Background: Breast cancer (BC) is the most common non-skin cancer affecting women but is extremely uncommon in the adolescent population. Genetic inheritance has been linked to <10% of BCs. CHEK2 is an uncommon genetic variant with a reported incidence of 0.3–1.6% in the general population and 4.9–5.7% in those with a family history of BC. Commonly, this mutation presents in females of European descent and is rare in North America. Case Presentation: A 19-year-old Caucasian female presented with breast pain and mass. She had an extensive family history of cancer, as well as a known CHEK2 gene mutation in 2 of her paternal aunts. Ultrasound and MRI confirmed a 4.5-cm mass with an enlarged right axillary lymph node. Image guided biopsy of the breast mass showed ER/PR-positive grade 1 invasive mucinous ductal cancer. Genetic testing confirmed an isolated CHEK2 mutation. After discussion by a multidisciplinary tumor board, the patient deferred bilateral mastectomy and underwent a right mastectomy with sentinel-lymph-node biopsy and immediate tissue-expander reconstruction. Final pathology confirmed ER/PR-positive Stage 1A (pT2 pN0 M0) invasive mucinous carcinoma. Chemotherapy was not recommended. Summary: Malignant adolescent breast masses are relatively rare and CHEK2 does not typically present at younger than 20 years of age. While there are many different differential diagnoses when evaluating an adolescent with a breast mass, we wish to increase providers’ suspicion of malignancy, specifically in those individuals who have a strong family history of BC and the CHEK2*1100delC mutation.

  • Breast cancer (BC) is the second most common cancer affecting women, but it is extremely rare in the adolescent population.

  • CHEK2*1100delC is a genetic variant associated with BC, with a reported incidence of 0.3–1.6% in the general population and up to 5.7% in those with a family history of BC. Commonly, this mutation presents in females of northern European descent.

  • We present a case of an adolescent Caucasian female with the CHEK2*1100delC mutation and familial BC, who was diagnosed at a very young age.

  • Despite the low prevalence of CHEK2*1100delC in North America, this genetic mutation should be considered among those with northern European ancestry and familial BC.

Breast cancer (BC) is the most common cancer among women, excluding non-melanoma skin cancers. Approximately 5–10% of BCs are known to be hereditary, and <1% of cases present in the adolescent population [1]. Adolescent BC has a lower 10-year survival rate than that for older women; this is related to the higher grade and more biologically aggressive disease at diagnosis [2]. In addition to the BRCA1 and BRCA2 mutations, there are several moderate risk genes identified as being associated with BC. Checkpoint kinase 2 (CHEK2) is a protein involved in DNA damage repair and is encoded by the CHEK2 gene. The 1100delC variant of CHEK2 is associated with an increased risk of BC and is prevalent in 0.3–5.7% of people with northern European ancestry. The average age of diagnosis of BC is higher amongst patients with the CHEK2 mutation, 54 years (vs. 52 years without this mutation) [3]. Here, we present a case of an adolescent Caucasian female with the CHEK2*1100delC mutation and familial BC who was diagnosed at the age of 19 years.

A 19-year-old Caucasian female presented to her primary care physician with 2 days of pain in her right breast, followed by palpation of a breast mass. She denied any history of trauma to the breast or any skin changes or nipple discharge. She reported a history of inverted nipple on the right side. She had a history of anxiety and depression as well as amenorrhea for 18 months prior to presentation. She had an extensive family history of cancer including metastatic colon cancer in her paternal grandmother (who died at the age of 58 years), metastatic uterine leiomyosarcoma in a paternal aunt (diagnosed at the age of 40 years and who died in her 50s), and BC in 2 paternal aunts (diagnosed in their 40s and 60s). These last 2 aunts were found to carry the CHEK2*1100delC mutation (Fig. 1).

Fig. 1.

Patient’s pedigree.

Fig. 1.

Patient’s pedigree.

Close modal

On examination, she was found to have a subareolar, irregular, firm mass, without any palpable lymph nodes. An ultrasound of the right breast confirmed the presence of the mass and the absence of any lymphadenopathy. She underwent ultrasound-guided biopsy of the mass and pathology showed a grade 1 invasive ductal cancer with mucinous features as well as being ER-positive (91–100%), PR-positive (91–100%), and HER2/Neu-negative. A diagnostic MRI of the breasts showed a unifocal right-breast mass, and a 0.5 cm right axillary lymph node (Fig. 2). Biopsy of the enlarged lymph node was negative for malignancy.

Fig. 2.

Diagnostic MRI of the breast.

Fig. 2.

Diagnostic MRI of the breast.

Close modal

Considering the patient’s significant personal and family history, she underwent genetic testing. She was found to be positive for the CHEK2*1100delC gene mutation. The remainder of the 47-gene panel was negative for pathogenic mutations. PET/CT scan showed no definitive evidence of FDG-avid distant metastatic disease.

The case was discussed by a multidisciplinary tumor board. Due to the retroareolar location and size of the tumor relative to the breast, mastectomy was recommended. Based on the increased risk due to the CHEK2 mutation, she was offered prophylactic mastectomy of the contralateral breast. However, she elected to forgo this latter option as she wanted to have the option of breast-feeding in the future. She underwent a right skin-sparing mastectomy with sentinel-node biopsy (SLNB), and immediate reconstruction with a tissue expander. A frozen section of the SLNB was negative for metastasis. She tolerated the surgery well and was discharged home on postoperative day 2. Final pathology was consistent with Stage IA (pT2 pN0 M0) invasive mucinous carcinoma, ER/PR-positive (91–100%) and HER2-negative.

Genomic testing “oncotype DX” was obtained from the specimen and showed a recurrence score of 24, consistent with a distant recurrence risk (RR) of 10% at 9 years. Therefore, based on the Group average absolute chemotherapy benefit of <1%, chemotherapy was not recommended. Based on the data from the SOFT/TEXT trials, ovarian function suppression was recommended, with a preference for aromatase inhibitor [4].

CHEK2 and Genetics

Cell cycle checkpoint kinase 2 is a protein encoded by the CHEK2 gene located on chromosome 22q [5]. These proteins stabilize the p53 tumor suppressor protein in response to DNA damage, leading to cell cycle arrest and preventing entry into mitosis [6]. An association between CHEK2 and cancers was first suggested in reports of the presence of germline mutations of CHEK2 in families with Li-Fraumeni syndrome [7]. Different mutations of the CHEK2 gene have been reported, but c.1100delC and p.I157T are the 2 variants most studied and correlated with an increased risk of cancer. The link between CHEK2*1100delC and BC was first established by 2 independent studies in 2002 [5, 8]. These studies observed a higher frequency of the CHEK2*1100delC variant in familial BC patients without a BRCA mutation.

Incidence and Demographics of CHEK2

The frequency of the CHEK2*1100delC mutation varies among populations, with the highest reported frequency in northern and eastern European countries [5]. A multicenter study reported a frequency of 0.3–1.6% among controls in the UK and The Netherlands, and 4.9–5.7% in patients affected with BC who also had a family history of BC [5]. A similar finding was reported for the Finnish population [8] and in a Russian study [9]. In contrast, in Australia [10] and southern Europe, including Italy [11] and Spain [12], the frequency of CHEK2*1100delC was found to be very low.

A meta-analysis in 2012 reviewed results from 25 studies and >15 countries. This global study detected a CHEK2*1100delC frequency of 1.3% in BC patients and 0.44% in the controls. However, a critique of the study was the lack of differentiation between northern European heritage and other ethnicities [13].

North America has a long history of immigrants and multiple ethnicities, in addition to the high-risk European demographics already discussed. A Canadian study, looking at individuals with BC in different ethnic groups, reported that the allele was not seen in Asian patients and was present in only 0.64% of the cases from Brazil. Among White women, the allele was present in 1.5% of patients with familial BC and 0.7% of 1,106 patients with non-familial BC. They estimated that the CHEK2*1100delC is associated with an odds ratio of 2.6 for breast cancer, corresponding to a 24% lifetime risk [14].

In the USA, the frequency of this mutation in the control healthy population has also been estimated to be lower. Offit et al. [15] reported a frequency of 0.3% in healthy controls in New York City and 1.0% in individuals with a family or personal history of BC. In a study conducted by the University of Michigan, CHEK2*1100delC was not detected in any of the individuals from 90 hereditary BC and ovarian cancer families; the authors recommended against screening for CHEK2 in patients with familial BC/ovarian cancer without northern Europe origin [16].

CHEK2 and Family History Risk Factors

Our patient reported having Irish and British ancestry. Additionally, she had a strong paternal family history of BC and uterine cancer. Previous studies have shown that the lifetime risk of BC in carriers of CHEK2 mutations is strictly correlated with a positive family history. In a Polish study, this risk was estimated to be as high as 20% for women with no family history of BC, 28% for women with 1 second-degree relative affected, 34% for those with 1 first-degree relative, and 44% for women with both first- and second-degree relatives [17].

BC in the Adolescent

The patient presented in this case report was diagnosed at a very young age as having BC. According to the WHO, adolescents are defined as those aged between 10 and 19 years. Less than 1% of BC patients are younger than 30 years and the incidence of BC in females younger than 20 years is 1 in 1,000,000 [1]. BC in adolescents and young adults is associated with worse survival; the tumors are usually larger at diagnosis, are less hormone-sensitive, have a higher grade, spread more frequently to lymph nodes, and have more involved nodes than those in older women [2]. Women with BC who are under 40 years of age are also more likely to have a triple-negative tumor, which is associated with a worse prognosis. Young women with BC have a higher incidence of genetic mutations [2].

Although BC in adolescents is usually diagnosed at a later stage, our patient presented in an early stage (pT2 pN0 M0). This might be attributable to her self-awareness due to the known family history of CHEK2 mutation. Despite women under the age of 40 years having a higher risk of more lymph node spread and a higher positive lymph node count, CHEK2 appears to trend towards less lymph node metastasis for the mutation carrier patients [3], which could be another factor towards a positive prognosis for our patient.

Our patient is one of the youngest patients reported with CHEK2*1100delC and the youngest reported with an isolated mutation of CHEK2 only. Jóźwik et al. [18] reported a fatal case of BC in an 18-year-old Polish female with CHEK2*1100delC along with 3 other genetic mutations. Huszno et al. [3] demonstrated a dichotomous distribution, with CHEK2*1100delC patients being more often from the extremes of age, i.e., >65 or <35 years.

Pathology

Our patient’s pathology was consistent with an ER/PR-positive tumor. This is similar to reports of de Bock et al. [19] who showed that the CHEK2*1100delC mutation was more prevalent in patients with a positive ER status (4.2 vs. 1.0% with a negative ER status).

Treatment

Based on the recommendations from our multidisciplinary tumor board, our patient underwent tumor resection. She elected unilateral skin-sparing mastectomy. Few previous studies have shown up to 6-fold increase in the risk of bilateral BC amongst carriers of the CHEK2 mutation [8, 19]. In a study of a Dutch cohort, the 10-year incidence of contralateral BC was 29%. However, only a small subset of their study population had received hormonal therapy [20]. Our patient is scheduled to be followed very closely, especially with regard to screening of the contralateral breast, including a biannual physical exam and annual MRI. Previous studies have also shown an unfavorable prognosis regarding the occurrence of distant metastasis-free survival (RR 2.81) and disease-free survival (RR 3.86) [19].

Screening Considerations

According to NCCN guidelines, standard BC screening with MRI and clinical breast exam is at the age of 40 years or 10 years before the age of a relative at diagnosis. A very young age at diagnosis changes the NCCN recommended screening for the entire family. Our case was due to have her screening in her 30s, i.e., more than a decade after her diagnosis. Screening in adolescents is not generally recommended unless the patient has a history of chest radiation.

Other cancer risks reported with CHEK2*1100delC include a moderate risk to develop colon cancer (1.5-fold increase) for which colonoscopy screening is recommended to begin at the age of 40 years and be repeated every 5 years [17]. Other cancers have also been reported with CHEK2*1100delC, such as prostate, thyroid, gastric, and uterine cancers [21].

Malignant adolescent breast masses are relatively rare and CHEK2 does not typically present at younger than 20 years of age. While there are many different differential diagnoses when evaluating an adolescent with a breast mass, we wish to increase the providers’ suspicion of malignancy, specifically in individuals who have a strong family history of BC and the CHEK2*1100delC mutation.

Ethics approval was obtained from the Sparrow Hospital Ethics Committee. Informed consent was obtained from the patient for accessing the medical records, publication of the case report, and any accompanying images.

The authors have no conflicts of interest to declare.

No funding was received for this case report.

T.S.: data acquisition, and conception and drafting of the work. A.J.E.: data acquisition and drafting of the work. C.B.: Analysis and interpretation of data for the work (especially the genetic data) and revising the work critically for important intellectual content. M.A.T.: conception of the work and revising it critically for important intellectual content. T.F.: data acquisition, and conception of the work and revising it critically for important intellectual content. All authors gave their final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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