| Abstract|| |
A 60-year-old Chinese male with a hard mass, pressure pain, and ulcerous skin under his left axilla was first diagnosed with apocrine carcinoma, most likely metastasis from breast cancer. PET/CT scan detected multiple bone metastasis and enlarged lymph nodes at left axilla, mediastinal area 7, and left pulmonary hilus. Lumpectomy was performed to remove the mass followed by chemotherapy and radiotherapy against focal bone metastasis, left axillary lesion, and left subcutaneous chest wall. PET/CT examination showed progressive disease after the completion of the treatments. Two nontender hard nodules were noticed on the patient's left upper arm and multiple immobile nodules were palpated under his left axillary skin. Immunohistochemistry (HER2++, ER+, PR+, AR-) of the biopsy tissue combined with histopathology indicated invasive ductal carcinoma with neuroendocrine differentiation. Metastatic Luminal B subtype breast cancer was preferred. Anti-estrogen endocrine therapy was then performed and PET/CT scan showed partial remission after one month's fulvestrant administration. Two significant somatic mutations, AR R616H and GATA3 S408Afs*99, were detected in the biopsy tissue by next-generation sequencing. GATA3 is associated with estrogen receptor signaling and was identified as a driver gene of female breast cancer. However, the function of GATA3 in male breast cancer remains controversial. Report of this case hopefully will contribute to exploring the role of GATA3 mutation in molecular mechanisms and endocrine therapy of male breast cancer.
Keywords: Estrogen receptor (ER) signaling, ER antagonist, fulvestrant, next-generation sequencing
|How to cite this article:|
Xia Y, Liu X, Li W, Zhu Y. Potential role of significant GATA3 mutation in male breast cancer responding to endocrine therapy: A case report. Indian J Pathol Microbiol 2021;64:161-4
|How to cite this URL:|
Xia Y, Liu X, Li W, Zhu Y. Potential role of significant GATA3 mutation in male breast cancer responding to endocrine therapy: A case report. Indian J Pathol Microbiol [serial online] 2021 [cited 2022 Aug 14];64:161-4. Available from: https://www.ijpmonline.org/text.asp?2021/64/1/161/306496
| Introduction|| |
Male breast cancer is a rare malignancy with a morbidity rate of less than 1/100,000 per year, which accounts for less than 1% of all breast cancers, and less than 1% of all male cancers as well. The morbidity rate of male breast cancer increases by age. The average age at diagnosis for male breast cancer is about 5 - 10 years older than that for female breast cancer. The most common pathological subtype of male breast cancer is invasive ductal carcinoma, which accounts for about 84.6% of all male breast cancer. Although breast cancer presents similarities in both genders, it was reported that there were significant differences in onset ages, hormone levels, prognosis, and genomic and transcriptional profiles between the two genders. However, the standard diagnosis and treatment protocols for male breast cancer are extrapolated from female breast cancer due to the rarity of male breast cancer and lack of large-scale clinical study.
Therapies for breast cancer include surgery, chemotherapy, radiotherapy, targeted therapy, endocrine therapy, and immune-supportive therapy. Estrogen-activated pathways have been the primary targets of endocrine therapy. Testing for mutations in oncogenes and cancer suppressor genes, such as BRCA1 and BRCA2, has evolved into an integral part of cancer care, which enables doctors to personalize therapy decisions for each patient by targeting driver mutations. In this report, we present a Chinese male breast cancer patient with multiple bone metastasis at diagnosis who harbors somatic mutations in transcriptional activator GATA3, an estrogen receptor pathway-associated gene identified as one of the driver genes of female breast cancer, and in androgen receptor (AR) as revealed by targeted next-generation sequencing. After failure of the first-line chemoradiotherapy, the patient responded to anti-estrogen endocrine therapy and partial remission was achieved.
| Case Report|| |
A 60-year-old Chinese male of Li nationality in good condition unintentionally noticed a mobile nontender nodule with a diameter of about 5 mm under his left axillary skin in 2011 but didn't seek diagnosis or treatment. He was a non-smoker and occasional drinker; he had had high blood pressure and taken Valsartan for the treatment of hypertension for 4 years; he had a medical history of allergic rhinitis and denied receiving any hormone therapy. He denied any family medical history of infectious diseases, hereditary diseases, and malignancies except that all his siblings had allergic rhinitis and his younger sister had been diagnosed with lung cancer.
The patient came to seek diagnosis and treatment in May, 2014 after the nodule has grown to a hard mass of about 20 mm in diameter. There was pressure pain, ulcerous skin and no purulent discharge under his left axilla. Lumpectomy was subsequently performed to remove the mass. Immunohistochemical staining of the lesion tissue showed Syn+, CgA+, CK5/6-, CD56+, SMA-, Des-, P63-, HMB45-, S-100-, and CD34-, which likely suggested neuroendocrine carcinoma. Pathology consultation with Cancer Institute and Hospital, Chinese Academy of Medical Sciences suggested possibly cutaneous Merkel cell carcinoma. Further immunohistochemical staining showed AE1/AE3+++, EMA+++, GCDFP-15++, NSE+++, Chromogranin A+, Synaptophysin+-, CK20--, TTF-1-, CD117-, CD99-, S-100-, Syn+, CgA+, CK5/6 -, CD56-, HMB45-, and Desmin-, which suggested apocrine carcinoma, highly possible breast cancer metastasis. PET/CT scan detected multiple bone metastasis and enlarged lymph nodes at left axilla, mediastinal area 7, and left pulmonary hilus. The patient subsequently received systematic chemotherapy (etoposide 200 mg d1-3, cisplatin 50 mg d1-3 and recombinant human endostatin 210 mg/7 days) for 2 cycles and local radiotherapy (DT39Gy/13F/20d, DT300cGy/F) against focal bone metastasis. PET/CT examination enlarged lesions behind the left pectoralis major with enhanced metabolism activity [Figure 1]a and [Figure 1]b. The chemotherapy regimen was then changed to paclitaxel (270 mg, d1) + nedaplatin (130 mg, d1) + recombinant human endostatin (210 mg/7 days). The patient further received 4 cycles of chemotherapies, radiotherapy against focal bone metastasis (DT36Gy/12F/15d, DT300cGy/F), and radiotherapy against left axillary lesion (DT50Gy/25F/36d, DT200cGy/F) and left subcutaneous chest wall (DT70Gy/35F/50d, DT200cGy/F). Zoledronic acid was administrated intermittently during the period of these treatments. 3 months after completion of the treatments, PET/CT examination showed enlarged lymph nodes near the mediastinal area and left pulmonary hilus, indicating progressive disease [Figure 1]c and [Figure 1]d.
|Figure 1: Progression of disease after chemoradiotherapy. PET/CT showed enlarged lesions behind left pectoralis major with enhanced metabolism activity at the intermediate stage of chemoradiotherapy (b) comparing to before the therapy (a), and enlarged lymph nodes near the mediastinal area and left pulmonary hilus after the therapy (d) comparing to the intermediate stage of the therapy (c)|
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In Oct., 2015, two small nontender hard nodules with red color were noticed at examination on the patient's left upper arm. Multiple immobile nontender hard nodules were palpated under his left axillary skin, with the largest one about 20 mm × 20 mm in size. Formalin-fixed and paraffin-embedded biopsy tissue and matched blood sample were sent to 3DMed Biotechnology (Shanghai) for genomic profiling by targeted next-generation sequencing. The assay simultaneously sequenced the entire coding sequence of 372 cancer-related genes. Two significant somatic mutations, homozygous AR R616H, and heterozygous GATA3 S408Afs*99 mutations, were detected in the specimen [Figure 2]. Immunohistochemical staining of the biopsy tissue showed HER2++, estrogen receptor (ER)+ (~95%), progesterone receptor (PR)+ (~90%), and androgen receptor (AR)- [Figure 3]. Immunohistochemistry combined with histopathology [HE staining, Figure 3]e indicated invasive ductal carcinoma with neuroendocrine differentiation. Metastatic Luminal B subtype breast cancer was preferred. However, no abnormal mass or nodule was palpated in the breasts and biopsy of breast tissues failed to detect any tumor tissue. Occult breast cancer, therefore, was considered. The patient was then treated with fulvestrant (500 mg, D1, D15), which is an ER antagonist. One month after fulvestrant administration, PET/CT scan showed that part of the focuses had shrunk by size accompanied by decreased SUV value and no new metastatic focus was detected [Figure 4], demonstrating response to the endocrine treatment. Partial remission was achieved after one month's anti-estrogen treatment. The patient chose to receive tamoxifen (10 mg × 2/day) and goserelin (3.6 mg/4 weeks) thereafter to lower the medicine cost. The patient has already survived for 20 months and is still alive with fair conditions.
|Figure 2: Mutations of AR and GATA3 detected in the biopsy tissue by next-generation sequencing|
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|Figure 3: Immunohistochemical and hematoxylin.eosin staining of the biopsy tissue. Immunohistochemistry showed ER+ (a), PR+ (b), HER2+ (c), and AR. (d); Hematoxylin.eosin staining demonstrated nest-like distribution and the infiltration of tumor cells (e)|
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|Figure 4: Response of the patient to fulvestrant treatment. PET/CT showed shrinked lesions near left pectoralis major and left axilla (b), no obvious change in lymph nodes near the mediastinal area, and left pulmonary hilus with decreased activity in some lesions (d) after one month of treatment comparing to before the treatment (a and c)|
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| Discussion|| |
Male breast cancer is a very rare malignancy but its morbidity rate is ascending. Though sharing some common characteristics with female breast cancer, male breast cancer differs from female one in some aspects, especially in hormone levels and genomic profiles. Standard therapies for male breast cancer, however, are extrapolated from female's due to lack of large-scale randomized controlled clinical trials. There is no distinct treatment guideline or large-scale clinical study for male breast cancer. In male breast cancer, percentage of ER and PR positive cases is as high as 97% and 88%, respectively, while HER2 positive cases account for only 8%. In this case, ER expression was detected in 90% of the tumor tissue by IHC. High percentage of ER positivity indicates importance of endocrine therapy for male breast cancer. Reported endocrine therapies include ER antagonist tamoxifen and fulvestrant, aromatase inhibitors with or without gonadotropin-releasing hormone (GnRH) analogues, progesterone, and anti-androgen therapies, which all achieved some degree of clinical effect.,, However, efficacy analyses of these endocrine therapies were limited to retrospective studies of clinical data from small amount of patient samples. Large-scale randomized controlled clinical trial is lack. Further clinical and pharmacokinetic studies are required to optimize and verify standard endocrine therapies for male breast cancer.
Pathogenesis of male breast cancer is yet to be unraveled. Several risk factors have been proposed, including family history of hereditary tumorigenesis, gene mutations (BRCA2, CHECK2, CYP17 polymorphism, AR, etc.), alcohol, obesity, gynecomastia, estrogen intake, anti-androgenic therapy, cryptorchidism, liver cirrhosis, adult mumps, orchiditis, high temperature, and long-term radiation exposure., BMI of the patient was about 2.0 and obesity could be a risk factor in this case. In addition, two important somatic mutations, homozygous AR R616H, and heterozygous GATA3 S408Afs*99 mutations, were detected by targeted next generation sequencing.
Previous studies showed that AR mutation was related to the development of male breast cancer and proposed as a new target for treatment of male breast cancer. Androgen receptor functions as a steroid-hormone activated transcription factor. R616H mutation was found in colon cancer and gastric cancer (COSMIC). Mutations at site R616, including R616S, R616P, R616G, were reported to associate with complete androgen insensitivity. AR expression was detected in 75% of invasive breast cancer and 40.2% of male breast cancer. Expression of AR in male breast cancer indicated poor efficacy with tamoxifen treatment and poor prognosis. Negative expression of AR in this case might assure anti-estrogen therapy as a favorable strategy.
GATA3 is a zinc finger transcriptional factor and plays an essential role in the normal development and function of the mammary gland where it promotes a transcriptional program specifying luminal cell identity. In tumor tissues, GATA3 is mostly expressed in breast cancer and urothelial carcinoma. According to the Cancer Genome Atlas (TCGA), GATA3 is frequently mutated, approximately 10%, in breast cancer. Dimerized GATA3 occupies GATA sites. On exposure to hormone, ER binds to these loci and activates gene expression. It was proposed that mutation of GATA3 prolonged half life of GATA3 and ER, and thus enhanced ER signaling by lengthening the expression period of growth promoting genes. GATA3 S408Afs*99 is a frame-shift mutation in exon 6 which alters the reading frame at the carboxyl terminus of GATA3. Although S408Afs*99 mutation was not detected previously, it is very similar to ample frame-shift mutations detected at proline 409. These mutations account for 20% of GATA3 mutations in breast cancer and all extend the protein from 444 to approximately 500 amino acids. GATA3 S408Afs*99 mutation in this case, therefore, may presumably be important for development of the disease by enhancing ER signaling and contribute to the sensitivity of anti-estrogen endocrine therapy.
Although GATA3 was identified as a driver gene of female breast cancer and a biomarker of response to aromatase inhibitor therapy, function of GATA3 in male breast cancer remains controversial, and roles of GATA3 mutation in the development and anti-estrogen endocrine therapy of male breast cancer necessitate further study. Report of this case hopefully will help accumulate data for exploring molecular mechanism and treatment of male breast cancer.
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Conflicts of interest
There are no conflicts of interest.
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Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Chenggong District, Kunming 650500, Yunnan Province
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]