Two synchronous malignancies: nodular melanoma and renal cell carcinoma in a patient with an underlying germline BRCA2 mutation

Abstract

Modernised genetic testing among patients with cancer has led to an increasing wealth of knowledge regarding cancer biology and aetiology. Furthermore, some germline mutations have the potential to direct therapeutic approaches as well. While BRCA1/2 mutations are well-established risk factors for breast and ovarian cancers, their impact on other cancers is less understood. We describe a patient with a germline BRCA2 mutation who developed synchronous melanoma and renal cell carcinoma, but responded well to treatment and is now cancer free.

Background

Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are tumour suppressor genes that maintain genomic integrity.^{1 2} Mutations in BRCA1 and BRCA2 lead to defective double-stranded DNA repair, dysregulation of the cell cycle and chromosomal aberrations.^3–6 Germline mutations in BRCA1 and BRCA2 may result in hereditary breast and ovarian cancers and account for up to 10% of all breast and ovarian cancers. A recent prospective study demonstrated the lifetime risk of breast cancer to be around 65% to 79% and 61% to 77% in BRCA1 and BRCA2 carriers respectively, while the development of ovarian cancer was estimated to be 36% to 53% and 11% to 25% for BRAC1 and BRCA2 carriers, respectively.⁷ These values correlated with prior retrospective study estimates. Other malignancies, including pancreatic, prostate, and gastric cancer, are associated with both BRCA1 and BRCA2 mutations.^8–10 We present a case of a BRCA2 mutation carrier who developed synchronous cutaneous melanoma and renal cell carcinoma (RCC), yet had a complete response to sorafenib treatment.

Case presentation

A 54-year-old woman of Mexican descent presented to our clinic in February 2014 with an ulcerated mass on her right thumb. One year prior, the patient suffered an occupational trauma to her right thumb with loss of her nail matrix and poor wound healing. Six months later, she noted a dark hyperpigmented lesion on her nail bed, which enlarged to the size of a golf ball and prompted her to seek medical attention.

The patient’s medical history included diabetes mellitus. She denied any alcohol, tobacco or drug use. She reported no prior history of sunburns or skin cancer. Her family history was notable for multiple paternal relatives with cancer diagnoses (figure 1). Both sides of the patient’s family were of Mexican ancestry.

Figure 1.

Patient’s family pedigree at diagnosis. RCC, renal cell carcinoma.

On review of systems, she denied constitutional symptoms, cardiac, respiratory or abdominal complaints, enlarged lymph nodes, or other skin changes. Physical examination of the right thumb revealed a 4 cm black and red protuberant mass with discoloration of the entire nail bed and serosanguinous discharge. There were no enlarged lymph nodes or other skin lesions appreciated on physical examination.

Investigations

Biopsy of the thumb mass revealed an ulcerated, nodular melanoma. Positron emission tomography (PET)/CT showed focal hypermetabolic activity with maximum standardized uptake value (SUV) 2.4 in the right distal first phalanx corresponding to the primary melanoma, as well as a hypermetabolic left renal mass, measuring 4.5×3.6 cm in size, with maximum SUV 5.6 (figures 2A and 3). The patient underwent right thumb amputation and right axillary lymph node dissection, with pathology demonstrating a nodular melanoma, 4 cm in greatest dimension, Breslow thickness of 9 mm, with ulceration, lymphovascular invasion and perineural invasion, minimal tumour infiltrating lymphocytes, and 1 out of 23 lymph nodes involved, pathological stage IIIC, pT4bN1b, by American Joint Committee on Cancer seventh edition staging. Percutaneous biopsy of the renal mass showed RCC, clear cell type. Due to the concomitant diagnosis of advanced melanoma, no intervention was recommended for the RCC. In addition to the two synchronous malignancies, the pertinent family history of malignancy led to genetic testing. A next-generation sequencing panel of 25 hereditary cancer genes revealed a germline BRCA2 4436del5 pathogenic alteration (c.4208_4212del) and an alteration of unknown significance involving the ATM gene (c.4414T>G).

Figure 2.

(A) Initial FGD PET in March 2014 at diagnosis demonstrating lesions in the right thumb. (B) FGD PET in March 2015 demonstrating diffuse metastases. (C) FDG PET in September 2017 demonstrating resolution of diffuse metastases. FGD, fluorodeoxyglucose; PET, positron emission tomography.

Figure 3.

Positron emission tomography/CT in March 2014 showing left renal cell carcinoma.

BRCA2 c.4208_4212del is a frame-shift mutation, located in exon 11, which is predicted to result in the premature truncation of the BRCA2 protein at amino acid position 1404 (p.Thr1403Lysfs*2). Verbal communication with the commercial laboratory that performed this analysis confirmed this pathogenic alteration had been identified five times at their laboratory to date. Test requisition forms filled out by the ordering providers reported Latino/Caribbean ancestry for all individuals in whom this alteration has been identified to date.

ATM c.4414T>G (rs539676759) is a missense alteration of uncertain significance that results in the substitution of leucine for valine at amino acid 472 of the ATM protein (p.Leu1472Val). ClinVar contains eight entries for this alteration, all of which classify this of uncertain significance. Additionally, the commercial lab that performed the analysis in our patient now classifies this alteration as ‘favour polymorphism’. To date, it has been identified 190 times, and 27% of those were in individuals whose test requisition identified them as being of Latin American/Caribbean ancestry.

The patient underwent adjuvant external beam radiation, 48 Gy over 18 fractions, and started adjuvant interferon alfa-2b treatment. In November 2014, she presented with multiple painful, subcutaneous nodules along the right upper extremity. Biopsies of the nodules showed melanoma. BRAF gene testing revealed a somatic BRAF V600 mutation, and the patient started combined BRAF and MEK inhibition therapy using trametinib and dabrafenib. After 1 month of treatment, the right upper extremity nodules resolved with residual areas of hypopigmentation. However, a PET/CT in March 2015 showed progression with multiple liver, lung and lymph node metastases, as well as a larger renal mass with increased hypermetabolic activity (figures 2B, 4A, 5A, 6A and 7A). Given the synchronous BRAF mutated melanoma and RCC, she was switched to salvage therapy using sorafenib 400 mg two times per day.

Figure 4.

(A) FGD PET in March 2015 demonstrating right arm cutaneous lesions, liver lesions and vertebral lesions. (B) FGD PET in September 2017 demonstrating complete resolution of right arm cutaneous lesions, liver lesions and vertebral lesions. FGD, fluorodeoxyglucose; PET, positron emission tomography.

Figure 5.

(A) FGD PET in March 2015 demonstrating mediastinal and hilar lymph nodes, and pulmonary and left humerus lesions. (B) FGD PET in September 2017 demonstrating resolution of the mediastinal and hilar lymph nodes, and pulmonary and left humerus lesions. FGD,  fluorodeoxyglucose; PET, positron emission tomography.

Figure 6.

(A) FGD PET in March 2015 demonstrating metastatic right breast, pulmonary, liver, axillary, mediastinal and hilar lymph node lesions. (B) FGD PET in September 2017 demonstrating resolution of metastatic right breast, pulmonary, liver, axillary, mediastinal and hilar lymph node lesions. FGD, fluorodeoxyglucose; PET, positron emission tomography.

Figure 7.

(A) FGD PET in March 2015 demonstrating right and left femur lesions. (B) FGD PET in September 2017 demonstrating resolution of right and left femur lesions. FGD, fluorodeoxyglucose; PET, positron emission tomography.

Outcome and follow-up

Repeat imaging after 5 months of sorafenib revealed a dramatic decrease in the lung and lymph node metastases; over the next 24 months, the patient had near resolution of her lung and liver metastases. Conversely, her primary RCC enlarged; thus, a laparoscopic radical left nephrectomy was performed in March 2017. Surgical pathology confirmed a 6.7 cm RCC, clear cell type, Fuhrman grade 2/4, with involvement into the renal vein and segmental branches, but negative margins, pT3aNX, stage III disease. The surgical specimen contained tumour necrosis. She continued the sorafenib therapy. After 36 months, CT scan showed no evidence of disease (figures 2C, 4B, 5B, 6B and 7B).

Discussion

This case report describes a BRCA2 carrier with melanoma and RCC that responded exceptionally well to sorafenib. To our knowledge, this is the first reported case of a BRCA2 germline mutation carrier presenting with synchronous cutaneous melanoma and renal clear cell carcinoma. While the incidence of breast and ovarian cancers are higher among BRCA1 mutation carriers, the incidence of other malignancies may be higher among BRCA2 mutation carriers.⁸ The Breast Cancer Linkage Consortium examined the risk of developing secondary cancers in patients with BRCA2 mutations and found 2.5 times higher relative risk of melanoma among BRCA2 mutation carriers compared with non-carriers.¹¹ In contrast, a study of patients with BRCA1 germline mutations found increased rates of melanoma compared with the average population, but not compared with BRCA2 carriers.⁸ In Sweden, a germline nonsense variant in BRCA2 (rs11571833) had a possible link with melanoma.¹² ATM mutations have also been observed in melanoma patients. One study examining ATM mutations in the general population found ATM Ser49Cys heterozygosity to be associated with melanoma.¹³

Recurrent BRCA2 mutations have been identified in studies focused on Latino/Hispanic individuals, though the specific mutations that are recurrent have varied by study and country of origin.¹⁴ To our knowledge, the BRCA2 mutation identified in our patient has not been previously described in the scientific literature or databases; including ClinVar, The Human Gene Mutation Database, Breast Cancer Information Core and the International Cancer Genome Consortium. While all five individuals with this mutation do report Latin American/Caribbean ancestry, this term applies to a geographically and ethnically diverse population. Our patient is of Mexican ancestry, but the countries of origin of the others are unknown, and further studies, such as haplotype analysis, would be necessary to determine if there is shared ancestry or if there were independent mutational events.

Renal clear cell carcinoma is most commonly associated with von Hippel-Lindau (VHL) syndrome and aberrations of chromosome 3,¹⁵ yet cases of RCC in association with BRCA1 mutations are rare. ¹⁶ At least one study reported that the BRCA2 variant, rs11571833, may increase the risk of bladder cancer but had a non-significant association with RCC. Notably, the study analysed a population of European ancestry.¹⁷ Another study determined both BRCA2 and ATM variants had the lowest RCC risk in comparison with eight other genes involved in double-strand break repair.¹⁸ There are several reported cases of BRCA2 mutations RCC patients, but the significance and impact of these mutations are unknown.^{8 19} Notably, an ATM single-nucleotide polymorphism (rs611646) had increased risk of developing RCC.²⁰ Additional mutations of BAP1 (BRCA-associated protein 1), also located on chromosome 3, have been described in RCC,²¹ as well as cutaneous and uveal melanoma.^22–25

Concerning our case, it is unlikely that the patient’s ATM mutation played any role in the development of her melanoma or RCC. Contrarily, the effect of her BRCA2 mutation in the evolution of her multiple malignancies is unknown, and further investigations would need to be performed to determine its pathogenicity outside of breast and ovarian cancer risk.

Furthermore, renal clear cell carcinoma is mediated by loss of VHL tumour suppressor protein, leading to dysregulation of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor, which collectively regulates angiogenesis and lymphangiogenesis.¹⁵ Preclinical studies have demonstrated that sorafenib has significant anti-angiogenic activity in RCC leading to reduced tumor vasculature and increased tumor hypoxia. Phase III studies have confirmed the efficacy of sorafenib in RCC, for which it is FDA approved.²⁶ Response rates to first-line sorafenib in RCC are around 10-35%.²⁶ Complete response for metastatic RCC is rare and estimated to be around 1.6% for tyrosine kinase inhibitors.²⁷

Melanoma is characterised by constitutive signalling of the mitogen-activated protein kinase pathway, and approximately 50% of cases contain BRAF V600 mutations.²⁸ The multikinase inhibitor, sorafenib, targets resting rapidly accelerated fibrosarcoma (RAF), also VEGF, PDGF, FMS-like tyrosine kinase-3 (FLT-3), fibroblast growth factor receptor 1 (FGFR1), cKIT and RET.²⁹ In clinical trials using sorafenib monotherapy to treat patients with melanoma, response rates were low, irrespective of BRAF status.³⁰ ECOG 2603 found the addition of sorafenib to carboplatin and paclitaxel improved outcomes in patients with melanoma with copy number gains of CRAF, KRAS or CCND1, suggesting that biomarkers may be needed to identify patients who benefit from sorafenib.³¹ In contrast, type I RAF inhibitors (eg, dabrafenib), in combination with MEK inhibitors, led to response rates as high as 63%–68% in melanoma with BRAF V600 mutations.²⁸

Because we did not have biopsies of any visceral metastases in the context of two synchronous malignancies, we could not definitively determine which cancer responded to sorafenib. Initially, it was felt the visceral metastases originated from melanoma, given her staging at diagnosis; however, given a complete response to sorafenib, we favour the hypothesis that her metastatic disease was metastatic RCC. Furthermore, her burden of melanoma was likely limited to the right upper extremity, given her response to BRAF and MEK inhibition. A second theory would pose the patient’s metastases were melanoma but were also sensitive to inhibition of off-target effects by sorafenib, which may vary between melanoma subtypes. A less likely third hypothesis would be the patient had metastases from both malignancies.

When her BRCA2 mutation was identified, risk-reducing surgeries were not discussed as the patient had metastatic disease. She continued high-risk breast imaging per national guidelines. Currently, risk-reducing bilateral salpingo-oophorectomy, in the context of her recurrence risk and disease status, will be explored in the future should she remain disease free. National guidelines recommend an annual mammogram and breast MRI in BRCA2 mutation carriers, as well as risk-reducing bilateral salpingo-oophorectomy by ages 40–45.³²

Learning points.

• Hereditary cancer syndromes account for up to 10% of all cancers. In patients with significant personal or family history of malignancy, genetic testing should be considered to detect germline mutations and identify patients at increased risk of developing cancer.

• The molecular pathways of hereditary cancer syndromes impact not only the development of malignancy but may have clinical relevance in guiding personalized treatment approaches.

• BRCA1 and BRCA2 mutations result in defective DNA damage repair, which may cause hereditary breast and ovarian cancer syndromes, as well as other malignancies.

• A thorough discussion about risk-reducing surgeries should be carefully weighed in those with germline mutations and concurrent malignancies as these patients have a risk of recurrence of their primary cancer along with developing new malignancies.

• Future studies are warranted to investigate how patients with germline BRCA mutations may respond differently to standard treatment options, such as multi-kinase inhibitors and immunotherapy.