Breast cancer is a rare malignancy below the age of 20 years and is rarely seen by pediatric oncologists. However, in women aged 25 to 39 years, breast cancer is the most frequently diagnosed
malignancy, accounting for 14% of cancer cases in the AYA population. In the United States, approximately 6.6% of breast cancer cases are diagnosed in women younger than 40 years. Breast cancer in AYA women is believed to represent a more aggressive disease that is biologically different from that more commonly seen in postmenopausal women.²⁷ The more aggressive phenotypes seen, coupled with larger mass size, the higher grade of the disease, and lymph node involvement has resulted in poorer outcomes for young women diagnosed with breast cancer; in a large retrospective study of more than 200,000 patients in the SEER database, women under 40 years with breast cancer were 39% more likely to die compared with older women.²⁸

The intrinsic molecular classification of breast cancer by gene expression profiling has allowed us to start subdividing breast cancer into distinct subtypes.²⁹ Four subgroups have shown correlation with the clinical features that previously were defined by histologic grade and on the basis of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status as well as the proliferation marker Ki-67.³⁰ The basal-like breast cancers mostly correspond to ER-negative, progesterone receptor (PR)-negative, and HER2-negative tumors and are also called triple-negative tumors. Triple-negative breast cancer is more commonly found in young adults and in African American women, and it is has been historically correlated with worse outcomes than the other subtypes.³¹ The majority of triple-negative breast cancer cases share clinical and pathological features with hereditary breast cancer 1 (BRCA1)-related breast cancers. The luminal-A cancers are ER-positive and histologically appear as low-grade tumors. The luminal-B cancers are mostly ER-positive, although they can express low levels of either ER- or PR-hormone receptors and are classified as high-grade tumors. The fourth subtype includes HER2-positives, classified as such due to amplification and high expression of the ERBB2 gene and several other genes of the ERBB2 amplicon. With recent U.S. Food and Drug Administration (FDA) approval of pertuzumab, which targets HER2 mutations, outcomes for these patients have significantly improved.^32,33,34 However, outcomes for the remaining subtypes have not yet benefited from the evaluation of the genomic landscape, and identification of new agents has not altered the course for patients.

Age-specific differences in the biology of AYA breast cancer have been explored in large-scale genomic studies, with mixed results. Understanding the challenges of AYA breast cancer requires an appreciation of numerous complex issues, which highlight treatment challenges and long-term physical and psychosocial effects. Germline mutations in genes known to predispose women to breast cancer (i.e., BRCA1/2) play a role in a relative minority of patients, yet lend additional challenges to the treatment approach of this disease.³⁵

Although the pediatric oncologist is rarely involved in the delivery of care to breast cancer patients, they serve as an important patient resource regarding screening and early detection of disease when it is most treatable. Breast cancer in the AYA patient can be divided into three common types of presentations. First, patients with no family history or known risk factors may develop de novo breast cancer. Next, adult survivors of pediatric cancer who received alkylating agents or radiation therapy are at increased risk of developing treatment-related malignancies such as breast cancer. Female patients with a prior diagnosis of Hodgkin lymphoma who received whole-lung irradiation have a markedly increased risk of developing breast cancer.³⁶ The third group includes patients with a familial predisposition to breast cancer, including those who harbor the well-described mutations BRCA1 and BRCA2. Up to 15% of patients with breast cancer have a first-degree female relative who also have breast cancer.³⁷ A substantial minority of cases, however, are caused by non-BRCA mutations, such as those in TP53, PTEN, STK11, CHEK2, ATM, BRIP1, and PALB2.³⁸

The two best-studied cohorts of patients with preexisting genetic risk are those with BRCA and Li-Fraumeni predisposition syndrome. The molecular diagnosis of hereditary breast and/or ovarian cancer (HBOC) is mostly based on the genetic testing for the germline inactivating mutations within BRCA1 and BRCA2. In BRCA1 and BRCA2 mutation carriers, the cumulative risk of breast cancer at 70 years has been estimated at 65% and 45%, respectively.^39,40,41 Li-Fraumeni syndrome, a rare inherited autosomal dominant cancer predisposition syndrome, predisposes carriers to a high lifetime cumulative cancer risk estimated at 73% in males and 93% in females.^42,43 Premenopausal breast cancer is one of the types of cancers observed in affected individuals.

In recent years, pediatric and adult cancer programs have been developing high-risk predisposition cancer genetic programs utilizing a multidisciplinary approach with, minimally, a medical geneticist, genetic counselor, breast surgeon, and breast oncologist. It is recommended that risk-reducing mastectomies be discussed with patients based on a case-by-case basis. Counseling regarding the degree of protection and cancer risk, as well as options for breast reconstruction is best facilitated by an appropriate expert team such as that described earlier.⁴³ The Toronto Surveillance Protocol, developed by David Malkin at The Hospital for Sick Children, is an example of a cancer surveillance protocol that has successfully decreased the incidence of cancers in patients with Li-Fraumeni syndrome.⁴⁴ Close monitoring of affected individuals permitted detection of malignancy prior to onset of symptoms and, in some cases, eliminated the need for aggressive cancer therapy. Villani et al.⁴⁴ reported that 100% survival was obtainable in the surveillance group compared with 21% in the nonsurveillance group. The Toronto Surveillance Protocol is now being implemented in cancer programs in the United States and throughout the world.

Pediatric oncology teams are uniquely positioned to educate patients and survivors of childhood cancer about breast self-examinations. Starting at 18 years of age, all patients, regardless of risk, should be trained to properly perform these examinations and be educated about the importance of regular, monthly self-examinations. Per the National Comprehensive Cancer Network (NCCN) guidelines, patients at high risk for development of breast cancer, such as those described earlier, should have clinical breast examinations semiannually, starting at ages 20 to 25 years or 5 to 10 years before the earliest known breast cancer in the family (whichever comes first), coupled with an annual mammography and/or breast magnetic resonance imaging.⁴⁵

Cancers of the cervix uteri, the oropharynx, and the colon/rectum are rare in AYA patients. However, with over 95% of cervical cancer cases, 72% of oropharyngeal cancer cases, and 5% to 11% of colorectal cancer cases attributed to infection with human papillomavirus (HPV), these largely preventable diseases should be of concern for pediatric oncologists treating AYA cancer patients and survivors of pediatric cancer as interventions (e.g., vaccination, screening procedures, safe sexual practice education) for the patients and survivors can preclude secondary cancer development.^46,47,48

Over 100 variants of HPV have been identified of which at least 13, including HPV 16 and HPV 18, are cancer-causing.⁴⁹ Results from sampling performed as part of the 2011 U.S. National Health and Nutrition Examination Survey (NHANES) and the HPV in Men (HIM) study of men residing in Brazil, Mexico, and the United States demonstrated an infection rate with high-risk HPV (variants identified as cancer-causing) in 29% of young women and 12% of young men surveyed, although the overall rates for
HPV infection were higher.^50,51 In the early 1980s, when zur Hausen and colleagues were starting to document the presence of HPV in biopsy specimens of genital cancers as well as in cervical cancer cell lines, it was not yet understood how the viral infection induced the formation of malignancies.⁵² Over the last 30 years we now appreciate that infection with specific variants of HPV are necessary, but not sufficient, for the development of cervical, oropharngeal, and other carcinomas.^49,53

Given the strong link between high-risk HPV infection (e.g., HPV 16 and HPV 18) and the development of some cancers, including those addressed earlier, we must consider the role of HPV vaccination. In 1987 the World Health Organization (WHO) called upon the scientific and medical communities to develop and test the efficacy of vaccines to prevent or control HPV infections.⁵⁴ In 2006, the FDA-approved Gardasil^TM (Merck & Co.), which is effective against HPV types 6, 11, 16, and 18; and 3 years later, it approved Cervarix^TM (GlaxoSmithKline), which is effective against HPV types 16 and 18.^55,56 In the United States, HPV vaccine administration with either Gardasil^TM or Cervarix^TM is recommended for girls aged 11 to 12 years, and Gardasil^TM may be used in males aged 9 to 26 years, although administration prior to onset of sexual activity is recommended.⁵⁷ At this time, the U.S. CDC recommends vaccination of both boys and girls starting at age 11 or 12 years (http://www.cdc.gov/features/hpvvaccineboys/). In 2009 the Advisory Committee on Immunization Practices (ACIP) issued “permissive” guidelines for the vaccination of males 9 to 26 years of age; the permissive classification means that medical providers are not expected to proactively provide the vaccine as standard of care.⁵⁸ Both the Children’s Oncology Group (COG) long-term follow-up guidelines and the National Comprehensive Cancer Network guidelines for AYA cancer recommend HPV vaccination. However, neither organization provides guidance regarding vaccination “catch up,” nor do they provide clear direction regarding vaccination of adolescent males.^59,60

Finally, vaccination does not preclude the need for annual physical examination or adhering to the recommended cervical cancer screening recommendations. In particular, the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), the American Society for Clinical Pathology (ASCP), U.S. Preventive Services Task Force (USPSTF), and the American College of Obstetricians and Gynecologists (ACOG) all recommend currently (for women at average risk) that cervical cancer screening start at 21 years of age regardless of age of sexual initiation or practice of other risk factors (http://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf). The frequency of cytology-based (conventional or liquid) screening for women aged 21 to 29 years is now recommended every 3 years. An important point of education for adolescent female patients is that a pelvic examination does not equate to a cytology test and that women who may not need a cytology test still need regular health care visits, including gynecologic care.⁶¹ The ACOG currently recommends that the first visit with a gynecologist is to occur between the ages of 13 to 15 years with external examination of genitalia, and an internal pelvic examination, unless warranted, is not performed until 21 years of age.⁶² It can be expected that cervical cancer screening practices, including use of the Pap cytology methodologies, will continue to evolve in light of the current recommendations related to HPV vaccination.⁶³

Pediatric oncologists need to consider that their adolescent and emerging adult patients are likely sexually active, to some degree. Although the proportion of adolescents engaging in sexual intercourse has reportedly declined over the last 15 years, the average age of onset remains young—17.8 years for women and 18.1 years for men.⁶⁴ Perhaps of greater importance, over half of adolescents and young adults aged 15 to 24 years are engaging in other sexual behaviors, including oral sex, which they may not perceive to constitute “sex,” before taking the next step of sexual intercourse.^65,66 It is thus incumbent on the physician providing care to adolescent patients to discuss sexual activity, including the risks of disease transmission and measures that may be taken to reduce those risks.^66,67 To comprehensively address adolescent sexual health education, the medical team should do the following:

Cutaneous malignant melanoma (CMM) is an uncommon disease in pediatric oncology; however, the number of cases starts increasing in the AYA population, particularly among non-Hispanic whites and females.^69,70,71,72 Ward et al.’s analysis of the 15- to 19-year-old age group demonstrated that melanoma accounts for 6% of all cases diagnosed just behind bone tumors and acute lymphoblastic leukemia (ALL), and in the age group beyond 19 years of age, the disease moves into the list of top five cancer types in the young adult age group up to age 39 years.^3,18 Analyses of the AYA populations in the United States, Australia, Brazil, Canada, and England have demonstrated consistency of CMM prevalence in the younger than the typical (60 plus years of age) patient with cancer.^{72,73,74,75,76} Not surprisingly, the distribution of cases around the world is not consistent, and as expected, regions closer to the equator, which have a higher ultraviolet (UV) index, also have higher rates of melanoma.^71,77 For example, in Australia, where UV exposure is one of the highest in the world and on the rise, melanoma is the most commonly diagnosed cancer in AYA patients and accounts for 20% of all cancer cases in persons 15 to 39 years of age.^78,79

The etiology of melanoma is complex with a combination of underlying genetic, host, and environmental factors all playing a role. It has been estimated that approximately 10% of cases of melanoma are hereditary, and at least three genes have been shown to be associated— CDKN2A, CDK4, and p16.^80,81,82 The CDK4 gene mutation is responsible for 2% of all cases, with CDKN2A accounting for another 20% to 60%.⁸³ The role of p16 in hereditary melanoma has also been controversially established, although it appears to be significant only in the case of some families.⁸⁴ Most recently, POT1 has been implicated in the development of familial melanoma.^85,86 The story of the hereditary causes of melanoma is still unfolding, especially in this era of genomics and next-generation sequencing; much is still to be learned about how heredity plays a role in the melanocytes’ propensity to become malignant when they are exposed to UV light.^77,87,88 When observed in younger patients, melanoma often presents as one of three types: conventional melanoma, large/giant congenital melanocytic nevus (most often occurs in the first decade of life), and spitzoid melanocytic tumors.⁸⁹ At the molecular level, the conventional melanoma observed in younger patients resembles that seen in older adults, with tumors reflecting a high number of somatic single nucleotide variations consistent with UV-induced DNA damage, an activating BRAF V600 mutation, and an alteration in PTEN.⁹⁰

On the basis of data from the SEER program, Goggins and Tsao⁹² demonstrated that survivors of CM have a rate of a second primary diagnosis of CM >10 times the rate of a first primary diagnosis of CM in the general population; this risk remains elevated up to 20 years after the first diagnosis. Survivors of CM are at greatest risk of a second primary diagnosis of CM within 2 years of their first diagnosis and should be followed up closely by a high-risk melanoma team which includes dermatologists, oncologists, and surgical oncologists.⁹² In addition to survivors of CM, medical practitioners should be aware that survivors of childhood cancer are also at increased risk of developing melanoma compared with the general population. Pappo et al.⁹³ have reported that although low, childhood cancer survivors have a nearly threefold increased risk of melanoma. Of risk factors assessed—biologic sex, first-degree relative with cancer, treatment era, alkylating score, race, and radiation therapy—only the presence of a first-degree relative with cancer approached statistical significance.⁹³ Time from initial cancer diagnosis as a child to the development of melanoma averaged 18.9 years (range 5.6 to 35.2 years) in a study performed by Friedman and colleagues.⁹⁴

Compared with other diseases, the long-term consequences and survivorship of melanoma remain understudied, particularly in the AYA patient population.⁹⁵ Although reflective of an older patient population (average age of 62 years), the report of Swetter and colleagues⁹⁶ on long-term sequelae of melanoma and its treatment in a single institution demonstrated that survivors experience anxiety, numbness of scar site, forgetfulness, sleep problems and depression, and pain and fatigue. Further, consequences of treatment using new modalities such as targeted therapy or immunotherapy are starting to emerge as we gain more long-term experience with these agents. Of note, with emerging use of selective BRAF inhibitors to treat CMM, we have started to see side effects, including proliferative skin toxicities (ranging from hyperkeratosis and keratoacanthomas to squamous cell sarcomas, and new primary melanomas), emergence of gastric/colonic polyps, and RAS mutant malignancies.⁹⁷

Compared with other cancers seen in AYA patients, melanoma is largely preventable, with most cases caused by exposure to UV radiation.⁶⁹ Although there are well-defined beneficial effects of UV rays, there must be a balance where one receives enough UV exposure to create vitamin D and avoids the harmful effects to the skin as a result of excessive exposure. Establishment of that balance has long been a subject of both cultural and medical debate. Unfortunately, the concept of the “healthy tan,” first articulated in The Lancet in 1910 and exemplified by notable individuals such as Coco Channel in 1923, has created a public endorsement of sun exposure that has sustained over the last century.^98,99 Despite efforts of medical and public health professionals to counteract pervasive social norms, more than 10% of high school students reported, via the National Health Interview Survey (NHIS), use of an indoor tanning device in 2010.⁶⁹ When looking at an international data set, Wehner et al.¹⁰⁰ found exposures to indoor tanning were highest among university students, with 55% reporting use. Efforts to limit access to artificial UV sources through local, state, and federal regulations in the United States and around the world are still in their nascent stage, and as such, efficacy of these efforts has not yet been determined.⁶⁹

In July 2014, the U.S. Surgeon General issued a Call to Action to Prevent Skin Cancer. The stated goal was to increase awareness of skin cancers and a call to reduce the risk by creating awareness programs.¹⁰¹ Importantly, although an individual’s phototype is a contributor to the etiology of melanoma, outreach efforts must extend beyond those directed at persons with Fitzpatrick skin phototype I or II (those who have an inability to tan and are at increased risk of severe sunburn), as darker-skinned persons are more likely to have the acral lentiginous melanoma subtype that typically has worse outcomes.^102,103 Messages to patients to maximize protection must include the following sun-safe habits to be practiced between 10 AM and 4 PM: (1) wear sunscreen; (2) wear a hat; (3) wear sunglasses; (4) wear protective clothing; and (5) seek shade (http://johnwayne.org/skin-cancer-education/) whenever possible. In addition to prevention messaging, outreach efforts should also address the importance of early detection. Of particular interest is Euromelanoma—a concerted public health campaign facilitated by dermatologists, governmental agencies, professional societies, and pharmaceutical companies to screen people across the whole of Europe.^104,105

Early detection—when lesions are small, thin, and localized— is key in improving overall survival rates of CM.¹⁰⁶ To maximize the likelihood of identifying melanoma at an early stage, patients must not only perform self-screening but also have physician-initiated skin examinations.^91,107 Physicians, including pediatric oncologists, are uniquely positioned to identify high-risk patients, to educate patients and survivors about the proper performance of self-screening examinations, and to facilitate recommendations of mass marketing efforts. Screening, whether self- or physician-initiated, efforts must consider that melanoma lesions in AYAs do not always fit the norm. Without doubt, lesions meeting the ABCDEs of melanoma—Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, and Evolving—need to be addressed.¹⁰⁸ However, one must remember that Spitz nevi do not follow the criteria defined for typical CM and clinically present as benign, small, and asymptomatic lesions that are dome-shaped and usually pink or tan.¹⁰⁹