fatty-replaced breast tissue in their postmenopausal years.¹ Therefore, this group of patients will most likely benefit from MRI surveillance.

Potential Harms of Breast Cancer Surveillance

False-positive findings are common in breast cancer surveillance, which may result in additional imaging and biopsy. The introduction of MRI to screening programs has increased the number of additional investigations for survivors of Hodgkin lymphoma.^41,42 However, the percentage of recalls decline substantially over subsequent screening rounds. Ng et al⁴¹ showed that the false-positive rate for MRI decreased from 13.4% after year one to 9.0% after year two and 2.0% after year three, whereas breast cancer rates remained stable (5%, 6%, and 4%, respectively). Nevertheless, these false-positive findings may lead to increased anxiety.^8,9,68 Moreover, sometimes mammography and MRI do not detect an occult cancer or cancer develops between screening rounds. Two studies showed that 0% to 6% of survivors of CAYA cancer who underwent mammography and breast MRI had a false-negative finding, leading to false reassurance.^41,42

Another potential harm is overdiagnosis of a breast cancer that would not have led to clinical symptoms. No published study directly provides reliable data about overdiagnosis in survivors of CAYA cancer or the general population. Estimates in the general population vary widely, from less than 5% to more than 50%.^8,9 In survivors of CAYA cancer, overdiagnosis is expected to be rare (< 1%) as a result of a low prevalence of indolent DCIS.

Breast cancer surveillance tests have disadvantages as well. Mammography may be painful for some women and involves low-dose, low-energy radiation exposure. The estimated mean breast dose with contemporary standard two-view mammograms is approximately 3.7 to 4.7 mGy.⁸ In a woman treated with chest radiation 20 Gy, 15 additional surveillance mammograms from age 25 to 39 years would increase the total radiation exposure from 20.0 Gy to 20.058 Gy or by approximately 0.3%. Thus, this small increase in radiation exposure administered at regular intervals many years after chest radiation would unlikely significantly increase breast cancer risk. Cost (to the patient) is a significant barrier in the United States or other countries without a single-payer system that covers breast MRI.⁶⁹ In addition, some women with claustrophobia, medical devices, or other metal hardware or MRI contrast allergy are unable to have an MRI.

Translating Evidence Into Recommendations

The Data Supplement presents the Evidence-to-Decision framework. Although it is still unclear if breast cancer surveillance among survivors of CAYA cancer results in better outcomes—that is, improved life expectancy, quality of life, decreased morbidity related to avoidance of new cancer treatment—studies among women age 40 to 75 years from the general population have shown that mammography significantly reduces breast cancer mortality.^8,9 Potential harms include the risk of false-positive findings leading to unnecessary emotional distress and costs of additional imaging and biopsies, risk of false-negative findings leading to false reassurance, risk of overdiagnosis, the burden of regular surveillance, and the risk of potential radiation exposure from mammography (Table 2). Consideration of the threshold at which benefits outweigh harms is important. An appropriate surveillance interval is difficult to define. Early detection of breast cancer is essential as diagnosis at an early stage increases the likelihood of a favorable outcome and survival.^51,70-74 For women with node-positive breast cancer, previous therapy for the CAYA cancer may limit options for anthracycline-based adjuvant therapy or additional radiation for subsequent breast cancer and may result in poorer outcomes.^1,73 The frequency of surveillance is a balance between missing early-stage breast cancer and the burden of regular surveillance. The biologic mechanisms of radiation-induced breast tissue apoptosis and carcinogenesis suggest that the cumulative incidence will continue to increase and that the excess risk will remain significantly elevated. The panel agreed that, on the basis of the current knowledge, there is no reason to stop annual surveillance after a certain age.

TABLE 2.

Potential Benefits and Harms of Breast Cancer Surveillance

The panel concluded that for patients treated with 10 Gy or greater chest radiation—with a relative risk of breast cancer that is four times or more than the risk in survivors who were not administered chest radiation—the benefits of initiating early annual mammography and MRI are expected to outweigh the harms. Therefore, annual breast cancer surveillance with both mammography and MRI is recommended for survivors of CAYA cancer treated with 10 Gy or more chest radiation with an attained age of 25 years or 8 years after radiation, whichever occurs last, for at least up to age 60 years (level A, strong recommendation). Although the combination of mammography and MRI is superior to either test alone in survivors of CAYA cancer, there may be circumstances in which only one surveillance test is performed. Therefore, informed decision making using the survivor information form is important (Table 3).

TABLE 3.

Survivor Information Form Summarizing Benefits and Harms of Breast Cancer Surveillance

Because the balance of benefits and harms is less clear for patients treated with upper abdominal radiation exposing breast tissue, annual surveillance is reasonable at age 25 years for survivors treated with upper abdominal radiation—that can extend above the diaphragm—at a young age (level B, moderate recommendation). The surveillance decision should be an individual one, taking into account additional risk factors—that is, patient age, family history, breast density, menopausal status, and other cancer treatment exposures, like ovarian-toxic therapy—and personal values regarding the benefits and harms of surveillance (Table 2). Shared decision making can be facilitated by the survivor information form (Table 3).

Because there is no evidence regarding the potential increased breast cancer risk in patients treated with a prescribed TBI dose less than 10 Gy, the balance is uncertain and thus we were not able to make a recommendation.

Available data regarding the impact of ovarian insufficiency on breast cancer risk reduction after chest radiation are insufficient to guide surveillance strategies. For example, TBI is ovarian toxic, as are the alkylating agents often received by individuals conditioned with TBI for hematopoietic cell transplantation. Therefore, a reduced risk of breast cancer might be expected among women treated with TBI because of their substantial risk of ovarian insufficiency. However, the resultant breast cancer risk after a prescribed TBI—or chest radiation—dose of 10 Gy or more remains well above that of women of the same age in the general population. Therefore, our surveillance recommendations do not vary according to the level of ovarian-toxic exposures in survivors treated with chest radiation.

Lastly, the guideline panel recognizes that females treated with high-dose anthracyclines in the absence of chest radiation are at increased risk of breast cancer. There is currently inconsistent evidence about the dose thresholds for survivors at low, moderate, and high risk. So far, increased breast cancer risk associated with anthracyclines has only been examined in survivors who have been treated at younger than age 21 years. In addition, data regarding absolute breast cancer risk, potential gene-anthracycline interaction, and risk of anthracyclines as a function of age at exposure are pivotal. Therefore, no recommendation can be formulated for routine breast cancer surveillance for survivors of CAYA cancer treated with anthracyclines without chest radiation. Because the evidence suggests that survivors treated with high-dose anthracyclines (≥ 250 mg/m²) have a moderately to highly increased breast cancer risk and that survivors of Li-Fraumeni syndrome–associated childhood cancer types—leukemia, CNS tumor, and non-Ewing sarcoma—also have a highly increased breast cancer risk, the decision to undertake breast cancer surveillance should be made by the survivor of CAYA cancer and the health care provider after careful consideration of the potential harms and benefits of breast cancer surveillance. The panel agreed that testing for genetic cancer predisposition syndromes, such as Li-Fraumeni syndrome, may be considered for survivors of leukemia, CNS tumor, and non-Ewing sarcoma who have been treated with high-dose anthracyclines to determine an additional genetic contribution to breast cancer risk.

DISCUSSION

The publication of new evidence prompted significant changes in the breast cancer surveillance recommendations for female survivors of CAYA cancer related to surveillance for survivors treated with 10 Gy or more chest radiation, upper abdominal radiation exposing breast tissue at a young age, and anthracyclines in the absence of chest radiation; the upper age limit for surveillance; and the surveillance modality. High-quality evidence supports our strong recommendation for annual breast cancer surveillance with mammography and breast MRI for survivors of CAYA cancer treated with prescribed chest radiation doses of 10 Gy or more. For patients treated with upper abdominal radiation exposing breast tissue at a young age, there is uncertainty regarding the benefits of surveillance and we therefore formulated a recommendation of moderate strength for surveillance. To facilitate counseling and informed decision making by survivors, we developed a survivor information form that summarizes the benefits and harms of surveillance (Table 3). Among survivors for whom the benefits of surveillance less clearly outweigh the harms, this form can also be used to facilitate shared decision making by providing survivors with the information they need to make the best individualized care decisions while allowing clinicians to feel confident in their care management.^75,76 In addition, the guideline panel identified gaps in knowledge and future directions for research (Table 4).

TABLE 4.

Gaps in Knowledge and Directions for Future Research

Since the publication of our original recommendations, several investigations have evaluated the effects of moderate-dose chest radiation (10 to 19 Gy) and the joint effects of radiation dose and radiation volume,⁵ the effects of anthracyclines and alkylating agents in patients treated without chest radiation,^16,21,23,39 and the effects of ovarian function on breast cancer risk among survivors of CAYA cancer.^14,15,38 In addition, the diagnostic accuracy of mammography and MRI for detecting breast cancer among survivors of Hodgkin lymphoma has also been investigated by several groups.^41-45 Whereas data from these studies have guided the present changes in breast cancer surveillance recommendations, no studies have assessed the cost effectiveness of breast cancer surveillance and its impact on mortality in this population.

Although this guideline focuses on female survivors of CAYA cancer, it should be noted that males treated with chest radiation also have an increased breast cancer risk.⁷⁷ However, surveillance is not recommended because the absolute excess risk across survivor populations is low.^16,35,77 Nevertheless, clinicians should assess for symptoms and signs related to breast cancer in male survivors treated with chest radiation.

Strengths of our process are the evidence-based approach, the transparency in deriving and rating the strength of recommendations, and the multidisciplinary working group involved in the harmonization process. The ongoing interactive relationship between those who appraise the evidence and those who formulate recommendations also increases the validity and trustworthiness of our guideline development process. This IGHG breast cancer surveillance guideline aims to improve health outcomes by facilitating consistent, long-term follow-up care for female survivors of CAYA cancer and to promote strategically planned future research that will inform future guideline updates.

AUTHOR CONTRIBUTIONS

Conception and design: Renée L. Mulder, Melissa M. Hudson, Smita Bhatia, Gill Levitt, Louis S. Constine, W. Hamish Wallace, Flora E. van Leeuwen, Leontien C.M. Kremer, Kevin C. Oeffinger

Administrative support: Kevin C. Oeffinger

Collection and assembly of data: Renée L. Mulder, Melissa M. Hudson, Gill Levitt, W. Hamish Wallace, Tara O. Henderson, Charlotte Demoor-Goldschmidt, Leontien C.M. Kremer

Data analysis and interpretation: Renée L. Mulder, Melissa M. Hudson, Wendy Landier, Gill Levitt, W. Hamish Wallace, Cécile M. Ronckers, Tara O. Henderson, Chaya S. Moskowitz, Danielle N. Friedman, Andrea K. Ng, Helen C. Jenkinson, Charlotte Demoor-Goldschmidt, Roderick Skinner, Leontien C.M. Kremer, Kevin C. Oeffinger

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Melissa M. Hudson

Consulting or Advisory Role: Oncology Research Information Exchange Network, Princess Máxima Center

Wendy Landier

Research Funding: Merck Sharp & Dohme (Inst)

Louis S. Constine

Honoraria: UpToDate, Springer, Lippincott

Travel, Accommodations, Expenses: Particle Therapy Cooperative Group of North America

Tara O. Henderson

Research Funding: Seattle Genetics

Other Relationship: Seattle Genetics

Uncompensated Relationships: National Academies of Medicine, Engineering, and Sciences Committee on Disability and Childhood Cancer

Open Payments Link: https://openpaymentsdata.cms.gov/physician/402343

Danielle N. Friedman

Consulting or Advisory Role: Fennec Pharma

No other potential conflicts of interest were reported.