A metastatic breast cancer patient with twice HER2 status changes and BRCA2 secondary mutations: a case report

Introduction

Breast cancer has been the most common cancer in women and the second leading cause of cancer deaths in females worldwide (1). Invasive ductal carcinoma (IDC) is the most common histological type in invasive breast cancer, accounting for about 70% (2). Nowadays, the treatment of breast cancer includes surgery, radiotherapy, chemotherapy, endocrine therapy, and the rapid development of targeted therapy. Targeted agents such as trastuzumab, which targets human epidermal growth factor receptor 2 (HER2), and the PARP inhibitor olaparib, which targets BRCA1/2 mutations, are also in use (3).

HER2-positive breast cancer accounts for about 15–20% of all breast cancers (4). Generally, HER2-positive is related to malignant behaviours, resistance to traditional treatment, poor prognosis, and decline in overall survival (5,6). In this case, the patient’s tumor samples showed HER2 status changes together with hormone receptor status changes. Similar changes have also been reported several times that the status of HER2 might be changed as the disease progresses (7-10). Besides, in 2018, the patient’s plasma DNA sequencing, based on next-generation sequencing (NGS), revealed a BRCA2 germline mutation. After platinum chemotherapy, the patient gained several secondary BRCA2 mutations that could lead to PARP inhibitors resistance (11,12). This study reported the change of HER2 and hormone receptors status during breast cancer treatment, and emphasized the importance of pathology tests such as immunohistochemical (IHC) staining and fluorescent in situ hybridization (FISH) throughout the whole duration of treatment. In addition, this study showed that PARP inhibitor failed to recover BRCA2 secondary mutations-mediated platinum-resistance in patients with BRCA2 germline mutation. This representative case may provide a clue for treatment decision-making in breast cancer treatment. We present this article in accordance with the CARE reporting checklist (available at https://bc.amegroups.com/article/view/10.21037/bc-24-6/rc).

Case presentation

In August 2007, a 30-year-old female was diagnosed with stage I IDC. She had a family history: her father suffered from lymphoma in his 30s. Figure 1 summarizes the treatment history of the patient. B-mode ultrasound showed a lump in the left breast (Figure 2). IHC staining of the left breast tumor showed weak positive for estrogen receptor (ER) expression, positive for progesterone receptor (PR) expression and negative for HER2 expression (Figure 3). Subsequently, the patient accepted six cycles of docetaxel and epirubicin as first line chemotherapy. In December 2007, she was switched to tamoxifen at a dose of 10 mg BID to target ER and the therapy lasted for 54 months.

Figure 1 The changes in the medication regimen and the patient’s response time during the treatment were illustrated. Red triangles indicate the timing of NGS. CR, complete response; NGS, next-generation sequencing; PD, progressive disease; SD, stable disease.

Figure 2 B-mode ultrasound and computed tomography images showed primary tumor in left breast and multiple metastatic lesions in liver. Tumors are marked by red arrows.

Figure 3 Microscopy examination of the breast cancer specimen. The immunohistochemical staining of (A) ER (weak +), (B) PR (+) and (C) c-erbB2 (1+) in 2007.08 (original magnification, ×20). The immunohistochemical staining of (D) ER (90% ++), (E) PR (5% +), (F) c-erbB2 (2+) and (G) Ki-67 (20%) in 2012.06 (original magnification, ×20). (H) The fluorescent in situ hybridization result (HER2=3.23, CEN17=1.52, HER2/CEN17=2.13) in 2012.06 (original magnification, ×100). The immunohistochemical staining of (I) ER (+++ 90%), (J) PR (−), (K) c-erbB2 (1+/2+) and (L) Ki-67 (20%) in 2017.12 (original magnification, ×20). (M) The fluorescent in situ hybridization result (HER2=3.17, CEN17=1.60, HER2/CEN17=1.98) in 2017.12 (original magnification, ×100). ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

In June 2012, the patient had a progressive disease (PD) with liver, bone and left supraclavicular lymph node metastasis. The tumor at the left supraclavicular lymph node was positive for ER, PR, HER2 by IHC, and for amplification of the HER2 gene by FISH (HER2=3.23, CEN17=1.52, HER2/CEN17=2.13) (Figure 3). Therefore, trastuzumab, an anti-HER2 monoclonal antibody, combined with paclitaxel (120 mg d1, d8 and d15) was administered in June 2012 and achieved a partial response (PR) after 4 cycles. In addition, zoledronic acid was given for anti-bone metastasis treatment. However, the patient had a PD after 10 months of treatment. It was reported that vinorelbine combined with trastuzumab therapy gained a better response than monotherapy in HER2-positive patients (13). Thus, the patient was treated with vinorelbine and trastuzumab (d1 and d8) in April 2013. After 10 cycles of the treatment in early November 2013, a complete response (CR) was achieved. Therefore, she was switched to trastuzumab (350 mg d1 and d8) and exemestane, an anti-estrogen drug, as maintenance treatment. However, the disease progressed after 6.5 months of treatment. Based on previous response, the combination therapy of vinorelbine (40 mg d1 and d8) and trastuzumab (330 mg d1) was applied again in June 2014 and achieved a progression-free survival (PFS) of 7.1 months. In February 2015, the regimen was switched to another HER2 targeted drug lapatinib at a dose of 1,250 mg QD combined with capecitabine. She suffered grade III diarrhea and the disease progressed after 1.4 months. In March 2015, larger multiple liver metastatic lesions were observed by magnetic resonance imaging (MRI) of her upper abdomen. Then, she was commenced on trastuzumab plus chemotherapy (vinorelbine and capecitabine) in April 2015. About 6.4 months later, the patient achieved stable disease (SD) and received trastuzumab and capecitabine as maintenance chemotherapy. In September 2016, the disease progressed and MRI showed new lesions in inferior segment of right liver posterior lobe. Subsequently, she was treated with paclitaxel liposome (120 mg d1, d8 and d15) plus trastuzumab (330 mg d1) and achieved a PFS of 8.8 months. In August 2017, ultrasound-guided core needle biopsy of liver mass and microwave ablation for liver tumor were administered. Subsequently, 4 cycles of capecitabine (1.5 g BID d1 to d14) plus fulvestrant (500 mg d1 Q4W) were given (August to December 2017).

In December 2017, MRI showed that multiple new metastases in the liver occurred. The tumor cells of right liver were strongly ER-positive, PR and HER2 negative (HER2=3.17, CEN17=1.60, HER2/CEN17=1.98) (Figure 3). In January 2018, the patient received vinorelbine 40 mg on d1 and d8, and trastuzumab 6 mg/kg on d1. By March 2018, 4 cycles of chemotherapy have been completed and the disease progressed. MRI of the upper abdomen revealed that the liver lesions were enlarged. Furthermore, plasma sample were collected and subjected to NGS-based genetic testing. A BRCA2 germline mutation p.K2104fs*6 (Table 1 and Figure 4) was detected but no PARP inhibitor was approved in China. Subsequently, the patient was treated with albumin bound paclitaxel (200 mg d1, d8 and d15) and trastuzumab (110 mg d1). Unfortunately, in August 2018, the patient had a PD after two months. And letrozole at a dose of 2.5 mg QD and everolimus at a dose of 10 mg QD were administered. About 5 months later, MRI of upper abdomen revealed that some of the lesions were enhanced. Therefore, the regimen was changed to fulvestrant (500 mg d1) and palbociclib (125 mg d1 to d21) but the disease progressed after 3 months.

Figure 4 Sequence analysis of BRCA2 mutants. (A) Examination of the sequencing reads in Integrative Genomic Viewer (IGV) software showed the four different BRCA2 mutations. (B) Diagram of BRCA2 protein domain structures of wild-type and different mutation types of BRCA2. DBD, DNA-Binding domain.

In April 2019, MRI of upper abdomen indicated an obvious progression of liver lesions (Figure 2). Considering the BRCA2 mutation, the patient was then switched to platinum-based chemotherapy (carboplatin 30 mg on d1 and d8) plus gemcitabine at a dose of 1,500 mg on d1 and d8. MRI indicated that liver metastases tend to become smaller in early November 2019 (Figure 2) but after 8 months of this therapy, the disease progressed. Interestingly, after platinum chemotherapy, several new BRCA2 mutations were revealed by NGS, including p.S2103_V2109del, p.K2104_P2114delinsNTYT and p.D1864_H2251del (Table 1 and Figure 4). These newly acquired BRCA2 mutations restored the frameshift of DNA bind domain (DBD) caused by germline mutation (Figure 4B). Subsequently, olaparib (300 mg, BID) was initiated in January 2020 but multiple new metastatic lesions were observed by MRI of liver only after two months (Figure 2). In March 2020, eribulin was given, but it still didn’t relieve the condition. Ultimately, the patient died in May 2020.

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Due to new treatment being approved and better understanding of breast cancer development mechanism, the overall survival of breast cancer patients is much better than before (14). Besides, precision medicine also plays an irreplaceable role in modern breast cancer treatment. In addition to mammography or other imaging evidence, other pathological examinations such as IHC, FISH, and gene sequencing can more accurately identify the subtyping of breast cancer, which can help to tailor individualized treatment for different patients.

In this report, we present the case of a patient first diagnosed with metastatic breast cancer (MBC), positive for both ER and PR, while negative for HER2. After surgery and the first line chemotherapy, endocrine therapy was given, using tamoxifen, which is an estrogen modulator. The therapy lasted for 54 months until disease progressed. Simultaneously, the results of left supraclavicular lymph node pathology tests revealed a series of expression changes including a relatively rare change that HER2 turned from negative to positive, confirmed by FISH (HER2=3.23, CEN17=1.52, HER2/CEN17=2.13). It corresponded to the cancer becoming unstable after this change. Statistically, positive HER2 stands for worse prognosis (5). Therefore, trastuzumab was administered immediately targeting at the emerging HER2 overexpression, together with paclitaxel.

Based on the understanding of the patient’s HER2-positive expression, trastuzumab or another HER2 inhibitor had been used since the pathology test is completed, until the tumor progression in August 2017. Then four months later the IHC staining revealed ER expression turned strongly positive while PR and HER2 both turned negative. After this change, the tumor progressed more quickly. Interestingly, during the 13-year-long treatment to our patient, we observed the HER2 status changed two times, from negative to positive then back to negative, which was a rare case to our knowledge. It is noteworthy that in our case the patient’s response showed a high correlation between HER2 status and targeted therapy. Thus, routine pathology tests such as IHC and FISH are suggested to be performed throughout the whole duration of treatment.

Throughout the whole treatment so far, our medical decisions based on the first two pathology tests of hormone receptors and HER2 expression, both led to relatively long PFS. It showed that pathology tests based on IHC and FISH or other biology approaches should be considered more often while treating patients, even if some cases could be very rare like HER2 expression turning from negative to positive. However, when the test showed HER2 turned back to negative, trastuzumab was not removed from the regimen. It was immediately proven to lose efficacy in three months. Therefore, routine tests are suggested to be conducted and the results should be taken into consideration seriously to benefit for patients.

In another report, a patient also underwent the same HER2 negative to positive change with highly similar treatment of docetaxel (7). Studies found that HER2 status changes with disease progression, with higher HER2 expression at relapse (15). This seems to explain the first change in HER2 status. Another study showed that HER2 expression changed from positive to negative in 47.3% of cases after treatment with trastuzumab alone (16). It may be very suspicious that this kind of turning can be treatment-induced. Meanwhile, a study shows that dual HER2 blockade in HER2-enriched disease induces a low-proliferative Luminal A phenotype both in patient’s tumors and in vitro models (17). Therefore, we hypothesized that under the selective pressure of targeted drugs, HER2-positive breast cancer has a tendency to turn negative, while breast cancer with low HER2 expression is associated with favorable prognosis (18).

For druggable mutations calling, NGS-based genetic tests of plasma samples were conducted and revealed a germline BRCA2 mutation, which is related to high risk of breast cancer. The BRCA2 gene plays an important role in DNA damage repair through homologous recombination (HR) repair and DNA replication fork protection (19). This BRCA2 p.K2104fs*6 mutation caused loss of function of BRCA2 via harms the DNA binding domains (DBD) of wild type BRCA2 (Figure 4). Tissue biopsy remains the gold standard for determining ER/PR/HER2 status and BRCA2 mutations. However, cell-free DNA (cfDNA) shows greater potential in tracking secondary BRCA2 mutations or treatment resistance, though it requires complementary use with tissue biopsy (20). According to published clinical approaches, PARP inhibitors and platinum-based chemotherapy showed high efficiency in BRCA2-mutated breast cancer patients (21). Therefore, carboplatin combined with gemcitabine was administered and then reached a reduced liver metastatic tumor size (Figure 2) and 8-month-long PFS. However, tumor progressed rapidly, accompanied with three newly occurred BRCA2 secondary mutations. Then, a PARP inhibitor olaparib was used but showed no response. Reversal mutations in BRCA genes have been found to indicate a poor response to platinum-based therapy or PARP inhibition, which was consistent with this case report (22). Walmsley suggested that PARP inhibitors exert a strong selective pressure on BRCA-reversing mutations in BRCA-mutated tumors. Patients who developed acquired resistance to PARP inhibition experienced minimal clinical benefit from platinum-based chemotherapy, supporting the possibility of cross-resistance between PARP inhibitors and platinum-based therapies (23).

Conclusions

In conclusion, we traced a rare breast cancer patient who underwent several different regimens during disease progression and achieved an overall survival of 13 years. Two changes of HER2 status occurred during treatment, which highlighted the importance of pathology tests throughout the whole duration of treatment. Besides, the patient harbored a BRCA2 germline mutation, developed a secondary mutation after 8 months of platinum-based chemotherapy, and showed primary resistance to olaparib therapy. Therefore, NGS in the course of disease can help to understand the mechanisms that guide subsequent therapy and drug resistance. This representative case may provide a clue for treatment decision-making in breast cancer treatment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://bc.amegroups.com/article/view/10.21037/bc-24-6/rc

Peer Review File: Available at https://bc.amegroups.com/article/view/10.21037/bc-24-6/prf

Funding: This work was supported by grants from Zhejiang Provincial Natural Science Foundation (Nos. Y2101312 and LY17H160041), the Zhejiang Provincial Medical Science and Technology Program (Nos. 2010QNA006 and 2021KY551), Zhejiang science and Technology Program (No. 2016C33199), the Special Fund of Wu Jieping Medical Foundation Clinical Research (No. 320.670010007), Key Research and Development Projects in Zhejiang Province/International Cooperation Technology Research and Development and Demonstration Promotion Projects (2020C04012).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://bc.amegroups.com/article/view/10.21037/bc-24-6/coif). X.W. serves as the Editor-in-Chief of Breast Communication. X.S. serves as an unpaid editorial board member of Breast Communications from November 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are 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. All procedures performed in this study were in accordance with the ethical standards of the institutional research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
2. Chen X, Zhang C, Guo D, et al. Distant metastasis and prognostic factors in patients with invasive ductal carcinoma of the breast. Eur J Clin Invest 2022;52:e13704. [Crossref] [PubMed]
3. Jacobs AT, Martinez Castaneda-Cruz D, Rose MM, et al. Targeted therapy for breast cancer: An overview of drug classes and outcomes. Biochem Pharmacol 2022;204:115209. [Crossref] [PubMed]
4. Loibl S, Gianni L. HER2-positive breast cancer. Lancet 2017;389:2415-29. [Crossref] [PubMed]
5. Vi C, Mandarano G, Shigdar S. Diagnostics and Therapeutics in Targeting HER2 Breast Cancer: A Novel Approach. Int J Mol Sci 2021;22:6163. [Crossref] [PubMed]
6. Guo L, Shao W, Zhou C, et al. Neratinib for HER2-positive breast cancer with an overlooked option. Mol Med 2023;29:134. [Crossref] [PubMed]
7. Sivarajan L, Sivarajan KM, Natarelli J, et al. Change in HER-2/neu Status from Negative to Positive following Treatment in Breast Cancer: A Case Report. Case Rep Oncol 2011;4:19-24. [Crossref] [PubMed]
8. Bo J, Yu B, Bi R, et al. Conversion of ER and HER2 Status After Neoadjuvant Therapy in Chinese Breast Cancer Patients. Clin Breast Cancer 2023;23:436-46. [Crossref] [PubMed]
9. Tarantino P, Ajari O, Graham N, et al. Evolution of HER2 expression between pre-treatment biopsy and residual disease after neoadjuvant therapy for breast cancer. Eur J Cancer 2024;201:113920. [Crossref] [PubMed]
10. Niikura N, Tomotaki A, Miyata H, et al. Changes in tumor expression of HER2 and hormone receptors status after neoadjuvant chemotherapy in 21,755 patients from the Japanese breast cancer registry. Ann Oncol 2016;27:480-7. [Crossref] [PubMed]
11. Waks AG, Cohen O, Kochupurakkal B, et al. Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Ann Oncol 2020;31:590-8. [Crossref] [PubMed]
12. Bhin J, Paes Dias M, Gogola E, et al. Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. Cell Rep 2023;42:112538. [Crossref] [PubMed]
13. Chan A. A review of the use of trastuzumab (Herceptin) plus vinorelbine in metastatic breast cancer. Ann Oncol 2007;18:1152-8. [Crossref] [PubMed]
14. Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primers 2019;5:66. [Crossref] [PubMed]
15. Bergeron A, Bertaut A, Beltjens F, et al. Anticipating changes in the HER2 status of breast tumours with disease progression-towards better treatment decisions in the new era of HER2-low breast cancers. Br J Cancer 2023;129:122-34. [Crossref] [PubMed]
16. Ignatov T, Gorbunow F, Eggemann H, et al. Loss of HER2 after HER2-targeted treatment. Breast Cancer Res Treat 2019;175:401-8. [Crossref] [PubMed]
17. Brasó-Maristany F, Griguolo G, Pascual T, et al. Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade. Nat Commun 2020;11:385. [Crossref] [PubMed]
18. Liu C, He J, Shang J, et al. Changes of HER2 low expression status in primary and recurrent/metastatic breast cancer. Zhonghua Bing Li Xue Za Zhi 2023;52:912-7. [Crossref] [PubMed]
19. Yoshimura A, Imoto I, Iwata H. Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management. Int J Mol Sci 2022;23:7481. [Crossref] [PubMed]
20. Huang H, Hu C, Na J, et al. Functional evaluation and clinical classification of BRCA2 variants. Nature 2025;638:528-37. [Crossref] [PubMed]
21. Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer 2018;119:141-52. [Crossref] [PubMed]
22. Zong H, Zhang J, Xu Z, et al. Comprehensive Analysis of Somatic Reversion Mutations in Homologous Recombination Repair (HRR) Genes in A Large Cohort of Chinese Pan-cancer Patients. J Cancer 2022;13:1119-29. [Crossref] [PubMed]
23. Walmsley CS, Jonsson P, Cheng ML, et al. Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy. NPJ Precis Oncol 2024;8:34. [Crossref] [PubMed]