|REAL WORLD DATA
|Year : 2020 | Volume
| Issue : 2 | Page : 275-280
Fulvestrant in hormone-positive advanced breast cancer: Real-world outcome
Indhuja Muthiah Vaikundaraja1, Manikandan Dhanushkodi1, Venkatraman Radhakrishnan1, Jayachandran Perumal Kalaiarasi1, Nikita Mehra1, Arun Kumar Rajan1, Gangothri Selvarajan1, Siva Sree Kesana1, Balasubramanian Ananthi2, Priya Iyer2, Geetha Senguttuvan2, Manjula Rao3, Arvind Krishnamurthy3, Sridevi Velusamy3, Hemanth Raj3, Rama Ranganathan4, Shirley Sundersingh5, Selvaluxmy Ganesarajah2, Trivadi S Ganesan1, Tenali Gnana Sagar1
1 Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
2 Department of Radiation Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
3 Department of Surgical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
4 Department of Epidemiology and Biostatistics, Cancer Institute (WIA), Chennai, Tamil Nadu, India
5 Department of Oncopathology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Submission||18-Feb-2020|
|Date of Decision||17-Mar-2020|
|Date of Acceptance||02-Apr-2020|
|Date of Web Publication||19-Jun-2020|
Department of Medical Oncology, Cancer Institute (WIA), Sardar Patel Road, Chennai - 600 036, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Fulvestrant has been shown to improve survival in hormone-positive, HER2-negative advanced breast cancer (ABC). There is no study on fulvestrant from India.
Objectives: This study was done to assess the prognostic factors and outcome of patients with ABC treated with fulvestrant.
Materials and Methods: This was a retrospective study from the case records of patients who received fulvestrant for hormone receptor (HR)-positive breast cancer from May 2011 to July 2019.
Results: A total of 37 women were included in this analysis, with a median follow-up of 9 months. The median age was 63 years. The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0–2 (78%) and 3–4 (22%). The sites of metastasis were bone (59%), lung (43%), liver (32%), lymph node (24%), and bone only (20%). Patients with visceral metastasis and visceral crisis constituted 60% and 13%, respectively. The median number of lines of prior systemic therapy for metastatic disease was 2 (range, 0–6). The dose of fulvestrant used was 500 mg in 76% and 250 mg in 24%. There were no Grade 3 or 4 toxicities due to fulvestrant. The median progression-free survival and overall survival were 10 months (95% confidence interval [CI], 4–15.9 months) and 21 months (95% CI, 8.9–33.1 months), respectively. Univariate analysis showed that patients with ECOG PS 3–4 had a worse survival as compared to patients with PS 0–2.
Conclusion: This is the first study on the outcomes of fulvestrant in advanced breast cancer from India. Fulvestrant is safe, well-tolerated, and effective in patients with hormone-positive ABC. Fulvestrant can be recommended even in heavily pretreated HR-positive advanced breast cancer and in those with a poor general condition (ECOG PS 3 or 4) who are ineligible for chemotherapy.
Keywords: Advanced breast cancer, fulvestrant, hormone positive
|How to cite this article:|
Vaikundaraja IM, Dhanushkodi M, Radhakrishnan V, Kalaiarasi JP, Mehra N, Rajan AK, Selvarajan G, Kesana SS, Ananthi B, Iyer P, Senguttuvan G, Rao M, Krishnamurthy A, Velusamy S, Raj H, Ranganathan R, Sundersingh S, Ganesarajah S, Ganesan TS, Sagar TG. Fulvestrant in hormone-positive advanced breast cancer: Real-world outcome. Cancer Res Stat Treat 2020;3:275-80
|How to cite this URL:|
Vaikundaraja IM, Dhanushkodi M, Radhakrishnan V, Kalaiarasi JP, Mehra N, Rajan AK, Selvarajan G, Kesana SS, Ananthi B, Iyer P, Senguttuvan G, Rao M, Krishnamurthy A, Velusamy S, Raj H, Ranganathan R, Sundersingh S, Ganesarajah S, Ganesan TS, Sagar TG. Fulvestrant in hormone-positive advanced breast cancer: Real-world outcome. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Jul 7];3:275-80. Available from: http://www.crstonline.com/text.asp?2020/3/2/275/287251
| Introduction|| |
Fulvestrant is a selective estrogen receptor degrader (SERD) that binds, blocks, and degrades the estrogen receptor (ER), leading to complete inhibition of estrogen signaling through the ER. In 2002, fulvestrant was approved for patients with hormone receptor (HR)-positive advanced breast cancer (ABC) who had progressed on tamoxifen. Fulvestrant at a dose of 500 mg as compared to 250 mg was shown to improve overall survival (OS) by 3 months in HR-positive ABC. Fulvestrant (250 mg) has similar efficacy as compared to anastrozole in patients who had progressed on prior endocrine therapy., Fulvestrant (500 mg) with an extra loading dose on day 14 was shown to improve progression-free survival (PFS) by 3 months as compared to anastrozole as first-line therapy for hormone-positive ABC. Fulvestrant overcomes the acquired resistance due to endocrine therapy (ESR1 [ER mutation]).
Fulvestrant in combination with anastrozole has been shown to improve OS by 10 months as compared to anastrozole alone. In combination with cyclin-dependent kinase (CDK) 4/6 inhibitors (palbociclib, ribociclib, and and abemaciclib), fulvestrant has been shown to improve survival in HR-positive, HER2-negative advanced breast cancer. The combination of fulvestrant with alpelisib, has been shown to improve PFS in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase-mutated catalytic subunit alpha (PIK3CA) and HR-positive, HER2-negative ABC. Network meta-analysis has shown that palbociclib in combination with fulvestrant had a superior PFS as compared to other fulvestrant-based combinations.
Unfortunately, the majority of the patients in India cannot afford newer drugs such as CDK 4/6 inhibitors and PIK3CA inhibitors and have inferior survival., Fulvestrant is a potential treatment option in this subset of patients. There is no published study with fulvestrant from India. We did this study to assess the prognostic factors and outcome of patients treated with fulvestrant.
| Materials and Methods|| |
This study was done in the Department of Medical Oncology in Cancer Institute (WIA), Chennai, a tertiary care cancer center in South India. Data were captured from the case records of patients who received fulvestrant from May 2011 to July 2019. The patient list was retrieved from the electronic medical records (EMRs) by checking the number of patients for whom the fulvestrant prescription was given. At our institution, all case records registered from 1954 to 2016 and records of expired patients are scanned. We obtained the data from the scanned files from EMR. For alive patients registered after 2016, we obtained data from the individual case record procured from the tumor registry. This was a retrospective analysis. As per our institutional policy, retrospective studies do not require permission from the ethics committee. The study was conducted according to various guidelines for the ethical conduct of studies, including the Declaration of Helsinki, good clinical practice guidelines, and the Indian Council of Medical Research.
The inclusion criteria were patients with ABC, HR-positive status, ER, or progesterone receptor (PR) positive who received fulvestrant. ER and PR were tested using immunohistochemistry (IHC) with the Allred score; ≥1% was taken as positive. HER2 was tested using IHC; 2 + was considered positive if fluorescent in situ hybridization was positive. The exclusion criteria were patients who had taken less than two doses of fulvestrant and those who were lost to follow-up. Fulvestrant was administered at 250 mg or 500 mg intramuscularly on days 1, 15, and 29 and monthly thereafter until disease progression. Patients were assessed clinically for response and toxicity before each cycle. Imaging was done with either chest X-ray, ultrasound of the abdomen/pelvis, or positron imaging tomography–computed tomography once every 3–4 months and when clinically indicated. Responses were assessed as per the Response Evaluation Criteria in Solid Tumors, version 1.1 criteria. Toxicity was graded as per the Common Terminology Criteria for Adverse Events, version 4.0.
Statistical analysis was performed using the Statistical Package for the Social Sciences software version 15 (SPSS, Chicago, IL, USA). Descriptive statistics were used to analyze the baseline characteristics. PFS was calculated from the date of initiation of fulvestrant to the date of recurrence or death. OS was calculated from the date of the initiation of fulvestrant to the date of death due to any cause. Survival was estimated by the Kaplan–Meier method and compared across groups using the log-rank test. Cox proportional hazards model was used to find the prognostic factors affecting the outcome., All P values were two-sided, and values <0.05 were considered significant.
| Results|| |
A total of 37 women are included in this analysis [Figure 1], with a median follow-up of 9 months (range, 1–112 months). The median duration from diagnosis to the start of fulvestrant was 66 months (range, 7–257 months). The median age at presentation was 63 years (range, 45–90 years). HER2-positive disease constituted 33%. The most common sites of metastasis were bone, followed by lung. Patients with visceral metastasis and visceral crisis constituted 60% and 13%, respectively. The median number of sites of metastasis was 1 (range, 1-4).
|Figure 1: The flowchart of patients enrolled in the study evaluating the use of fulvestrant for hormone receptor positive advanced breast cancer|
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The median number of lines of prior systemic therapy for metastatic disease was 2 (range, 0–6). The median number of lines of prior endocrine therapy for metastatic disease was 1 (range, 1–3). Among patients with HER2-positive disease, 42% (n = 5/12) had received prior anti-HER2 therapy. Two patients had received fulvestrant as the first-line therapy. The dose of fulvestrant used was 500 mg in 76% and 250 mg in 24%. Fulvestrant was used as a single agent and as part of a combination regimen in 62% and 38%, respectively [Table 1]. The most common agent used in combination with fulvestrant was exemestane (4/14).
Response and survival
The response to fulvestrant was complete response, partial response, stable disease, progressive disease, and unknown in 0%, 11%, 30%, 19%, and 40%, respectively. There were no grade 3 or 4 toxicities due to fulvestrant. The median PFS [Figure 2] and OS [Figure 3] were 10 months (95% confidence interval [CI], 4–15.9 months) and 21 months (95% CI, 8.9–33.1 months), respectively. The 1-year PFS and OS were 41% and 64%, respectively. The systemic therapies used after progression on fulvestrant were capecitabine (n = 4, 33%), exemestane (n = 4, 33%), tamoxifen (n = 3, 26%), and palbociclib + tamoxifen (n = 1, 8%).
|Figure 2: Kaplan–Meier analysis showing progression-free survival of 37 patients with hormone receptor-positive advanced breast cancer who received fulvestrant. The median progression-free survival was 10 months (95% confidence interval, 4–15.9 months)|
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|Figure 3: Kaplan–Meier analysis showing overall survival of 37 patients with hormone receptor-positive advanced breast cancer who received fulvestrant. The median overall survival was 21 months (95% confidence interval, 8.9–33.1 months)|
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Univariate analysis [Table 2] was done with variables including age, PS, site of metastasis, type of metastasis, fulvestrant dose, HER2 status, and prior lines of therapy with correlation with survival. Patients with ECOG PS 3–4 as compared to PS 0–2 had worse survival (Hazard Ratio: 2.77; 95% CI, 1.1–7.0; P = 0.03).
|Table 2: Univariate analysis with correlation with progression-free survival|
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| Discussion|| |
Our study provides real-world evidence of patients treated with fulvestrant in HR-positive ABC. We found that the response to fulvestrant in patients with relapsed HR-positive ABC was 11%, with no grade 3 or higher toxicities and a median PFS of 10 months (95% CI, 4–15.9) and a median OS of 21 months (95% CI, 8.9–33.1). We included patients with poor performance status (PS 3 and 4), HER2-positive disease, extensive visceral metastasis, visceral crisis, and patients who had been heavily pretreated (median two prior lines of therapy) subset. There are no published studies on the efficacy, toxicity, and outcomes of fulvestrant from India.
The FALCON Phase III randomized controlled trial (RCT) excluded patients with ECOG PS 3 or 4, HER2-positive subset, life-threatening/metastatic visceral metastasis, previous hormonal therapy, and >1 line of chemotherapy. The CONFIRM Phase III RCT excluded patients with brain/leptomeningeal metastasis, extensive liver/lung metastasis, and >1 line of prior chemotherapy/hormonal therapy for advanced disease. Our study included these categories of patients as it reflects our real-world practice.
In our study, the response rate to fulvestrant was minimal (11%) as the majority of the patients had prior exposure to endocrine therapy with a median of two lines of prior therapy for metastatic disease. Our results are comparable to the CONFIRM trial where the response rate was 9% with fulvestrant 500 mg dose and 10% with 250 mg dose. In endocrine-naïve patients (FALCON trial), the response to fulvestrant was 40%.
The PFS and OS in our study were 10 and 21 months, respectively. Two RCTs from the USA  and UK  with fulvestrant 250 mg dose reported a median PFS of only 5 months. A study from China showed that PFS of first-line, second-line, and third-line fulvestrant was 15, 7, and 5 months, respectively. A prospective study from Germany also showed that patients had longer PFS if fulvestrant was used in the first line as compared to later lines. The FALCON trial  and a study from Japan  showed that patients with nonvisceral metastasis had a longer PFS with fulvestrant. An RCT showed that tamoxifen and fulvestrant (250 mg dose) had similar efficacy in patients with endocrine-naïve ABC. A retrospective study from the US in hormone-positive ABC treated with fulvestrant showed a PFS of 8 and 15 months in early and late relapses, respectively. A retrospective study in hormone-positive ABC showed better PFS with everolimus as compared to fulvestrant. There is a paucity of studies in HR-positive ABC from India. A study from Tata Memorial Hospital in Mumbai in which everolimus was used in patients with heavily pretreated breast cancer showed a response rate of 30% and a median PFS of 5 months.
A meta-analysis of 1,530 Chinese patients with ABC showed that 28% of tumors harbored ESR1 mutation, and those who were treated with an aromatase inhibitor had a worse outcome. Patients with ESR1 mutation have improved PFS when treated with fulvestrant as compared to an aromatase inhibitor. The mechanisms of resistance to fulvestrant could be related to PIK3CA mutation, estrogen-independent growth factor signaling, stimulated downstream kinase, and altered cell cycle mediators. Newer SERDs including orally active drugs (GDC-0810/AZD9694) are under evaluation.
A study from the UK among patients with ABC receiving endocrine therapy showed that the majority (63%) preferred oral therapy as compared to injectable therapy (26%). However, the drawback of long-term oral endocrine therapy is the lack of adherence to treatment. Cost-effectiveness was assessed in a study from the UK using the Markov cohort simulation model in patients who received fulvestrant as second-line or third-line therapy and demonstrated the cost-effectiveness when fulvestrant was added to the treatment sequence. A study from Sweden using three-state (preprogression, postprogression, and death) partitioned survival model showed that fulvestrant 500 mg was a cost-effective alternative to an aromatase inhibitor. In India, generic drugs have significantly resulted in cost reduction and increased usage of anticancer drugs.
Options for systemic therapy after progression on fulvestrant include capecitabine and exemestane plus everolimus. CDK 4/6 inhibitors in combination with hormonal therapy have shown to significantly improve survival in the first-line and second-line setting. However, the limitation is the prohibitive cost. Fulvestrant is a cost-effective option for patients who cannot afford CDK 4/6 inhibitors.
Univariate analysis showed that patients with poor ECOG PS (3–4) had a worse outcome. The ECOG PS of a patient has been shown to correlate with survival. The other factors such as fulvestrant dose, HER2 status, and site of metastasis were not significant possibly, due to the lower number.
The limitations of our study are the retrospective nature, small numbers, single-institutional study, and lack of ESR1 mutational analysis.
| Conclusion|| |
This is the first study on the use of fulvestrant in advanced breast cancer from India. Fulvestrant is a safe, well-tolerated, and effective treatment option in patients with HR-positive ABC. It can be recommended even in heavily pretreated HR-positive advanced breast cancer. Fulvestrant could be a treatment option in patients with a poor general condition (ECOG PS 3 or 4) who are ineligible for chemotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]