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  Table of Contents  
Year : 2016  |  Volume : 53  |  Issue : 3  |  Page : 464-467

Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication24-Feb-2017

Correspondence Address:
J Bajpai
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.200657

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 » Abstract 

BACKGROUND: Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. MATERIALS AND METHODS: A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AI's) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken. RESULTS: There were 41 patients with median age 55 years, 73% with visceral metastasis, and 73% with ≥2 sites of metastases. Thirty (73%) patients had received 3 prior lines of therapy including AI (100%), tamoxifen (94%), fulvestrant (39%), and chemotherapy (100%) while the remaining had received <3 lines of prior therapy. The commonest Grade 3/4 adverse events were stomatitis (19%), hyperglycemia (new/worsening, 17%), fatigue (14.5%), nonneutropenic infections (14%), anemia (12%) and pneumonitis (7%). Everolimus dose reductions were required in 31% patients. There were 30% partial responses, 38% prolonged disease stabilizations and 32% disease progression as best responses to everolimus. The median progression-free survival was 22 weeks (5 months). CONCLUSIONS: Everolimus based treatment has meaningful activity in heavily pretreated patients with HR-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

Keywords: Everolimus, India, metastatic breast cancer

How to cite this article:
Bajpai J, Ramaswamy A, Gupta S, Ghosh J, Gulia S. Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?. Indian J Cancer 2016;53:464-7

How to cite this URL:
Bajpai J, Ramaswamy A, Gupta S, Ghosh J, Gulia S. Everolimus in heavily pretreated metastatic breast cancer: Is real world experience different?. Indian J Cancer [serial online] 2016 [cited 2019 Dec 9];53:464-7. Available from:

 » Introduction Top

Hormone receptor (HR)-positive tumors constitute about 75% of patients with metastatic breast cancer (MBC).[1] Endocrine therapy (ET) constitutes the major component of treatment in this subgroup of MBCs.[2],[3],[4]

ET are standard of care for HR+ tumors; however, not all patients have a response to first-line ET (primary or de novo resistance), and most of the responders will also eventually become resistant to ET (acquired or secondary resistance).[5],[6],[7],[8] One of the purported mechanisms of ET resistance is explained by “cross-talk” between the growth factor receptor and ER pathways.[6] Aberrant signaling via the mammalian target of rapamycin (mTOR) signaling pathway is one of the key regulators for the resistance; it regulates transcription and translation by phosphorylating downstream proteins, including the 40S ribosomal protein S6. S6 kinase 1, phosphorylates the activation function domain 1 of the ER, causing ligand-independent receptor activation and further resistance to ET.[9],[10] Everolimus is an mTOR inhibitor that has shown activity in Phase 2 trial with tamoxifen (TAMRAD)[11] and later, a Phase 3 trial with exemestane (BOLERO 2).[12],[13]

However these trial populations have an under-representation of Asian population (BOLERO 2:20%)[12] and no representation from India and may not be a true representation of the real world scenario (100% patients Eastern cooperative oncology group performance status <2, low tumor burden, less number of prior therapies). Pharmacogenomic differences are also a well-recognized factor for differential efficacy and toxicity profile of various agents, as seen with tyrosine kinase inhibitors in lung.[14],[15]

Thus, we conducted this retrospective study in HR-positive MBC patients who have progressed on aromatase inhibitors (AI's) and then had received everolimus with ET. The primary aim was to evaluate its pattern of usage, tolerance and clinical benefit in the real world scenario in India.

 » Materials and Methods Top

A retrospective review of clinical evaluation and treatment records, including electronic data for all the patients, was carried out, and stored on an anonymous database for analysis.

Patients from March 2012 to June 2014, who received everolimus with ET for a duration of at least 2 weeks were included for analysis. All patients should have progressed or, at least, received an AI as previous treatment. Response rates were measured by RECIST criteria or by clinical examination. Toxicity was recorded as per NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0. Patients in whom responses could not be measured (early stoppage due to toxicity or other reasons) had their data used for toxicity analysis.

Statistical analysis

Standard summary statistics were used for continuous and discrete variables. Response rates-complete response (CR), partial response (PR), stable disease (SD) and clinical benefit rates (CBR = CR, PR and SD) were calculated. The associations and prognostic factors evaluated were, baseline metastatic versus nonmetastatic, number of metastatic sites (n ≤ 2 vs. n > 2), number of prior therapies (n ≤ 3 vs. n > 3), grade of tumor, Her2 status, progression-free survival (PFS) on therapy prior to everolimus, and accompanying type of ET. These factors were analyzed by the Chi-square test or Fisher exact test, as required. PFS was calculated by the Kaplan–Meier product-limit method. PFS was calculated from date of first dose of Everolimus to date of documented progression or last date of follow-up. Cutoff date for entry into analysis was June 2014.

 » Results Top

A total of 41 patients with ER-positive MBC, pretreated with at least one prior line of AI's, were started on Everolimus with ET. Main patient and tumor characteristics are reported in [Table 1]. The median age was 54 years, (range: 31–67), with 15 patients (37%) being metastatic at baseline while 26 (63%) patients had progressed on or after adjuvant therapy in the curative setting.
Table 1: Baseline characteristics

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The commonest sites of disease was bone in 30 (73%) patients, followed by loco regional disease in 27 (65.9%), nodal sites in 24 (58%), lung parenchyma in 20 (50%), liver in 19 (46%), pleural effusion in 10 (24%), and adrenal in 5 (12.2%) patients, respectively.

Thirty patients (73%) had received more than three lines of prior therapy while 11 patients (27%) received three or fewer lines of prior treatment. Majority of the patients had progressed after a short progression free interval on prior therapy, including 13 (32%) within 3 months, 8 (19.5%) within 6 months, 12 (29%) between 6 months to a year of prior therapy and 8 (19.5%) had a progression free interval of more than 1 year.

The starting dose of everolimus in 21 (51%) of the patients was 10 mg per oral per day; 16 (39%) were started on 5 mg/day and 4 (10%) were started on alternating doses of 10 mg and 5 mg/day.

Responses were evaluable in 34 patients [Table 2]. In seven patients, everolimus was discontinued early due to severe toxicity before any pertinent response to treatment could be evaluated or because there was no documentation of response as per the records. PFS, as stated earlier was calculated for all 41 patients.
Table 2: Response rates and progression-free survival

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The CBR was 68% (23/34) with PRs seen in 10 (29%), SD status in 13 (39%) patients, and progressive disease on everolimus in 11 patients (32%) patients. Response rates were maintained across all subgroups, with no significant differences in the various prognostic factors we assessed. Both Her2 positive patients achieved clinical benefit while CBR in Her2 negative subgroup was seen in 21 patients (65.6%). Median PFS in our patients was 22 weeks, (range 3–76 weeks) [Figure 1]. There were no significant differences in PFS between the different subsets and prognostic factors we tested for. Patients who had progression-free interval of >1 year on their prior therapy, had a PFS of 30 weeks, which was greater than those patients who had progressed in a shorter duration.
Figure 1: Kaplan–Meier curve of progression free survival

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Toxicity analysis [Table 3] was available for all 41 patients. The most common adverse effect noted was oral mucositis, with eight patients (19%) having Grade 3/4 mucositis and ten patients (24%) having Grade 1/2 mucositis. New onset hyperglycemia or worsening preexisting hyperglycemia was seen in 18 patients (43%) patients – these patients required further medications/insulin for control of sugar levels. However, no patient had any episode of diabetic ketoacidosis or hyperosmolar nonketotic acidosis. All grades of dyslipidemias or worsening of preexisting dyslipidemias requiring increased doses or addition of anti-lipemic medications was seen in 36.5% (15/41) of patients. Neutropenia was seen in 9.7% (4/41) with no episodes of febrile neutropenia in our patients. Nonneutropenic infections were seen in 9 (21%) patients, with pneumonia, cellulitis, and symptomatic urinary tract infections being common. 6 of them (14%) were Grade 3/4 infections – none of this caused cessation of treatment.
Table 3: Toxicity

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Fatigue of all grades was seen in ten patients (24%) with Grade 3/4 in six patients (14.5%) and it required dose reduction in three patients. Noninfectious pneumonia is one of the class side-effects of everolimus, and is diagnosed clinically with radiological concordance; this was diagnosed in seven patients (17%) and necessitated permanent termination of everolimus in 2 (5%) patients. One patient had Grade IV renal toxicity requiring cessation of treatment.

Toxicity requiring dose modifications [Table 4] occurred in 13 (31%) of patients. The most common causes being Grade 3/4 mucositis (23%), Grade 3/4 fatigue (23%) and uncontrolled hyperglycemia (23%). Other causes include Noninfectious pneumonia (15%), renal toxicity (8%) and multiple Grade 2 toxicities in 8% patient.
Table 4: Dose reduction and causes

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 » Discussion Top

As we look at newer therapies in oncology, the reproducibility of trial data in real world population is an increasing concern, with confirmation of trial data essential before using the same in clinical practice. One of the reasons for this difference is that patients in a real world population have greater co-morbidities, lesser monitoring and are more heterogeneous, compared to trial patients. It is here that retrospective data and observational data like the one presented here play a role.

While a Phase 3 trial with temsirolimus and letrozole (using a cyclical dosing regimen) versus letrozole alone as first-line therapy in advanced Ca breast did not show any benefit,[16],[17] subsequent trials found evidence of reversal of endocrine resistance. The TAMRAD trial showed an improvement in CBR (61% vs. 42%) and increase in TTP (8.6 months vs. 4.5 months) for the combination of everolimus and tamoxifen versus tamoxifen alone.[11] Further confirmation of benefit came from the BOLERO trials. BOLERO 2 showed a PFS of 7.8 months for the combination of everolimus and exemestane versus 3.2 months for single agent exemestane.[12] Although not quoted by the study, the proportion of patient achieving a clinical benefit was approximately 80% (PR 9.1%, SD: 70.9%, CR 0.4%) – Our study showed a comparable CBR of 67%, with a higher proportion of patients achieving PR (29%) in a more heavily pretreated population compared to the seminal study. The median PFS obtained in our study was 22 weeks (5 months), which is lower when compared to the BOLERO 2 trial. The PFS data from our study is also comparable to the PFS data obtained from patients on standard dose fulvestrant, (3.7 months), though lower than PFS on high-dose fulvestrant (6.5 months).[18] A subset analysis of Asian patients by Noguchi [19] showed that the combination of everolimus plus exemestane was equally efficacious in the Asian population, with a similar side-effect profile (with the possible exception of an increased incidence of interstitial pneumonia), lending further credence to the activity of this combination across ethnicities.

The preliminary results from the BRAWO study [20] indicate that up to 53% of patients starting on 10 mg/day and 23% of patients starting on 5 mg/day of everolimus required dose reduction, although dose intensity was maintained in 81% and 53%, respectively. About 31% of our patients required a dose reduction, with toxicity being the major cause of reduction. Toxicity is a major concern with everolimus, especially as hormonal agents themselves are very well tolerated. Our analysis shows that everolimus while being efficacious requires careful monitoring. We saw a high incidence of noninfectious pneumonia (17%), much higher than previously reported. The incidence of metabolic side-effects – hyperglycemia and dyslipidemias (43% and 36.5 respectively) was also markedly higher than the BOLERO 2 trial (hyperglycemia 17%).[12] We contend that this is an extension of the preexisting higher baseline diabetic and dyslipidemic status seen in a real world population compared to a trial population. Another possibility that should be entertained is the possibility of genetic polymorphisms that may exist regarding the metabolism of everolimus in Indian patients.

The main weakness of this study is the small sample size and the retrospective nature of the study. We are also unable to offer explanations for the higher incidence of certain side effects in our analysis, besides the study population being representative of a real world population. Measures taken to reduce the adverse effects have also not been commented upon, partly because of the heterogeneous nature of treatment offered for these complications.

The major strength of this analysis is its accurate representation of a real world population, quite unlike the populations who are taken up for clinical trials. The increased incidence of metabolic as well as other toxicities serves as a reminder of the gap between trial data and clinical practice when using everolimus. The results here are also more likely to be indicative of expected usage, outcomes, and toxicities in an Indian population where the cost of everolimus may be an issue when deciding treatment.

This is the first data set on everolimus in India, and we hope this furthers our understanding of everolimus in ER-positive MBC. We conclude by reiterating that everolimus offers an efficacious treatment option in heavily pretreated hormone positive MBC's with meaningful clinical benefit, but this should be measured against the potential for increased toxicity.

 » Conclusions Top

Everolimus-based treatment has meaningful activity in heavily pretreated patients with ER-positive MBC but is associated with considerable toxicity and requirement for dose adjustment.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

Clark GM, Osborne CK, McGuire WL. Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 1984;2:1102-9.  Back to cited text no. 1
Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431-42.  Back to cited text no. 2
Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: Results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-606.  Back to cited text no. 3
Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis. J Natl Cancer Inst 2006;98:1285-91.  Back to cited text no. 4
Lopez-Tarruella S, Schiff R. The dynamics of estrogen receptor status in breast cancer: Re-shaping the paradigm. Clin Cancer Res 2007;13:6921-5.  Back to cited text no. 5
Munzone E, Curigliano G, Rocca A, Bonizzi G, Renne G, Goldhirsch A, et al. Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 2006;8:R4.  Back to cited text no. 6
Encarnación CA, Ciocca DR, McGuire WL, Clark GM, Fuqua SA, Osborne CK. Measurement of steroid hormone receptors in breast cancer patients on tamoxifen. Breast Cancer Res Treat 1993;26:237-46.  Back to cited text no. 7
Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, et al. Molecular changes in tamoxifen-resistant breast cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 2005;23:2469-76.  Back to cited text no. 8
Yamnik RL, Holz MK. mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett 2010;584:124-8.  Back to cited text no. 9
Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem 2009;284:6361-9.  Back to cited text no. 10
Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 2012;30:2718-24.  Back to cited text no. 11
Baselga J, Campone M, Piccart M, Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone receptor-positive advanced breast cancer (BOLERO 2). N Engl J Med 2012;366:520-9.  Back to cited text no. 12
André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2014;15:580-91.  Back to cited text no. 13
Wu YL, Liao ML, Qin SK, Sun Y, Zhou CC. Efficacy and safety of erlotinib in the treatment for advanced non-small cell lung cancer in Chinese patients. Zhonghua Zhong Liu Za Zhi 2010;32:148-51.  Back to cited text no. 14
Wu YL, Kim JH, Park K, Zaatar A, Klingelschmitt G, Ng C. Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: A subanalysis of the phase III, randomized SATURN study. Lung Cancer 2012;77:339-45.  Back to cited text no. 15
Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 2011;62:233-47.  Back to cited text no. 16
Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 2013;31:195-202.  Back to cited text no. 17
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT. J Clin Oncol 2008;26:1664-70.  Back to cited text no. 18
Noguchi S, Masuda N, Iwata H, Mukai H, Horiguchi J, Puttawibul P, et al. Efficacy of everolimus with exemestane versus exemestane alone in Asian patients with HER2-negative, hormone-receptor-positive breast cancer in BOLERO-2. Breast Cancer 2014;21:703-14.  Back to cited text no. 19
Lueftner D, Schuetz F, Grischke E. Breast cancer treatment with everolimus and exemestane for ER+ women: Results of the first interim analysis of the non interventional trial BRAWO. J Clin Oncol 2014;32:5s. [Suppl; abstr 578].  Back to cited text no. 20


  [Figure 1]

  [Table 1], [Table 2], [Table 3], [Table 4]


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