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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 1  |  Page : 56-59

Long-term control of recurrent disease in a patient with hormones receptor-positive breast cancer


1 Department of Radiotherapy, Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India
2 Department of Radiation Oncology, AIIMS, Bathinda, Punjab, India
3 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India

Date of Submission12-Jan-2021
Date of Acceptance25-Jan-2021
Date of Web Publication23-Jul-2021

Correspondence Address:
Dr. Budhi Singh Yadav
Department of Radiotherapy, 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_4_21

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  Abstract 


A 45-year-old female was diagnosed with infiltrating duct carcinoma (IDC) left breast in 1982. She underwent a mastectomy followed by locoregional radiotherapy and chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil. The patient developed left axillary swelling (3 cm × 3 cm) in 2004; fine-needle aspiration cytology (FNAC) was suggestive IDC, metastatic. The patient was started on tablet letrozole 2.5 mg but stopped it due to a cardiac problem. She reported with increase in the size of left axillary swelling in 2008. FNAC was reported as IDC, recurrence. There were no metastases on further workup. She was started on exemestane 25 mg and was also given radiotherapy to the left axilla. In 2012, bone scan was suggestive of multiple skeletal metastases. She was put on exemestane till 5 years. Again in 2013, she had left axillary swelling but the patient was not willing for FNAC. The patient was now started on anastrozole 1 mg. She again had back pain; bone scan was done and it was suggestive of multiple skeletal metastases. She was continued on anastrazole. In February 2015, she developed small nodules in the left axilla and anterior abdominal wall. FNAC of both sites was positive for carcinoma, metastatic. Bone scan again showed multiple skeletal metastases. Positron emission tomography scan did suggest local recurrence with metastatic radiculopathy in left axilla and widespread metastases Biopsy from the left axilla revealed IDC and it was strong estrogen receptor, progesterone receptor positive, and Her 2 neu negative. She was 78 years now with KPS 40 and cardiac morbidity. Her disease progressed rapidly to lungs and she died.

Keywords: Breast cancer, hormones receptor-positive, long-term hormonal therapy, metastases, recurrence


How to cite this article:
Yadav BS, Mahajan R, Bal A, Gupta A. Long-term control of recurrent disease in a patient with hormones receptor-positive breast cancer. Ann Oncol Res Ther 2021;1:56-9

How to cite this URL:
Yadav BS, Mahajan R, Bal A, Gupta A. Long-term control of recurrent disease in a patient with hormones receptor-positive breast cancer. Ann Oncol Res Ther [serial online] 2021 [cited 2022 May 23];1:56-9. Available from: http://www.aort.com/text.asp?2021/1/1/56/322147




  Introduction Top


For women with estrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen for 5 years substantially reduces the rate of recurrence not only during the treatment period but throughout the first decade, and reduces breast cancer mortality by about a third throughout the first 15 years (including years 10–14), with little net effect on other mortality.[1] In the past extended use of tamoxifen beyond 5 years was not shown to improve survival.[2],[3] Recently, it has been shown that tamoxifen use for 10 years reduces recurrence and mortality as compared to 5 years tamoxifen in patients with hormone receptor-positive breast cancer.[4] However, data are lacking about the extended use of aromatase inhibitors (AIs). Here, we report a case where continuing hormonal treatment for more than 5 years with AIs provided a longer remission period in a patient with locally recurrent breast cancer.


  Case Report Top


A 45-year-old female presented with 6 months' history of lump in the left breast and retraction of nipple. The patient was diagnosed as infiltrating duct carcinoma (IDC) at some other hospital where simple mastectomy was done on August 28, 1982 and was referred to our institute for further management. Histopathology slides were reviewed and diagnosis was confirmed as IDC. Baseline investigations, ultrasonograph (USG) of abdomen and bone scan were normal. The patient was given external beam radiotherapy with a dose of 35 Gy in 15 fractions to chest wall, 40 Gy in 15 fractions to left axilla and internal mammary nodes. Adjuvant chemotherapy with (cyclophosphamide, methotrexate, 5-fluorouracil) was given every 2 weekly for 9 cycles completed on 20/6/1983. The patient was kept on follow-up until she developed thyroid swelling in 1984. Fine-needle aspiration cytology (FNAC) was suggestive of? follicular neoplasm/adenoma for which subtotal thyroidectomy was done. Histopathological examination (HPE) was Hashimoto's thyroiditis and thus the patient was kept on follow-up only. Chest X-ray and bone scan were normal at this time. The patient developed left axillary swelling (3 cm × 3 cm) in 2004; FNAC was done on October 11, 2004 which was suggestive IDC, metastatic. The patient was started on tablet letrozole 2.5 mg on October 12, 2004 and continued till the patient had some cardiac problem and it was stopped on January 20, 2006 and she was kept on follow-up only as she was clinically No evidence of disease (NED). During her follow-up, there was a vague small left axillary swelling from which FNAC was repeated thrice between July and November 2007 and it was reported as negative for malignancy. However, on March 25, 2008 she reported with increase in the size of left axillary swelling. This time FNAC was reported as IDC, recurrence. Blood investigations, chest X-ray, USG abdomen and bone scan were normal. The patient was then started on Tablet Exemestane 25 mg on April 11, 2008. She was given EBRT to left axilla 40 Gy/15#/3 weeks (April 24, 2009–May 14, 2009) and was continued on exemestane. The left axillary swelling subsided. Patient developed lower back pain in 2012 when bone scan was suggestive of multiple skeletal metastases. She was put on exemestane till 5 year completed on April 15, 2013. Patient at this time had no axillary swelling. Again in July 2013, she had left axillary swelling but the patient was not willing for FNAC. Patient was now started on Tablet anastrozole 1 mg. She again had back pain; bone scan was done and it was suggestive of multiple skeletal metastases. She was continued on anastrozole. Subsequently, axillary swelling disappeared as patient continued hormonal treatment. In February 2015, she developed small nodules in left axilla and anterior abdominal wall. FNAC of both sites was positive for carcinoma, metastatic. Bone scan again showed multiple skeletal metastases. Positron emission tomography scan did suggest local recurrence with metastatic radiculopathy in left axilla and widespread metastases [Figure 1]. Biopsy from the left axilla revealed infiltrating ductal carcinoma and it was strong estrogen receptor (ER), progesterone receptor (PR) positive and Her 2 neu negative [Figure 2]. Since patient had disease in the axilla and in the bones with cardiac comorbidity what line of (hormonal) therapy could be offered to this patient? She was 78 years old now with metastatic bone disease with osteoporosis due to disease and partly due to hormonal therapy. What will be the role of supportive therapy? Chemotherapy?? Patient was started on for Injection zoledronic acid and Injection fulvestrant. She could not afford palbociclib. She had rapid progression of disease to the lungs and died in the next 3 months.
Figure 1: Positron emission tomography showing fludeoxyglucose avid left axillary disease with skeletal metastases

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Figure 2: (a) Infiltrating ductal carcinoma. (b) Estrogen receptor positive staining in the tumor. (c) Progesterone receptor positive staining in the tumor. (d) Her2 neu negative staining in the tumor

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  Discussion Top


In patients with breast cancer extended use of hormonal therapy in the form of tamoxifen has reduced breast cancer mortality over 15 years. With 5 years of tamoxifen, its effect persists for a decade on the disease recurrence and mortality. Tamoxifen is used in premenopausal patients with breast cancer. Tamoxifen extended use has little effect on other mortality due to thromboembolic events and endometrial cancer. AIs, which are effective only in postmenopausal women and function by blocking the conversion of peripheral androgens to estrogens, are the second-line endocrine therapy of choice for postmenopausal metastatic breast cancer that progresses on tamoxifen. The level I evidence came from the adjuvant tamoxifen: longer against shorter trial. At a median follow-up of 7.6 years, it was seen that breast cancer recurrence and mortality were reduced more effectively during the second decade of 10 years of adjuvant tamoxifen as compared to 5 years. A UK study demonstrated little benefit during the year 5–9 but long term outcome is still awaited. The findings from both the studies are relevant to premenopausal patients. So what about the postmenopausal patients?

The role of extended use of AIs has not been observed or reported. MA.17 study in postmenopausal patients with breast cancer demonstrated that 5 years of letrozole after 5 years of tamoxifen significantly improved disease free (hazard ratio [HR]: 0.58, P < 0.001) and distant disease-free survival (DFS) (HR: 0.61, P = 0.04) at a median follow up of just 30 months. Overall survival (OS) was the same in both the arms. However, OS was significantly improved in patients with lymph node positive disease. The incidence of bone fractures and cardiovascular events was the same in both the arms.[5] Results of extended use of letrozole in MA.17 recently concluded that extension of treatment with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of DFS and a lower incidence of contralateral breast cancer than those with placebo, but the rate of OS was not higher with the aromatase inhibitor than with placebo.[6]

The NSABP B-33 trial included >1500 patients with a similar trial design using exemestane, a steroidal AI. At a median follow-up of 30 months, there was a significant improvement in relapse-free survival (96% vs. 94%, P = 0.004).[7] The index case demonstrates that the natural history of hormone-sensitive breast cancer may be quite long and extended use of AIs could be a good option in postmenopausal patients with hormone-responsive tumors. Although baseline ER and PR report were not available in this case, it responded to aromatase inhibitors one after another in a sequence. In the present case, the disease remained under control and even subsided as long as she took hormonal therapy with aromatase inhibitors. During interruption in hormonal therapy, the disease recurred. At first recurrence, she received letrozole for 1 year 3 months only but the disease remained under control for 3.5 years. At the time of the second recurrence, she was started on exemestane for 5 years but the disease progressed at the end of 4th year. Exemestane was continued for another year presuming it to be a hormone-responsive disease as disease in the axilla was stable. However, the disease recurred in the axilla for the third time, the bone scan at this point also revealed progressive disease so the hormonal therapy was changed to anastrozole. It was given for 1.5 years. Hence, a total she took hormonal therapy almost for 8 years. This case also demonstrates that micrometastatic cells resistant to one hormonal agent are source of subsequent recurrence and metastases can be targeted by another hormone to achieve long-term disease control in hormone receptor-positive tumors. This patient was also given local radiotherapy at the time of second recurrence, but she developed distant metastases after 4 years and then local recurrence which may reflect that hormonal resistant cells may not be sensitive to radiation or soil and seed theory might also explain this phenomenon.

Chemotherapy was not offered to this patient because there was no visceral crisis, old age, cardiac comorbidity, and disease only in the soft tissue and bones. She was not willing for chemotherapy either. The concern was also about the toxicity of extended use of aromatase inhibitors in the form of cardiac and skeletal events. Osteoporosis is a documented side effect of AIs because of estrogen depletion leading to decrease in bone mineral density. All patients on aromatase inhibitors should be monitored for osteoporosis and advised calcium and Vitamin D supplement. Bisphosphonates should be used in patients with high risk for fractures.

The next option for this patient could be fulvestrant, an estradiol analog that accelerates degradation of the estrogen receptor, and has been examined in combination with AIs with variable results.[8],[9] The other option could be AIs in combination with everolimus which has shown modest gain in terms of progression-free survival (PFS).[10] In addition, the CDK 4/6 inhibitor palbociclib in combination with AIs could also be a good option as reported in a study by Finn et al. where it has doubled PFS as compared to AIs alone (20.2 months versus 10.2 months).[11] Palbociclib was investigated in hormone receptor-positive metastatic disease with acquired resistance to endocrine therapy. In PALOMA-3 study, the median OS was 34.9 months (95% confidence interval [CI], 28.8–40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6–34.6) in the placebo–fulvestrant group (HR for death, 0.81; 95% CI, 0.64–1.03; P = 0.09; absolute difference, 6.9 months). The median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (HR, 0.58; 95% CI, 0.47–0.73; P < 0.001).[12] In the index case first, second, and third PFS was 42 months, 48 months, and 18 months, respectively. Hence, sequential hormonal therapy in ER/PR-positive tumors may be a good option if the patient is not able to afford palbociclib, which was demonstrated in this case.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet 2011;378:771-84.  Back to cited text no. 1
    
2.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687-717.  Back to cited text no. 2
    
3.
Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus more than 5 years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529-42.  Back to cited text no. 3
    
4.
Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 2013;381:805-16.  Back to cited text no. 4
    
5.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262-71.  Back to cited text no. 5
    
6.
Goss PE, Ingle JN, Prichard LI, Nicholas J Robert NJ, Muss H, Gralow J, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Eng J Med 2016;375:209-19.  Back to cited text no. 6
    
7.
Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: Intension-to-treat analysis of the national surgical adjuvant breast and bowel project B-33 trial. J Clin Oncol 2008;26:1965-71.  Back to cited text no. 7
    
8.
Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med 2012;367:435-44.  Back to cited text no. 8
    
9.
Bergh J, Jönsson PE, Lidbrink EK, Trudeau M, Eiermann W, Brattström D, et al. FACT: An open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012;30:1919-25.  Back to cited text no. 9
    
10.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 2015;16:25-35.  Back to cited text no. 10
    
11.
Verma S, Bartlett CH, Schnell P, DeMichele AM, Loi S, Ro J, et al. Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3) Oncologist. 2016;21:1165-75.  Back to cited text no. 11
    
12.
Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med 2018;379:1926-36.  Back to cited text no. 12
    


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