We report a rare case of hereditary breast and ovarian cancer syndrome (HBOC) with pathogenic variants in both BRCA1 and BRCA2. The patient was a 78-year-old woman who visited the hospital after noticing a lump in her left breast 6 months before, which gradually increased in size. According to her family history, her maternal aunt developed breast cancer in her 40s. On palpation, a 4-cm large mass was palpated in the upper outer part of the left breast. A needle biopsy revealed invasive ductal carcinoma of the breast, which was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2. The patient was diagnosed with cT2N0M0 stage IIA, and primary systemic treatment was planned. The patient developed drug-induced interstitial pneumonia after receiving paclitaxel. Although she recovered spontaneously, she did not wish to receive further chemotherapy, and thus surgery was performed. Four months after the surgery, the patient became aware of dyspnea. After a thorough examination, she was diagnosed with postoperative cancer recurrence of the left breast with multiple liver metastases, cancerous peritonitis, multiple bone metastases, and multiple lymph node metastases. Genetic testing was performed, and pathogenic variants were found in both BRAC1 and BRCA2. However, her condition worsened, and she died 8 months after the surgery. BRCA pathogenic variants had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. It is desirable to consider the optimal approach to the treatment of breast cancer in pathogenic variants. In elderly patients with triple-negative breast cancer, HBOC may be suspected, based on biomarkers and family history. It is important to provide information on genetic counseling, genetic testing, and effective treatment plans proactively.

Hereditary breast and ovarian cancer syndrome (HBOC) is one of the most common hereditary tumors caused by germline pathogenic variants of BRCA1 or BRCA2 and results in a high risk of developing breast or ovarian cancer [1, 2]. In recent reports, BRCA pathogenic variants remained an independent poor prognostic factor for cancer recurrence or death [3]. Also, rare cases of pathogenic variants in both BRCA1 and BRCA2 have been reported quite exceptionally in non-Ashkenazi individuals [4-6]. In this study, we report a case of triple-negative breast cancer (TNBC) with both BRCA1 and BRCA2 pathogenic variants that were revealed after early recurrence.

The patient was a 78-year-old woman who visited the hospital after noticing a lump in her left breast 6 months before, which gradually increased in size. She had no previous medical history or comorbid diseases. She did not take any medications, nor had she been subject to any hazardous exposures. She had a positive familial history of breast cancer and other cancers (Fig. 1). In her family history, her maternal aunt (II-10) developed breast cancer in her 40s and died in her 50s. Also, her sister (III-11) developed esophageal cancer at the age of 58 and died at the age of 62. Another 68-year-old sister (III-13) developed gastric cancer in her 30s and bladder cancer in her 40s. And, her father (II-2) developed bladder cancer in his 70s and died at the age of 94. Three paternal uncles (II-4, II-5, and II-6) and another maternal aunt (II-12), whose details are unknown, contracted cancer and died in their 70s.

Fig. 1.

Family tree of the patient: proband of this case; III-10, maternal aunt; II-10 developed breast cancer in her 40s and died in her 50s.

Fig. 1.

Family tree of the patient: proband of this case; III-10, maternal aunt; II-10 developed breast cancer in her 40s and died in her 50s.

Close modal

Palpation revealed a 4-cm large, irregularly shaped, firm mass in the upper lateral region of her left breast. A mammography identified a high-density mass with finely serrated margins in the middle-outer region of the left breast (Fig. 2a, b). A breast ultrasound revealed a 25 × 31 × 24 mm segmental, well-defined, coarse, hypoechoic mass in the left 1:00 central portion (Fig. 2c). The breast MRI showed a 39 × 30 × 25 mm mass in the upper lateral portion of the left breast, with early dark staining and a prolonged contrast effect (Fig. 2d). A needle biopsy was performed on the mass, which diagnosed invasive ductal carcinoma of the breast; Ki-67 labeling index: 60%; histological grade: grade II; immunohistological evaluation showing TNBC that lacked expression of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor type 2 (HER2); and clinical stage IIA.

Fig. 2.

a, b Mammogram; marginal micrographs in the middle-outer region of the left breast: a serrated hyperintense mass was found. c Breast ultrasound before PST: a hypoechoic mass of 25 × 31 × 24 mm was found (left) at 1 o’clock at the central portion. d Breast MRI before PST; 39 × 30 × 25 mm mass was found in the left upper lateral breast. e CT; diffuse reticular shadows in all lung fields were identified and determined as drug-induced interstitial pneumonia. f CT taken to assess pneumonia showed no apparent liver metastasis. g Breast MRI after PST; mass reduced to 16 × 13 × 18 mm. CT, computed tomography; PST, primary systemic treatment.

Fig. 2.

a, b Mammogram; marginal micrographs in the middle-outer region of the left breast: a serrated hyperintense mass was found. c Breast ultrasound before PST: a hypoechoic mass of 25 × 31 × 24 mm was found (left) at 1 o’clock at the central portion. d Breast MRI before PST; 39 × 30 × 25 mm mass was found in the left upper lateral breast. e CT; diffuse reticular shadows in all lung fields were identified and determined as drug-induced interstitial pneumonia. f CT taken to assess pneumonia showed no apparent liver metastasis. g Breast MRI after PST; mass reduced to 16 × 13 × 18 mm. CT, computed tomography; PST, primary systemic treatment.

Close modal

The patient was scheduled for primary systemic treatment (PST) and 12 cycles of weekly paclitaxel followed by 4 cycles of EC therapy. After 11 cycles of paclitaxel, the patient developed drug-induced interstitial pneumonia (Fig. 2e). The respiratory physician was consulted. As the clinical symptoms were mild, outpatient follow-up was decided on. The symptoms resolved spontaneously within approximately 2 weeks. Also, CT at the onset of pneumonia did not detect apparent metastasis including the liver (Fig. 2f). Adverse events, such as peripheral neuropathy and malaise, were moderate. The patient did not wish to receive further chemotherapy.

The reduction rate of the mass was 55%, and the treatment effect of PST was determined as a partial response (Fig. 2g). Surgery consisted of a total left mastectomy and sentinel lymph node biopsy. The histopathological examination revealed the following: invasive ductal carcinoma, scirrhous type, tumor size 2.0 × 0.9 × 1.5 cm, no vascular invasion, negative margins, Ki-67 labeling index: 32%, histological grade: grade II, preoperative histological grade: grade II, preoperative response to drug therapy: grade 1a, 1-mm micrometastasis in the sentinel lymph node, and pathological stage IB. An immunohistological evaluation showed TNBC that lacked ER, PgR, and HER2 expressions. The patient did not wish to receive additional postoperative drug therapy and was placed on a follow-up treatment plan. Four months after the surgery, the patient began to experience dyspnea, which worsened gradually. Based on a thorough examination, we diagnosed postoperative cancer recurrence of the left breast with multiple liver metastases, cancerous peritonitis, multiple bone metastases, and multiple lymph node metastases (Fig. 3a–h).

Fig. 3.

CT: a multiple liver metastases occupying the entire liver. b Pleural effusion on the left side superiority was recognized. PET: c–h FDG accumulation to the bone of the whole body such as the vertebral body and pelvis, left clavicle upper cavity lymph node, para-aortic lymph node, and strong FDG accumulation to the liver were recognized. These result in multiple bones, lymph nodes, liver metastasis, and carcinomatous pleurisy. CT, computed tomography; PET, positron emission tomography; FDG, 18F-fluorodeoxyglucose.

Fig. 3.

CT: a multiple liver metastases occupying the entire liver. b Pleural effusion on the left side superiority was recognized. PET: c–h FDG accumulation to the bone of the whole body such as the vertebral body and pelvis, left clavicle upper cavity lymph node, para-aortic lymph node, and strong FDG accumulation to the liver were recognized. These result in multiple bones, lymph nodes, liver metastasis, and carcinomatous pleurisy. CT, computed tomography; PET, positron emission tomography; FDG, 18F-fluorodeoxyglucose.

Close modal

Genetic testing was performed as a companion diagnosis, and pathogenic variants were found in both BRAC1 and BRCA2, c.5278-1G>A and c.6925C>T (p.Arg2318*), respectively. The history of breast cancer of the maternal aunt (Fig. 1, indicated by II-10) was clear, and it was considered that the germline pathogenic variant of BRCA might be from the maternal direction. After receiving these results, her husband and eldest son (Fig. 1, indicated by IV-1) were referred to genetic counseling. They did not wish to explain the results to account for the mental and physical burden of the patient. The eldest son and the second son (Fig. 1, indicated by IV-2) want to take the examination, but are considering the timing of the examination. To date, no other family member, including her sister (Fig. 1, indicated by III-12) has received genetic testing. However, the patient’s general condition continued to worsen and with no indication for drug therapy. The best supportive care was decided as the course of management. The patient was treated with palliative care and died 8 months after the surgery.

HBOC is a susceptibility syndrome for breast and ovarian cancers caused by the pathogenic variant in the germline of either BRCA1 or BRCA2; it is an autosomal dominant form of inheritance [1, 2]. The cumulative risk is reported as 72% for BRCA1 and 69% for BRCA2 in breast cancer by the age of 80 and 44% for BRCA1 and 17% for BRCA2 in ovarian cancer [7]. The frequency of HBOC in the general population is estimated to be 1 in 400 or 1 in 500, which is extremely high for a hereditary disease [8]. In contrast, 3–5% of breast cancer patients and about 10% of ovarian cancer patients are said to have HBOC [9].

To date, the co-existence in an individual of the pathogenic variant in both BRCA1 and BRCA2 is a very rare condition in most populations, particularly in non-Ashkenazi Jewish [4-6], and our patient has no known Ashkenazi heritage. The frequency of them is estimated at 1.8% in Ashkenazi Jewish due to founder mutations, whereas in non-Ashkenazi Jewish, it is in the range of 0.2–0.8% [10] and 0.3% [11]. Also, the Japanese Organization for Hereditary Breast and Ovarian Cancer (JOHBOC) reported the number of BRCA tests and the results carried out in Japan in 2018. In that report, 3,477 cases were tested, and 6 cases (0.2%) had both pathogenic variants [12].

Wang et al. [3] implied the more aggressive nature of breast tumors in BRCA germline pathogenic variants. They showed that BRCA pathogenic variants were more likely to be diagnosed with breast cancer already spread to the regional lymph node, and their breast cancer-related outcomes were significantly worse. The 5-year disease-free survival rate was only 73.3% for pathogenic variants, in contrast to 91.1% for nonpathogenic variants. The BRCA pathogenic variants were an independent prognostic factor with an adjusted hazard ratio of 3.03 (95% CI: 1.40–6.58) for cancer recurrence death. The poor clinical outcome in pathogenic variants mainly resulted from recurrence as distant metastasis, therefore excluding the contribution by new primary cancer in the ipsilateral or contralateral breast, of which the risk had been known to be elevated in pathogenic variants.

In addition to pathogenic variants, this case involved micrometastasis in the axillary lymph nodes and non-pCR. She was at a high risk for recurrence. If the patient did not wish to receive postoperative treatment, it was important to be flexible by considering the individual patient’s situation, such as by shortening the interval between regular visits to detect signs of recurrence.

As the clinical course of this case, the postoperative early recurrence was caused, and the prognosis was poor. It may raise up the possibility of a pejorative impact of either involved pathogenic variants or resulting from their association. Nevertheless, a review of the literature suggests that the co-existence of BRCA1 and BRCA2 pathogenic variants likely does not cause more severe phenotype of breast cancer with respect to age of disease onset, cumulative lifetime risk, and multiple primary tumors when compared with available population-specific cancer risk in carriers of a single BRCA pathogenic variant [4, 5]. It is an analysis of a small number of cases, and the evaluation of the prognosis is controversial. Further analysis by prospective accumulation is expected.

Both pathogenic variant-related breast cancers are usually of high grade. However, while there are no known histopathological features that distinguish BRCA2 from sporadic tumors, breast cancers occurring in the BRCA1 pathogenic variant are usually negative for expression of ER, PgR, and HER2 (the so-called triple-negative phenotype) and positive for p53 alterations [13]. According to a recent report, the breast cancers that occurred in the pathogenic variants were all high grade, stage II, mostly negative for hormonal receptors and/or HER2 expression, and with high proliferative index [14]. These data indicate that breast cancers in pathogenic variants are more likely to exhibit a BRCA1 histopathological phenotype and suggest that in these patients, breast carcinogenesis is mainly driven by the pathogenic variant in BRCA1, even if this hypothesis requires confirmatory studies on a larger number of cases.

The increased risk of cancer in both pathogenic variants, as in patients with a single variant in BRCA, is not limited to breast and ovarian cancer but also involves other cancers [14]. In line with this evidence, among the tumors reported in the analyzed pathogenic variants’ families, the most frequent was ovarian cancer (21.4%), followed by breast cancer, prostate cancer, and colon cancer, with a percentage of 14.3%, and bilateral breast cancer, breast and ovarian cancer, bladder cancer, leukemia, and laryngeal cancer, with a percentage of 7.1% [11].

We encountered a case of TNBC with pathogenic variants of BRCA1 and BRCA2 that caused early recurrence. BRCA pathogenic variants had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for pathogenic variants warrants further investigation. It is important that we strive to provide appropriate genetic counseling to patients and their families, in accordance with the NCCN guidelines [15]. Even in elderly TNBC patients, if HBOC is suspected, it is important to perform proactive genetic testing more and provide effective treatment.

It was not necessary to obtain ethical approval for this case report. Written informed consent was obtained from the patient’s family for the publication of this case report and the accompanying images.

All authors have no conflicts of interest to declare.

No funding was obtained from the private or public sectors for this research.

M.K. and Y.H. conceived and designed this study. All authors contributed to the data acquisition and analysis. M.K. and Y.H. were the major contributors in the writing of this manuscript. All authors have read and approved of the final manuscript.

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

1.
Miki
Y
,
Swensen
J
,
Shattuck-Eidens
D
,
Futreal
PA
,
Harshman
K
,
Tavtigian
S
,
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
.
Science
.
1994 Oct 7
;
266
(
5182
):
66
71
. .
2.
Wooster
R
,
Bignell
G
,
Lancaster
J
,
Swift
S
,
Seal
S
,
Mangion
J
,
Identification of the breast cancer susceptibility gene BRCA2
.
Nature
.
1995 Dec 21
;
378
(
6559
):
789
92
. .Erratum in
3.
Wang
YA
,
Jian
JW
,
Hung
CF
,
Peng
HP
,
Yang
CF
,
Cheng
HS
,
Germline breast cancer susceptibility gene mutations and breast cancer outcomes
.
BMC Cancer
.
2018 Mar 22
;
18
(
1
):
315
. .
4.
Smith
M
,
Fawcett
S
,
Sigalas
E
,
Bell
R
,
Devery
S
,
Andrieska
N
,
Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes
.
Fam Cancer
.
2008
;
7
(
2
):
119
24
. .Epub 2007 Jul 17
5.
Leegte
B
,
van der Hout
AH
,
Deffenbaugh
AM
,
Bakker
MK
,
Mulder
IM
,
ten Berge
A
,
Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations
.
J Med Genet
.
2005 Mar
;
42
(
3
):
e20
. .
6.
Meynard
G
,
Mansi
L
,
Lebahar
P
,
Villanueva
C
,
Klajer
E
,
Calcagno
F
,
First description of a double heterozygosity for BRCA1 and BRCA2 pathogenic variants in a French metastatic breast cancer patient: A case report
.
Oncol Rep
.
2017 Mar
;
37
(
3
):
1573
8
. .Epub 2017 Feb 3.
7.
Kuchenbaecker
KB
,
Hopper
JL
,
Barnes
DR
,
Phillips
KA
,
Mooij
TM
,
Roos-Blom
MJ
,
Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers
.
JAMA
.
2017 Jun 20
;
317
(
23
):
2402
16
. .
8.
Palmirotta
R
,
Lovero
D
,
Stucci
LS
,
Silvestris
E
,
Quaresmini
D
,
Cardascia
A
,
Double heterozygosity for BRCA1 pathogenic variant and BRCA2 polymorphic stop codon K3326X: a Case Report in a Southern Italian Family
.
Int J Mol Sci
.
2018 Jan 18
;
19
(
1
):
285
. .
9.
ACOG Committee on Practice Bulletins
.
ACOG practice bulletin No. 103: hereditary breast and ovarian cancer syndrome
.
Obstet Gynecol
.
2009 Apr
;
113
(
1
):
957
66
. .
10.
Le Page
C
,
Rahimi
K
,
Rodrigues
M
,
Heinzelmann-Schwarz
V
,
Recio
N
,
Tommasi
S
,
Clinicopathological features of women with epithelial ovarian cancer and double heterozygosity for BRCA1 and BRCA2: a systematic review and case report analysis
.
Gynecol Oncol
.
2020 Feb
;
156
(
2
):
377
86
. .Epub2019 Nov 18
11.
Vietri
MT
,
Caliendo
G
,
D’Elia
G
,
Resse
M
,
Casamassimi
A
,
Minucci
PB
,
Five Italian Families with two mutations in BRCA Genes
.
Genes
.
2020 Dec 3
;
11
(
12
):
1451
. .
12.
Nakamura
S
.
Current status of hereditary breast and ovarian cancer syndrome and future perspectives
.
J Jpn Surg Soc
.
2021
;
122
(
3
):
314
9
.
13.
Phillips
KA
.
Immunophenotypic and pathologic differences between BRCA1 and BRCA2 hereditary breast cancers
.
J Clin Oncol
.
2000 Nov
;
18
(
21 Suppl l
):
107S
12
.
14.
Zuradelli
M
,
Peissel
B
,
Manoukian
S
,
Zaffaroni
D
,
Barile
M
,
Pensotti
V
,
Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics
.
Breast Cancer Res Treat
.
2010 Nov
;
124
(
1
):
251
8
. .Epub 2010 Apr 7
15.
Daly
MB
,
Pal
T
,
Berry
MP
,
Buys
SS
,
Dickson
P
,
Domchek
SM
,
Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology
.
J Natl Compr Canc Netw
.
2021 Jan 6
;
19
(
1
):
77
102
. .
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.