PALB2-Positive Breast Cancer in a 40-Year-Old Man

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In July 2003, an asymptomatic 40-year-old man presented to his primary care physician for routine care and was found to have a palpable right axillary lymph node.

The Case

In July 2003, an asymptomatic 40-year-old man presented to his primary care physician for routine care and was found to have a palpable right axillary lymph node. The node was thought to be infectious, but it did not resolve with antibiotic treatment and continued to enlarge. Excisional biopsy showed metastatic adenocarcinoma of unknown primary, positive for CK7; and negative for estrogen receptor (ER) and progesterone receptor (PR), CD20, prostate-specific antigen, ribosome recycling factor, prostatic acid phosphatase, and gross cystic disease fluid protein 15 (GCFDP-15). Tumor markers were unhelpful in establishing a definitive primary source.

The patient was treated with 6 months of carboplatin/paclitaxel and followed with regular surveillance imaging until 2007, at which time he relocated for personal reasons. Imaging showed no evidence of persistent or recurrent disease. In mid-2013, he again noted right axillary lymph node enlargement, this time accompanied by a new palpable supraclavicular lymph node. Excisional biopsy of the latter showed metastatic adenocarcinoma; a subsequent positron emission tomography scan revealed no primary source.

He underwent a course of chemoradiation for unknown primary in 2013, but in 2014 he developed new left supraclavicular and mediastinal adenopathy, and a right pleural effusion. He received a third round of chemotherapy with carboplatin and paclitaxel. Repeat imaging showed further progression of disease, with metastasis to various lymph nodes, right breast, right pleura, both lungs, and spleen. At this time, he sought care at our academic medical center. Cytology of his pleural effusion was positive for GATA3 and GCFDP-15, findings suggestive of breast cancer. Follow-up mammography showed increased density of the right breast, consistent with a primary breast lesion. Biopsy was performed and a genomic profile of the tumor was ordered. A PALB2 truncating mutation was reported.

The patient was referred for genetic counseling and germline testing, which confirmed the presence of a constitutional PALB2 mutation in his blood. The extended family history obtained at that time was significant for a sister with ovarian cancer at age 57 and lung cancer in his father at age 80. It was noted that the patient’s family was quite large: he was 1 of 8 siblings, and he had 10 aunts and uncles on both his mother’s and his father’s side of the family. No other history of cancer was reported in any of these relatives.

1 Which of these statements is true?

A. The mean presenting age of male breast cancer is 40 to 50 years.

B. Male breast cancer typically presents at a less advanced stage than female breast cancer; however, it has higher 5-year mortality rates.

C. In the workup of axillary node adenocarcinoma, breast imaging is necessary.

D. Most cases of male breast cancer are ER/PR-negative.

2 Which of the following genes does germline testing most often find mutated in patients with breast cancer?






Approximately 70% of carcinomas of unknown primary are adenocarcinomas. The diagnostic approach to such cases typically includes CT scans of the chest/abdomen/pelvis; basic laboratory tests; and testing for biomarkers such as carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, human chorionic gonadotropin (hCG), and alpha-fetoprotein (AFP)-although biomarkers have not been found to be either diagnostic or prognostic in such cases.[1] With axillary node involvement, as in our patient, breast cancer should figure prominently in the differential diagnosis, and mammography should be requested. Answer C is thus correct for Question 1. If the results of mammography are negative, breast MRI should be considered, especially in women.

The mean age of presentation for male breast cancer is 60 to 70 years of age,[2] making Answer A to Question 1 incorrect-and underscoring that our patient’s presentation at age 40 was quite atypical. A painless unilateral breast mass is the most common initial presentation of male breast cancer, sometimes associated with nipple discharge or skin ulceration.[3,4] Male breast cancer typically presents at a more advanced stage than female breast cancer.[2,5] This later presentation is thought to be due to the rarity of male breast cancer and the resultant low index of suspicion among both providers and patients.[4,6] Although male breast cancer typically presents at a more advanced stage, the 5-year survival rates across stages do not differ between men and women.[7] Thus, on two counts, Answer B to Question 1 is incorrect. The overall mortality for male breast cancer is higher than that for female breast cancer, but this is thought to be due to comorbid conditions resulting from the later average age at presentation.

Between 65% and 90% of male breast cancers are both ER-positive and PR-positive, and 15% are human epidermal growth factor receptor 2 (HER2)-positive. Thus, Answer D to Question 1 is incorrect. Interestingly, our patient’s breast cancer was triple-negative. Management of male breast cancer is similar to the treatment for female breast cancer. Since the majority of male breast cancers are estrogen-positive, most cases respond to anti-estrogenic tamoxifen, with improved overall mortality.[4]

Mutations in BRCA2 genes are estimated to be responsible for approximately 10% of male breast cancer cases, and up to 75% of cases in high-risk families, with a relative risk of 80.[8,9] In the Icelandic population, the common BRCA2 999del5 founder mutation appears to account for up to 40% of male breast cancers.[10] Answer B is thus the correct answer to Question 2.

BRCA1 mutations occur much less commonly than BRCA2 mutations in male breast cancer patients: an estimated 1% to 2% of male breast cancer cases, and 10% to 15% of cases in high-risk families have detectable germline mutations in BRCA1-thus, Answer A to Question 2 is incorrect.

Defects in checkpoint kinase 2 (CHEK2), a cell-cycle checkpoint kinase important in DNA repair, appear to be associated with some increase in the risk of male breast cancer. Studies of men without BRCA mutations who have the common CHEK2 1100delC mutation appear to have about a 10-fold higher risk of breast cancer, and in some populations, this mutation has accounted for about 9% of male breast cancer.[9] However, CHEK2 mutations are still less common in male breast cancer than BRCA2 mutations; therefore, Answer C to Question 2 is incorrect.

PALB2 is a protein that works with the BRCA2 protein to perform important genome maintenance. Mutations in PALB2, the gene that encodes the PALB2 protein, have been associated with an increased risk for pancreatic cancer and breast cancer. Additionally, in biallelic carriers, PALB2 mutations result in Fanconi anemia. Germline heterozygous mutations in PALB2 appear to account for about 0.5% to 4% of familial breast cancers.[11] In female carriers of mutated PALB2, the risk of breast cancer is estimated to be 35% by age 70. This risk appears to be influenced by the family history, with female mutation carriers having up to a 58% risk if there are two or more first-degree relatives in whom breast cancer develops before age 50. PALB2 mutations have been reported in families with male breast cancer, but reliable estimates of the frequency are lacking; thus, Answer D to Question 2 cannot be correct. The relative risk of breast cancer in men with PALB2 mutations has been estimated to be about 8-fold higher. Interestingly, female breast cancers associated with PALB2 mutations are more likely to have triple-negative histology than are those not associated with PALB2 mutations. Our patient’s histology is consistent with this finding.

Current recommendations for management of PALB2 mutation carriers include increased cancer screening, including yearly breast MRI for women.[12] Evidence-based breast cancer screening recommendations for men are unavailable. Additional screening for pancreatic cancer can be considered in mutation carriers who have a first-degree relative with pancreatic cancer. Partner testing for PALB2 mutations should be considered as part of family planning for those with germline mutations, along with counseling regarding the risk of Fanconi anemia.

With the growing body of evidence implicating underlying genetic mutations in male breast cancer, independent of family history, we suggest that genetic testing be performed in all patients with male breast cancer. Such testing might include tests for BRCA1, BRCA2, and PALB2. Although more extensive “panel testing” has become increasingly common, it is imperative that genetic counseling regarding the pros and cons of this approach be made available.

Outcome of This Case

A right drainage catheter was inserted for the patient’s malignant pleural effusion, but because of persistent fluid reaccumulation, a thoracostomy with Eloesser flap was performed to create an open window for the pleural space to drain. He developed an incidentally-found venous thromboembolism in his right upper extremity. Ultimately, his disease progressed despite 3 cycles of eribulin and 2 cycles of doxorubicin, cyclophosphamide, and vinorelbine. In October 2015, treatment with capecitabine was initiated, but his cancer progressed and he ultimately succumbed to his disease.

Despite our patient’s having no family history of breast cancer, the PALB2 germline mutation we detected may place his family/children at risk for breast cancer. His family has been referred for further genetic counseling.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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12. Fisher CM, Klein CE, Kondapalli LA, et al. Management of young breast cancer patients with de novo genetic mutations. Oncology (Williston Park). 2014;28:895-6.