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01-06-2017 | Epidemiology

Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience

Authors: Mariangela Ciccarese, Alessandra Fabi, Luca Moscetti, Maria Elena Cazzaniga, Luciana Petrucelli, Rosachiara Forcignanò, Laura Isabella Lupo, Elisabetta De Matteis, Vincenzo Emanuele Chiuri, Giuseppe Cairo, Antonio Febbraro, Guido Giordano, Marianna Giampaglia, Domenico Bilancia, Nicla La Verde, Evaristo Maiello, Maria Morritti, Francesco Giotta, Vito Lorusso, Agnese Latorre, Claudio Scavelli, Sante Romito, Antonio Cusmai, Gennaro Palmiotti, Giammarco Surico

Published in: Breast Cancer Research and Treatment | Issue 3/2017

Abstract

Aim

This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability.

Methods

163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C).

Results

RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis.

Conclusions

No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

Theriault LR, Carlson RW, Alfred C, Anderson BO, Burstein HJ, Edge SB, Farrar BB, Forero A, Giordano SH, Goldstein LG, Gradishar WJ, Hayes DF, Hudis CA, et al. (2013) Breast Cancer version 3.2013: featured updates to the NCNN guidelines. J Natl Compr Cancer Netw 11:753–760 (quiz 761)

Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andrè F et al (2014) ESO-ESMO 2th International consensus guidelines for advanced breast cancer (ABC2). Ann Oncol 25:1871–1888CrossRefPubMedPubMedCentral

Boneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thurlimann B, Von Euler M, Sahmoud T, Webster A, Steinberg M (2001) Anastrozole is superior to tamoxifen as first line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92(9):2247–2258CrossRef

Nabholtz JM, Boneterre J, Buzdar A, Robertson JF, Thurlimann B (2003) Anastrozole (Arimidex) versus tamoxifen as first line therapy for advanced breast cancer in postmenopausal women: survival analysis and updated safety results. Eur J Cancer 39(12):1684–1689CrossRefPubMed

Mouridsen H, Gershanovich M, Sun Y, Perez Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP, Jaenicke F, Pluzanska A, Danl M, Becquart D, Bapsy PP, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyyld P, Bhatnagar A (2003) Phase III study of letrozole versus tamoxifen as first line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international letrozole breast cancer group. J Clin Oncol 21(11):2101–2109CrossRefPubMed

Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J, Therasse P (2007) Phase III study comparing exemestane with tamoxifen as first line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organization for research and treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 26(30):4883–4890CrossRef

Chia S, Gradishar W, Mauriac L, Bines F, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson John FR, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M (2008) Double blind randomized placebo controlled trial of fulvestrant compared with exemestane after prior non steroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor positive advanced breast cancer: results from EFECT. J Clin Oncol 26(10):1664–1670CrossRefPubMed

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko N, Rustem K, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JPO, Sapunar F, Martin M (2010) Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor positive advanced breast cancer. J Clin Oncol 28(30):4594–4600CrossRefPubMed

Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, Martin M (2014) Final overall survival: Fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst 106(1):1–7CrossRef

10.

Buzdar AU (2014) Phase III study of letrozole versus tamoxifen as first line therapy of advanced breast cancer in postmenopausal women: analysis of survival and updated of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 22:3199–3200CrossRef

11.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674CrossRefPubMed

12.

Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC et al (2012) The landscape of cancer genes and mutational processes in breast cancer. Nature 486:400–404PubMedPubMedCentral

13.

Miler TM, Hennessy BT, Gonzalez Angulo AM, Fax EM, Mils GB, Chen H et al (2010) Hyperactivation of phosphatydilinositol-3 kinase promotes escape from hormone receptor positive human breast cancer. J Clin Investig 120:2406–2413CrossRef

14.

Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Lialo JK (2000) Interaction of estrogen receptor with the regulatory submit of phospatydilinositol-3-OH kinase. Nature 407:538–541CrossRefPubMedPubMedCentral

15.

De Graffenned LA, Fulcher L, Friedrichs WE, Grunwald D, Ray RB, Hidalgo M (2004) Reduced pTen expression in breast cancer cells confers susceptibility to inhibitor of PI3k kinase/akt pathway. Ann Oncol 15:1510–1516CrossRef

16.

Baselga J, Campone M, Piccart M, Burris H, Rugo H, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrunn F, Beck T, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwhol D, Hortobagyi G (2012) Everolimus in postmenopausal Hormone receptor positive advanced breast cancer. N Engl J Med 366:520–529CrossRefPubMed

17.

Jackisch C, Grischke EM, Schneeweiss A, Decker T, Uleer C, Förster F, Tomé O, WimbergerP, Kurbacher C, Mueller B, Harbeck N, Mundhenke C, SherkoK, Muth M, Kreuzeder J, Bloch W, Tesch H, Lueftner D, Schütz F, Fasching P (2015) Subgroup analysis of efficacy in routine treatment—results of the 2nd interim analysis of BRAWO, the non-interventional trial “Breast Cancer Treatment With Everolimus and exemestane for HR+ woman” Abstract ♯ P 5-19, SABCS 2014 Congress

18.

Jerusalem G, Mariani G, Ciruelos EM, Martin M, Tjan-Heijnen VCG, Neven P, Gavila GJ, Michelotti A, Montemurro F, Generali D, Simoncini E, Lang I, Mardiak J, Naume J, Camozzi M, Lorizzo K, Bianchetti S, Conte P (2016) Safety of everolimus plus exemestane in patients with Hormone receptor positive Her-2 negative locally advanced or metastatic breast cancer progressing on prior non steroidal aromatase inhibitors: primary results of a phase 3b, open-label, single arm, expanded access multicenter trial BALLET. Ann Oncol 27(9):1719–1725CrossRefPubMed

19.

Cardoso F, Costa A, Norton L, Senkus L, Aapro M, Andrè F, Barrios CH, Bergh J, Biganzoli L, Blackwell L, Cardoso MJ, Cufer T, El Saghir N, Fallowfield L, Fenech D, Francis P, Gelmon K, Giordano SH, Gligorov J, Goldhirsch A, Harbeck N, Houssami N, Hudis C, Kaufman B, Krop I, Kyriakides S, Lin UN, Mayer M, Merjaver SD, Nordstrom EB, Pagani O, Partridge A, Penault-Lorca F, Piccart MJ, Rugo H, Sledge G, Thomssen C, Van’t Veer L, Vorobiof D, Vrieling C, West N, Xu B, Winer E (2014) ESO-ESMO 2^nd international consensus guidelines for advanced breast cancer (ABC2). Ann Oncol. 25(10):1871–1888CrossRefPubMedPubMedCentral

20.

Jatoi I, Chen BE, Anderson WF et al (2007) Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol 25:1683–1690CrossRefPubMed

21.

Partridge AH, Bryan R, Carey LA, Steven EC, Davidson NE, Di Leo A, Gralow J, Hortobagyi GH, Moy B, Yee D, Brundage SB, Danso MA, Wilcox M, Smith I (2014) Chemotherapy and targeted therapy for women with Human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Practice Guidelines. J Clin Oncol 32:3307–3329CrossRefPubMed

22.

Musgrove EA, Sutherland RL (2009) Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9:631–643CrossRefPubMed

23.

Piccart M, Hortobagyi GN, Campone M et al (2014) Everolimus plus exemestane for hormone receptor positive (HR+) human epidermal growth factor receptor-2 negative (Her-2) advanced breast cancer (BC): overall survival results from BOLERO-2. Eur J Cancer 50(Suppl 3):S1CrossRef

24.

Hortobagyi GN (2015) Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subset analyses from Bolero-2. Neoplasia 17(3):279–288CrossRefPubMedPubMedCentral

25.

Rugo HS (2016) Dosing and safety implications for oncologists when administering everolimus to patients with Hormone receptor positive breast cancer. Clin Breast Cancer 16(1):18–22CrossRefPubMed

26.

Hershman DL, Kushi LH, Buono D, Kershenbaum A, Tsai WY, Fehrenbacher L, Sl Gomez, Miles S, Neugut AI (2010) Early discontinuation and non adherence to adjuvant hormonal therapy in a cohort of 8769 early stage breast cancer patients. J Clin Oncol 28(27):4120–4128CrossRefPubMedPubMedCentral

27.

Yardley DA, Noguchi S, Pritchard KI, Burris HA III, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M et al (2013) Everolimus plus exemestane in postmenopausal patients with HR+ breast cancer: BOLERO-2 final progression free survival analysis. Adv Ther 30:870–884CrossRefPubMedPubMedCentral

28.

Rugo HS, Pritchard KI, Gnant M, Noguchi S, Piccart M, Hortobagyi GN, Baselga J, Perez A, Geberth M, Csoszi T et al (2014) Incidence and time course of everolimus related adverse events in postmenopausal women with hormone receptor positive advanced breast cancer insights from BOLERO-2. Ann Oncol 25:808–815CrossRefPubMedPubMedCentral

29.

Pritchard KI, Burris HA III, Yto I et al (2013) Safety and efficacy of everolimus with exemestane versus exemestane alone in elderly patients with Her-2 negative hormone receptor positive breast cancer in BOLERO-2. Clin Breast Cancer 13:421–432CrossRefPubMed

30.

Ravaud A, ShwetaRU, Grosch K, Wing KC, Oezlem A, Sellami DB (2013) Metanalysis on the relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology. Published online December 2013

31.

Anglicheau D, Legendre C, Beaune P et al (2007) Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics 8:835–849CrossRefPubMed

32.

Johnell K, Klarin I (2007) The relationship between number of drugs and potential drug-drug interactions in the elderly: a study of over 600000 elderly patients from the Swedish Prescribed drug Register. Drug Saf 30(10):911–918CrossRefPubMed

33.

Balducci L, Goetz-Parten D, Steinman MA (2013) Polypharmacy and the management of the older cancer patient. Ann Oncol 24(Suppl 7):vii36–vii40CrossRefPubMed

Title: Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience
Authors: Mariangela Ciccarese
Alessandra Fabi
Luca Moscetti
Maria Elena Cazzaniga
Luciana Petrucelli
Rosachiara Forcignanò
Laura Isabella Lupo
Elisabetta De Matteis
Vincenzo Emanuele Chiuri
Giuseppe Cairo
Antonio Febbraro
Guido Giordano
Marianna Giampaglia
Domenico Bilancia
Nicla La Verde
Evaristo Maiello
Maria Morritti
Francesco Giotta
Vito Lorusso
Agnese Latorre
Claudio Scavelli
Sante Romito
Antonio Cusmai
Gennaro Palmiotti
Giammarco Surico
Publication date: 01-06-2017
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4213-9

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