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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 48-51

Response to cisplatin in a metastatic triple-negative breast cancer patient


1 Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education & Research, Chandigarh, India
2 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission30-Mar-2021
Date of Decision01-Apr-2021
Date of Acceptance03-Apr-2021
Date of Web Publication23-Jul-2021

Correspondence Address:
Dr. Budhi Singh Yadav
Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aort.aort_8_21

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  Abstract 

Triple-negative breast cancers (TNBCs) are aggressive tumors with a high risk of visceral metastasis and poor prognosis. Here, we report a case of a 57-year-old postmenopausal female with gBRCA1-positive metastatic breast cancer. She was treated for endometrioid type, Stage IB Grade 2 endometrial carcinoma with pelvic external beam radiation in 2014. In 2016, she developed Stage I TNBC for which she underwent BCS followed by chemotherapy with anthracycline and taxanes. She also received accelerated partial breast irradiation. In 2019, she developed brain and lung metastasis. For the brain disease, she underwent gross total excision followed by whole-brain radiotherapy (WBRT). For the lung lesion, she received stereotactic body radiotherapy. Subsequently, she developed extensive metastases which were treated with cisplatin and vinorelbine chemotherapy and had a complete response. Within 5 months, she developed rapid progression of the disease in brain, lungs, and right adrenal. She was treated with palliative WBRT, but she died of progressive disease within the next 2 months.

Keywords: Cisplatin, metastatic breast cancer, triple negative


How to cite this article:
Yadav BS, Gupta A, Rai B, Bal A. Response to cisplatin in a metastatic triple-negative breast cancer patient. Ann Oncol Res Ther 2021;1:48-51

How to cite this URL:
Yadav BS, Gupta A, Rai B, Bal A. Response to cisplatin in a metastatic triple-negative breast cancer patient. Ann Oncol Res Ther [serial online] 2021 [cited 2022 May 23];1:48-51. Available from: http://www.aort.com/text.asp?2021/1/1/48/322150




  Introduction Top


Triple-negative breast cancers (TNBCs) are aggressive tumors with a high risk of visceral metastasis and poor prognosis.[1] Compared to other subtypes of breast cancers, women with TNBC have a higher prevalence of gBRCA mutations. Various studies have demonstrated that 15%–25% of women with TNBC carry gBRCA ½ mutations and approximately 60%–80% of breast cancer patients with BRCA1 germline mutations have triple-negative cancers.[2],[3] Moreover, BRCA1-associated and sporadic TNBCs share many histopathologic and molecular features. These similarities have led to speculation that BRCA1 associated and at least a subset of sporadic TNBCs may share defects in a BRCA1-associated pathway.[4] DNA repair defects are characteristic of BRCA deficient cells and confer sensitivity to DNA-damaging agents.[5],[6] Here, we report a case of gBRCA1-positive metastatic TNBC in a patient previously treated for endometrial carcinoma that showed complete response to treatment with cisplatin and vinorelbine.


  Case Report Top


A 57-year-old postmenopausal female presented with bleeding per vaginum for 2 months. She had a strong positive family history of pancreatic cancer in her mother, breast cancer in her maternal aunt, and ovarian cancer in her sister. She was evaluated and diagnosed with endometrioid adenocarcinoma of the endometrium, for which she underwent a staging laparotomy with total abdominal hysterectomy and bilateral salpingo-oophorectomy with infracolic omentectomy and pelvic lymph node dissection in March 2014. Her final diagnosis was adenocarcinoma of the endometrium, endometrioid type, Stage IB Grade 2. She received pelvic external beam radiation with a dose of 50 Gy in 25 fractions over 5 weeks in May 2014.

She was on regular follow-up till August 2016 when she noticed a 2 cm × 2 cm lump in the lower outer and inner quadrant of her left breast. A core biopsy was performed and reported as infiltrating ductal carcinoma, Grade 3 and triple negative on immunohistochemistry [Figure 1]. Her clinical stage was T2N0M0 (Stage IIA). She underwent a lumpectomy and axillary clearance in October 2016 and was pathologically staged as pT1N0M0 (Stage I) with a tumor size of 1.5 cm × 1 cm × 1 cm. She received adjuvant chemotherapy with four cycles of Adriamycin and cyclophosphamide and four cycles of docetaxel followed by accelerated partial breast irradiation with a dose of 34 Gy in 10 fractions over 5 days in June 2016.
Figure 1: (a) Pleomorphic tumor arranged in cords, islands, and nests with areas of sclerosis. (b) Lymph node showing reactive hyperplasia and are free of tumor. (c) Her2 neu negative staining in the tumor. (d) Tumor has a high Ki67 proliferative index of 80%

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In February 2019, while being evaluated for persistent headache for 2 months, she was diagnosed with a right parieto-occipital intracranial space-occupying lesion (ICSOL). A positron-emission tomography–computed tomography (PET-CT) was performed for metastatic workup and revealed an additional solitary 2.3 cm × 2.3 cm × 3 cm pulmonary mass in the left hilar region. She then underwent a right parietal craniotomy and gross total excision of the ICSOL in March 2019. The histopathology was suggestive of metastatic adenocarcinoma, GATA3 positive on IHC suggesting an origin from breast primary. An endobronchial ultrasound–transbronchial needle aspiration was performed and was reported as metastatic carcinoma. She was planned for whole-brain radiotherapy (WBRT) with a dose of 30 Gy in 10 fractions over 2 weeks in May 2019 and SBRT to the metastatic lung lesion with 40 Gy in 10 fractions over 2 weeks in June 2019. In August 2019, another PET-CT was performed and revealed fluorodeoxyglucose (FDG) avid cervical, mediastinal, anterior diaphragmatic, and abdominal lymph nodes as well and skeletal lesions and lung nodules suggestive of disease progression [Figure 2]a. In addition, there was another FDG enhancing lesion (SUVmax 14.3) in the right lateral border of the anterior two-third of the tongue [Figure 2]c. Fine-needle aspiration cytology was performed and was suggestive of metastatic carcinoma. Meanwhile, she was tested for BRCA mutation and was found to be positive for germline mutation in the BRCA1 gene. In August 2019, she was started on palliative chemotherapy with cisplatin (40 mg/m2) and vinorelbine (25 mg/m2) on days 1 and 8, repeated every 21 days. She completed three cycles in November 2019. No treatment-related toxicity was observed. A PET-CT was done for response assessment and showed no abnormal hypermetabolism anywhere in the body, suggesting a complete response to therapy with cisplatin and vinorelbine [Figure 2]b. In view of her remarkable response to chemotherapy, she was planned for three more cycles with the same regimen. However, soon after, she developed acute intestinal obstruction due to postoperative/radiation-related bowel adhesions for which she underwent resection anastomosis of the small bowel with a loop ileostomy. The histopathology of the intestinal segment revealed gangrenous tissue. Further chemotherapy could not be given.
Figure 2: (a) Positron-emission tomography image showing fluorodeoxyglucose avid cervical, mediastinal, anterior diaphragmatic, and abdominal lymph nodes, skeletal lesions, lung nodules, and fluorodeoxyglucose enhancing lesion in the tongue. (b) Positron-emission tomography image after three cycles of cisplatin and vinorelbine showing complete response to therapy. (c) PET image showing FDG enhancing lesion (SUVmax 14.3) in the right lateral border of the anterior two thirds of the tongue

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She was asymptomatic till April 2020 when she developed new metastatic lesions in the brain, lung nodules, and right adrenal metastases. She was given palliative WBRT with a dose of 20 Gy in five fractions over 5 weeks and was planned for a further course of chemotherapy with cisplatin and vinorelbine. However, her general condition continued to deteriorate. Symptomatic and supportive treatment followed. She finally succumbed to the illness in June 2020. Her daughter was also tested for BRCA mutation and is BRCA1/2 negative.


  Discussion Top


This report describes a remarkable response with the use of cisplatin and vinorelbine in the treatment of metastatic TNBC in a woman with a BRCA1 germline mutation. Complete remission (CR) was achieved after three cycles of therapy with a progression-free interval of 5 months.

TNBC is defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression and has a highly aggressive course.[1] In the metastatic setting, TNBC presents with higher rates of visceral metastases, has a relatively shorter median survival of 7–13 months, and a limited duration of response to successive lines of chemotherapy (median response duration of 12 weeks to the first line, 9 weeks to second, and 4 weeks to the third line).[7] Despite the poor prognosis, TNBC is characterized by molecular mechanisms that act as potential therapeutic targets, including abnormalities in the DNA repair process.[8] DNA repair defects are characteristic of BRCA-mutant cancers, which are present in 15%–25% of patients with TNBC and confer sensitivity to DNA-damaging agents.[5],[6]

Both BRCA1 and BRCA2 are required for DNA double-strand break repair by homologous recombination (HR-based DNA repair).[9],[10] Mutations in BRCA1 and BRCA2 inactivate protein function, and in cancer, the wild-type allele is almost invariably lost, leading to a defect in HR-based DNA repair. Platinum chemotherapy generates interstrand cross-links that can only be adequately repaired by HR-based DNA repair, and consequently BRCA1-deficient and BRCA2-deficient cells are highly sensitive to platinum chemotherapy and inhibitors of poly (ADP-ribose) polymerase (PARP) both in vitro and in vivo.[5],[6]

The activity of platinum in the BRCA1 population has recently been demonstrated in a few studies in literature. In a study of 25 BRCA1 patients in Poland in whom 80% were triple negative, a pathological complete response (pCR) rate of 72% was achieved with preoperative single-agent cisplatin (75 mg/m2) administered every 3 weeks for four cycles.[11] In a related retrospective study by the same group, among 102 consecutive BRCA1 carrier patients treated with a variety of preoperative regimens, cisplatin alone achieved a pCR rate of 83% (10 out of 12 patients) compared with significantly lower rates with CMF, AC, CAF, or doxorubicin– paclitaxel (AT) (7%, 22%, 21%, and 8%, respectively).[12]

Despite the intriguing data suggesting superior activity of platinum agents in BRCA-mutation carriers, there is presently no established role for adding platinum to early-stage regimens outside of a clinical trial. A recent meta-analysis demonstrated that the addition of platinum to chemotherapy regimens in the neoadjuvant setting increases pCR rate in BRCA mutated as compared to wild-type TNBC patients. However, this trend did not achieve statistical significance.[13]

For patients with metastatic BRCA1-related breast cancer, although the data are limited, it seems clear that these patients should be offered the option of platinum-containing chemotherapy at some point during their treatment course.

Byrski et al. in a prospective phase II study of single-agent cisplatin in 20 patients with BRCA1-positive metastatic breast cancer (of which 70% were TNBC) reported the evidence of substantial efficacy with an overall response rate of 80%, including 45% with complete response, and a time to progression of 12 months. However, the study lacked a control group.[14]

Whether platinum chemotherapy should be used as the first line in preference to other chemotherapy agents was the subject of the TNT study, which randomized 376 patients with metastatic TNBC or with known BRCA1/2 mutation to either carboplatin (area under the curve 6 every 3 weeks) or docetaxel (100 mg/m2 every 3 weeks) for 6–8 cycles or until progression. The initial results showed no statistical difference in progression-free survival (PFS) or overall survival for the TNBC group (3.1 months vs. 4.5 months and 12.4 months vs. 12.3 months, respectively). However, on subgroup analysis of BRCA1/2 carriers, PFS was improved in those receiving carboplatin (6.8 months vs. 3.1 months).

Further research into the role of cisplatin in the treatment of metastatic TNBC and BRCA mutation-associated breast cancer is ongoing (NCT02595905 at http://ClinicalTrials.gov).

Few reports in literature have described the successful use of platinum-based chemotherapy in metastatic BRCA-positive breast cancer. In one report, CR was achieved with a combination of bevacizumab, paclitaxel, and cisplatin-containing regimen in metastatic TNBC without additional treatment and the patient remained disease-free after 5 years. However, it was unclear whether the long-term CR reflects the efficacy of bevacizumab, the platinum agent, or the taxane agent and to what extent synergistic effects are responsible.[15] Another report has described complete radiological response after six cycles of cisplatin and nab-paclitaxel in a patient of relapsed BRCA2-positive breast cancer with liver metastasis. This patient remained in remission for 5 months.[16] Our patient also remained in remission for 5 months. This is comparable to PARP inhibitors, which are very expensive and majority of patients cannot afford these in developing and low- and middle-income countries.[16]

Partial response with the use of single-agent cisplatin has been demonstrated for the second-line treatment of anthracycline/taxane-resistant metastatic breast cancer in another report highlighting the increased sensitivity of BRCA-positive breast cancers to platinum agents.[17]

In addition to BRCA expression, studies have attempted to highlight other predictive factors for response to cisplatin in TNBC. In a neoadjuvant trial that explored the specific biomarkers of response to cisplatin in TNBC, factors associated with good cisplatin response were young age, low BRCA1 mRNA expression, BRCA1 promoter methylation, p53 nonsense or frameshift mutations, and a gene expression signature of E2F3 activation.[8]

Our patient achieved complete radiological and metabolic response after three cycles of combination chemotherapy with cisplatin and vinorelbine. Vinorelbine and cisplatin, which act on various targets, exhibit a synergistic anticancer activity and have shown a relatively high efficacy in metastatic TNBC.[18] This case adds to the hypothesis suggesting the high efficacy of platinum-containing regimens in BRCA-positive breast cancers and warrants their use especially in resource-constrained settings where PARP inhibitors seem to be a distant alternative.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Dawson SJ, Provenzano E, Caldas C. Triple negative breast cancers: Clinical and prognostic implications. Eur J Cancer 2009;45 Suppl 1:27-40.  Back to cited text no. 1
    
2.
Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 2008;26:4282-8.  Back to cited text no. 2
    
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Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer 2012;118:2787-95.  Back to cited text no. 3
    
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Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814-9.  Back to cited text no. 4
    
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Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 2000;275:23899-903.  Back to cited text no. 5
    
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Turner N, Tutt A, Ashworth A. Targeting the DNA repair defect of BRCA tumours. Curr Opin Pharmacol 2005;5:388-93.  Back to cited text no. 6
    
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Wahba HA, El-Hadaad HA. Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med 2015;12:106-16.  Back to cited text no. 7
    
8.
Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 2010;28:1145-53.  Back to cited text no. 8
    
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Moynahan ME, Chiu JW, Koller BH, Jasin M. Brca1 controls homology-directed DNA repair. Mol Cell 1999;4:511-8.  Back to cited text no. 9
    
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Tutt A, Bertwistle D, Valentine J, Gabriel A, Swift S, Ross G, et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J 2001;20:4704-16.  Back to cited text no. 10
    
11.
Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, et al. Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 2009;115:359-63.  Back to cited text no. 11
    
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Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 2010;28:375-9.  Back to cited text no. 12
    
13.
McAndrew N, DeMichele A. Neoadjuvant chemotherapy considerations in triple-negative breast cancer. J Target Ther Cancer 2018;7:52-69.  Back to cited text no. 13
    
14.
Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 2012;14:R110.  Back to cited text no. 14
    
15.
Ogata H, Kikuchi Y, Natori K, Shiraga N, Kobayashi M, Magoshi S, et al. Liver metastasis of a triple-negative breast cancer and complete remission for 5 years after treatment with combined bevacizumab/paclitaxel/carboplatin: Case report and review of the literature. Medicine (Baltimore) 2015;94:e1756.  Back to cited text no. 15
    
16.
Moiseyenko VM, Protsenko SA, Brezhnev NV, Maximov SY, Gershveld ED, Hudyakova MA, et al. High sensitivity of BRCA1-associated tumors to cisplatin monotherapy: report of two cases. Cancer genetics and cytogenetics. 2010;197:91-4.  Back to cited text no. 16
    
17.
Yadav BS, Chanana P, Sharma SC, Jhamb S. Systemic treatment strategies in triple negative breast cancer. WJCO 2014; 5:125-33.  Back to cited text no. 17
    
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Wang J, Zheng R, Wang Z, Yang Y, Wang M, Zou W. Efficacy and Safety of Vinorelbine Plus Cisplatin vs. Gemcitabine Plus Cisplatin for Treatment of Metastatic Triple-Negative Breast Cancer After Failure with Anthracyclines and Taxanes. Medical science monitor: international medical journal of experimental and clinical research. 2017;23:4657-64.  Back to cited text no. 18
    


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