Background
Adjuvant endocrine therapy significantly prolongs disease-free and overall survival in women with hormone-receptor-positive early breast cancer, but it is associated with several side effects, which may lead to early treatment cessation [
1‐
3]. In the combined analysis of the Tamoxifen and Exemestane Trial (TEXT) and Suppression of Ovarian Function Trial (SOFT) [
4], comparing adjuvant exemestane plus ovarian function suppression (OFS) with tamoxifen plus OFS in premenopausal patients with breast cancer, early cessation of OFS and the assigned oral endocrine treatment occurred in 16 % of patients receiving exemestane + OFS and 11 % of those receiving tamoxifen + OFS. Nonetheless, exemestane + OFS significantly improved disease outcome compared to tamoxifen + OFS after 5.7 years median follow up.
The acute onset of menopause induced by gonadotropin-releasing-hormone analogues (GnRHa) is associated with more frequent and severe side effects compared to natural menopause, significantly impacting the quality of life of young patients with breast cancer [
5]. The most common side effects associated with early menopause include vasomotor symptoms (hot flashes and sweating), decreased libido, insomnia, and dyspareunia secondary to vaginal dryness. The frequency and severity of hot flashes may depend on the abrupt fall in circulating estrogen levels as observed in several studies among women undergoing a natural menopausal transition [
6‐
8], although other factors also play a role [
9,
10]. While chemotherapy, OFS, and aromatase inhibitors (AIs) directly lower circulating estrogen levels, tamoxifen, a selective estrogen receptor modulator, has both agonistic and antagonistic effects on estrogen signaling [
11]. In addition to menopausal symptoms, AIs are frequently associated with joint and muscle pain [
12], decreased bone density [
13] and risk of fracture [
3], which appears to increase with better compliance with AIs [
14].
Common genetic polymorphisms of the genes involved in estrogen production and estrogen target genes have been linked to breast cancer risk, prognosis, treatment response and side effects. One of these genes, the
CYP19A1, encodes for the enzyme aromatase that promotes the bioconversion of androgens to estrogens. Genetic variations at the
CYP19A1 locus may result in increased or decreased aromatase activity and influence concentrations of circulating estrogens [
15‐
17]. For example, the rs10046 and rs4646 variants, located in a 3’ untranslated region, were associated with higher estradiol and estrone levels due to increased aromatase activity. Alternatively, these variants could be linked with other gene variants such as the rs749292, which is associated with even higher estrogen levels [
17]. A recent review and meta-analysis analyzed the influence of common
CYP19A1 polymorphisms on postmenopausal patients with breast cancer treated with AIs [
18], indicating a certain heterogeneity between studies.
The estrogen receptor α (
ESR1) gene was recently recognized as a low-penetrance breast cancer susceptibility gene. Numerous studies suggest an association between
ESR1 gene polymorphisms and breast cancer risk [
19]. However, results have been controversial due to heterogeneous data sources, differences in study designs, ethnic background, disease status, and sample size.
ESR1 is an important mediator of endocrine pathways involved in breast cancer risk and outcomes, including endocrine treatment response and side effects. Genetic polymorphisms altering the expression of
ESR1 have been suggested to affect breast cancer susceptibility [
20]. In particular, the restriction enzymes XbaI (rs9340799) and PvuII (rs2234693) have been extensively evaluated. Both are located in the first intron of the
ESR1 gene. The association between variant allele T of
ESR1 PvuII (C > T) and breast cancer appears to be linked to a higher transcriptional activity of the variant gene [
21] and correlated with circulating estrogen levels [
22].
A recent meta-analysis [
23] found that menopausal status modifies breast cancer risk associated with
ESR1 PvuII (C > T), with premenopausal variant carriers being at higher risk, possibly related to differences in circulating estrogen levels [
22]. However, an updated meta-analysis restricted the effect to the Asian population [
24]. Another meta-analysis of almost 19,000 individuals in eight European centers reported that
ESR1 XbaI (A > G) protects against overall fracture risk [
25], suggesting an involvement of these polymorphisms in bone metabolism. These
ESR1 polymorphisms have also been described to be involved in ovarian hyperstimulation response in assisted reproduction studies [
26], further highlighting their role in endocrine-related mechanisms.
Within the phase III TEXT trial in which 2672 premenopausal women were randomized to adjuvant therapy with exemestane + OFS or tamoxifen + OFS, with or without adjuvant chemotherapy, we prospectively designed a translational research project for blood collection to investigate the effect of selected single nucleotide polymorphisms (SNPs) on treatment efficacy and toxicity. The purpose of the current analysis was to investigate the association of common genetic variants of CYP19A1 (rs10046, rs4646) and ESR1 (rs2077647, rs2234693 and rs9340799) with early-onset vasomotor and musculoskeletal symptoms.
Discussion
This study provides evidence that CYP19A1 rs10046 variant carriers may face milder vasomotor symptoms under combined endocrine treatment. Notably, the effect was restricted to patients under OFS combined with exemestane (treatment-by-genotype interaction, P = 0.03) and not tamoxifen, after adjusting for patient characteristics and concomitant medications, including the selective serotonin-reuptake inhibitors known to reduce hot flashes/sweating.
This finding is in line with evidence from others, linking this SNP to enhanced aromatase activity and higher circulating estrogens [
15,
17] and underscores a possible relationship between the effect of this variant polymorphism (T/T), hot flashes/sweating and exemestane activity. This result may in fact be related to less effective estrogen suppression by exemestane + OFS in these women as a consequence of higher circulating estrogens compared to patients with wild-type SNPs, although the exact mechanism by which this SNP may affect exemestane efficacy in suppressing the aromatase activity is not known. One study recently reported similar associations in postmenopausal patients with breast cancer [
30] enrolled in the TEAM trial:
CYP19A1 variants linked with lower estrogen levels were associated with increased risk of early vasomotor and musculoskeletal symptoms under exemestane. The TEAM substudy, however, only included 27 % of the patients enrolled, less than two-thirds of patients, which represents a smaller proportion than is recommended by Simon et al. for evaluating predictive biomarkers [
31].
The ELPh trial was designed to address genetic associations with toxicity-related discontinuation of AI therapy for breast cancer [
32], including the SNP rs10046. The authors did not specifically report on vasomotor symptoms, but did not find any relationship between rs10046 and toxicity-related treatment discontinuation. In another study, in which the impact of
CYP19A1 SNPs with estrogen suppression during letrozole treatment was assessed, the degree of suppression was independent of the SNPs [
33].
To our knowledge this is the first study to evaluate the associations between common germline polymorphisms of the CYP19A1 and ESR1 genes and early-onset side effects under combined endocrine treatment in premenopausal patients with hormone receptor-positive early breast cancer. The strength of this translational research is its considerable sample size of 1967 patients, which represents 74 % of women enrolled in TEXT. Furthermore, blood samples were collected specifically for this research, i.e., to investigate treatment tolerability and disease outcome. Women enrolled prior to the amendment were asked to re-consent, but 693 TEXT participants were not assessed due to the retrospective nature of blood collection. As a result, we may have missed some patients who discontinued treatment early, possibly due to treatment-related side effects.
The combined analysis of TEXT and SOFT [
4] showed that adjuvant treatment with exemestane + OFS as compared with tamoxifen + OFS, significantly reduces the risk of recurrence. Although the overall incidence of adverse events and the quality of life were similar in the two treatment groups, between-group differences were observed with respect to specific symptoms. While vasomotor AEs (hot flashes and sweating) were quite frequent and evenly distributed amongst treatment groups, musculoskeletal AEs were more frequently reported in patients assigned to exemestane + OFS.
We did not observe any direct association between the
CYP19A1 SNPs and musculoskeletal symptoms, nor any interaction by endocrine treatment. This is in contrast with findings from the TEAM trial [
30], but as mentioned they studied a very small proportion of patients. Furthermore, genotyping in that study was performed on DNA extracted from tumor samples. A cross-sectional study of patients receiving AIs [
34] found that women carrying at least one 8-repeat allele of the tetranucleotide repeat polymorphism of
CYP19A1, associated with higher estrogen concentrations, had lower odds of AI-associated arthralgia. Conversely, they also did not find any association between the rs10046 SNP and arthralgia.
Contrary to findings from case–control studies conducted in different treatment settings, i.e., postmenopausal or premenopausal women with breast cancer treated with tamoxifen alone, we found no association between the three
ESR1 polymorphisms and endocrine-mediated side effects (hot flashes/sweating and musculoskeletal symptoms). Postmenopausal Chinese patients with breast cancer carrying an
ESR1 rs2234693 CC genotype or rs9340799 AA genotype had an increased risk of AI-related musculoskeletal AEs [
35]. In fact, several studies suggest that the effect of the
ESR1 polymorphisms on breast cancer risk is hormone-related and dependent on the woman’s hormonal context, showing statistically significant associations mainly in premenopausal women [
23]. Likewise, an association with increased mammographic density [
36] was shown only in women taking hormone replacement therapy. Possibly, the concurrent OFS by the GnRH analogue triptorelin masked the effect of these polymorphisms due to its complete estrogen deprivation effect. Thus, in the context of adjuvant combined endocrine treatment, these
ESR1 polymorphisms may be unlikely to exert their effect.
Musculoskeletal events are a common toxicity, leading to premature discontinuation of AI therapy [
37]. In the TEXT-SOFT combined analysis, early cessation of protocol treatment was more frequent among patients receiving exemestane + OFS than among those receiving tamoxifen + OFS. Several studies have investigated the relationship between endocrine treatment efficacy and associated side effects in different settings. Recent findings support an inverse association between the reporting of early side effects under adjuvant endocrine treatment and breast cancer recurrence [
38‐
40]. Vasomotor symptoms were associated with improved disease-free and overall survival in the TEAM trial [
38] and reduced breast cancer recurrence in the ATAC trial [
40], but not in the BIG 1–98 [
41] and MA.27 trials [
42]. Thus, we cannot exclude that the
CYP19A1 rs10046 (T/T) genotype might be associated with reduced exemestane + OFS efficacy: women with this polymorphism possibly lack complete estrogen suppression, despite receiving concomitant OFS. On the other hand, because the rs10046 polymorphism is located in a 3’ untranslated region, upstream of the coding sequence, it may interfere with aromatase transcription in a tissue-specific manner, depending on the transcriptional modulators present, thus influencing the degradation rate of the aromatase differently according to tissue and independently from circulating estrogen [
9].
Acknowledgements
The authors thank the patients who participated and the staff who conducted the study at the participating centers, and the CALGB Pathology Coordinating Office. Investigators and the International Breast Cancer Study Group participants include Steering Committee: P.A. Francis (Chair, SOFT Co-Chair), G.F. Fleming (SOFT Co-Chair), O. Pagani (TEXT Co-Chair), B. A. Walley (TEXT Co-Chair), M.M. Regan (Trial Statistician), L. Blacher, H. Bonnefoi, E. Ciruelos, A.S. Coates, M. Colleoni, N. Dif, R.D. Gelber, A. Goldhirsch, A. Hiltbrunner, R. Kammler, R. Maibach, O. Ortmann, K.N. Price, M. Rabaglio, B. Ruepp, H. Shaw, G. Viale, G. von Minckwitz, V. Katkade (Pfizer), E. Chetaille (Ipsen). IBCSG Scientific Executive Committee: M. Colleoni, F. Boyle, A. DiLeo, G. Jerusalem, K.N. Price, M.M. Regan, G. Viale. IBCSG Foundation Council: R. Stahl (President), S. Aebi, A.S. Coates, M. Colleoni, R.D. Gelber, A. Goldhirsch, P. Karlsson, I. Kössler. IBCSG Coordinating Center, Bern, Switzerland: A. Hiltbrunner (Director), R. Kammler, R. Maibach, M. Rabaglio, S. Roux, B. Ruepp, P. Sicher. IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA, USA: R.D. Gelber (Director), M.M. Regan (Group Statistician), M. Bonetti, Y. Feng, A. Giobbie-Hurder, K.P. Gray, H. Huang, W. Luo, K.N. Price, L. Zickl. IBCSG Data Management Center, Frontier Science & Technology Research Foundation, Amherst, NY, USA: L. Blacher (Director), K. Scott (DM Section Head), M. Blackwell, A. Cesario, A. Dickinson, K. Donahue, M. Greco, P. Gonzalez, T. Heckman-Scolese, R. Hecker, R. Hinkle, M. Kalera, K. Lupejkis, A. Mora de Karausch, V. Palermo, H. Shaw, R. Starkweather, J. Swick-Jemison. IBCSG Central Biomarker Laboratory, European Institute of Oncology, Division of Cancer Prevention and Genetics, Milan, Italy: B. Bonanni, H. Johansson, D. Macis. IBCSG Central Pathology Office, European Institute of Oncology, Division of Pathology, Milan, Italy: G. Viale, D. Lepanto, O. Pala. IBCSG Quality of Life Office, Bern, Switzerland: J. Bernhard, K. Ribi. U.S. National Cancer Institute: J. Abrams, J.A. Zujewski. U.S. NCI Clinical Trials Support Unit (CTSU)/Westat: M. Hering, M. Greene, A. Nelson, M. Balois-Ouellette, S. Riordan, O. Santos. ALMAC: W. Mahon, E. Whitney, J. Bryant. CTSU Regulatory Office: R. Catalano, D. Marinucci, B. Niewood, R. Lambersky. Alliance (CALGB) Pathology Coordinating Office, Ohio State University, Columbus, OH, USA: W. Frankel, S. Jewell. Dana-Farber Cancer Institute, Boston, MA, USA (US FDA IND): E.P. Winer, J. Savoie. Pfizer Study Support: B. Campanelli, S. Duong, J.A. Graham, C. Grant, B. Klingele, J. Passmore. Ipsen Study Support: E. Chetaille, J. Amauri Soares, C. Descot, S. Hemont-Dacosta, F. Bismuth, P. Chevreau, H. Bibas. TEXT Participating Centers and Principal Investigators include Centers with accrual of more than one patient: Breast International Group (BIG); International Breast Cancer Study Group (IBCSG). Australia and New Zealand Breast Cancer Trials Group (ANZBCTG): Austin Health, Heidelberg, Victoria: J. Stewart; Box Hill Hospital, Box Hill, Victoria: J. Chirgwin; Calvary Mater Newcastle, Waratah, New South Wales: A. van der Westhuizen; Coffs Harbour Health Campus, Coffs Harbour, New South Wales: K. Briscoe; Flinders Medical Centre, Bedford Park, South Australia: B. Koczwara; Launceston General Hospital, Launceston, Tasmania: S. Gauden; Liverpool Hospital, Liverpool, New South Wales: E. Moylan; Maroondah Hospital, Ringwood East, Victoria: J. Chirgwin; Peter MacCallum Cancer Centre, East Melbourne, Victoria: P. A. Francis; Royal Brisbane and Women’s Hospital, Herston, Queensland: M. Nottage; Royal Hobart Hospital, Hobart, Tasmania: D. Boadle; Royal Perth Hospital, Perth, Western Australia: E. Bayliss; St. Vincent’s Hospital Melbourne, Fitzroy, Victoria: R. Snyder; Tamworth Rural Referral Hospital, Tamworth, New South Wales: F. Sardelic; Tweed Hospital, The, Tweed Heads, New South Wales: E. Abdi; Victorian Breast and Oncology Care, East Melbourne, Victoria: M. Chipman. Belgium: Institute Jules Bordet, Brussels: A. Gombos; Centre Hospitalier Peltzer-La Tourelle, Verviers: A. Barbeaux; Centre Hospitalier Universitarie Sart Tilman, Liège: G. Jerusalem; U.Z. Gasthuisberg, Leuven: P. Neven. Hungary: National Institute of Oncology, Budapest; I. Láng. Italy: Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria di Udine, Udine: F. Plugisi; Centro di Riferimento Oncologico, Aviano: D. Crivellari; Fondazione Salvatore Maugeri, Pavia: L. Pavesi; Istituto Europeo di Oncologia, Milano: M. Colleoni; Ospedale degli Infermi, Rimini: L. Gianni; Ospedale di Circolo e Fondazione Macchi, Varese: G. Pinotti; Ospedali Riuniti di Bergamo, Bergamo: C. Tondini; Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Prato: A. Di Leo; Azienda Sanitaria di Bolzano, Bolzano: C. Graiff. Peru: Instituto de Enfermedades Neoplásicas, Lima: H. Gomez. Slovenia: Institute of Oncology, Ljubljana: E. Skof. South Africa: Sandton Oncology Centre, Johannesburg; D. Vorobiof. Sweden: Sahlgrenska University Hospital, Gothenburg; P. Karlsson. Switzerland: Swiss Association for Clinical Cancer Research (SAKK), Centre Hospitalier Universitaire Vaudois, Lausanne: K. Zamin; Inselspital, Bern: M. Rabaglio; Oncocare Engeried, Bern: K. Buser; Institute of Oncology of Southern Switzerland (Ospedale San Giovanni, Bellinzona; Ospedale Regionale di Lugano, (Civico & Italiano), Lugano; Ospedale Regionale Beata Vergine, Mendrisio; Ospedale Regionale La Carità, Locarno; Istituto Cantonale di Patologia, Locarno): O. Pagani; Kantonsspital St. Gallen, St. Gallen: T. Ruhstaller; Rätisches Kantonos-/Regionalspital, Chur: R. von Moos; Kantonsspital Basel, Basel: C. Rochlitz; Onkologiezentrum Thun-Berner Oberland, Thun: D. Rauch; Zürich Frauenklinik, Zürich: N. Gabriel. Germany: German Breast Group (GBG), Caritas-Krankenhaus St. Josef, Regensburg: S. Buchholz; Dr. Horst Schmidt Kliniken, Wiesbaden: F. Lorenz-Salehi. North American Breast Cancer Group: American College of Surgeons Oncology Group (ACOSOG, now part of Alliance for Clinical Trials in Oncology); Cancer and Leukemia Group B (CALGB, now part of Alliance for Clinical Trials in Oncology); Eastern Cooperative Oncology Group (ECOG, now part of ECOG-ACRIN Cancer Research Group); NCIC Clinical Trials Group (NCIC CTG); National Surgical Adjuvant Breast and Bowel Project (NSABP, now part of NRG Oncology); North Central Cancer Treatment Group (NCCTG, now part of Alliance for Clinical Trials in Oncology); Radiation Therapy Oncology Group (RTOG, now part of NRG Oncology); South West Oncology Group (SWOG); North American Participating Centers. Canada: Cross Cancer Institute, Edmonton, Alberta: K.S. Tonkin; Tom Baker Cancer Center, Calgary, Alberta: B.A. Walley (Chair), M. Webster (PI); London Regional Cancer Center, London, Ontario: K.R. Potvin; Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, Ontario: R.G. Tozer; Trillium Health Centre - W Toronto, Toronto, Ontario: J.A. Gapski; Hôpital Charles LeMoyne, Greenfield Park, Quebec: C. Prady; Allan Blair Cancer Center, Regina, Saskatchewan; M. Salim; Saskatoon Cancer Center, Saskatoon, Saskatchewan: A. Sami; The Vitalite Health Network - Dr. Leon Richard Oncology Centre, Moncton, New Brunswick: P. Whitlock. USA: Presbyterian Hospital, Whittier, CA: J.H. Freimann; University of California at San Diego, San Diego, CA: J.E. Mortimer; St. Joseph Medical Center, Burbank, CA: R.R. Mena; San Francisco General, San Francisco, CA: H.S. Rugo; University of California at San Francisco, San Francisco, CA: C.J. Ryan; University of California San Diego Cancer Center, San Diego, CA: B.A. Parker; University of Colorado, Aurora, CO: A.D. Elias; The Shaw Regional Cancer Center, Aurora, CO: A.D. Elias; University of Connecticut, Farmington, CT: S. Tannenbaum; Walter Reed Army Medical Center, Washington, DC: D.C. Van Echo; Northeast Georgia Medical Center, Gainesville, GA: R.J. LoCicero; Siouxland Hematology - Oncology Associates, Sioux City, IA: D.B. Wender; Saint Luke's Mountain States Tumor Institute, Boise, ID: T.A. Walters; Evanston Northwestern Healthcare, Evanston, IL: D.E. Merkel; Resurrection Medical Center, Chicago, IL: C. G. Rose; University of Chicago, Chicago, IL: H.L. Kindler; Saint Joseph's Medical Center, South Bend, IN: R.H. Ansari; Memorial Hospital of South Bend, South Bend, IN: R.H. Ansari; Northern Indiana Cancer Research Co, South Bend, IN: R.H. Ansari; Mount Carmel Regional Cancer Center, Pittsburg, KS; Stormont-Vail Regional Health Center, Topeka, KS: S.J. Vogel; Cancer Center of Kansas Wichita, Wichita, KS: S.R. Dakhil; Via Christi Regional Medical Center, Wichita, KS: S.R. Dakhil; Addison Gilbert, Gloucester, MA: A.P. McIntyre; Tufts Medical Center, Boston, MA: J.K. Erban; Massachusetts General Hospital, Boston, MA: H.J. Burstein; Dana-Farber Cancer Institute, Boston, MA: H.J. Burstein; Beth Israel Deaconess Medical Center, Boston, MA: H.J. Burstein; Faulkner Hospital, Boston, MA: H.J. Burstein; North Shore Cancer Center, Salem, MA: K.J. Krag; Emerson Hospital, Boston, MA: H.J. Burstein; Suburban Hospital, Bethesda, MD: C.B. Hendricks; University of Maryland Greenebaum Cancer Center, Baltimore, MD: K.H. Rak Tkaczuk; Mercy Medical Center, Baltimore, MD: D.A. Riseberg; Frederick Memorial Hospital, Frederick, MD: E.D. Eskander; William Beaumont Hospital, Royal Oak, MI: D. Zakalik; United Hospital, St. Paul, MN: P.J. Flynn; Abbott-Northwestern Hospital, St. Louis Park, MN: P.J. Flynn; Mercy Hospital, Coon Rapids, MN: P.J. Flynn; Mayo Clinic, Rochester, MN: J.N. Ingle; Saint John's Hospital - Healtheast, Minneapolis, MN: D.J. Schneider; Metro-Minnesota CCOP, Minneapolis, MN: P.J. Flynn; Washington School of Medicine, St Louis, MO: M.J. Naughton; Kansas City CCOP, Kansas City, MO: W.T. Stephenson; Moses H. Cone Memorial, Greensboro, NC: J.E. Feldmann; Mission Hospitals Inc, Asheville, NC: M.J. Messino; Hope, A Women's Cancer Center, Asheville, NC: D.J. Hetzel; Medcenter One Health Systems, Bismarck, ND: E.J. Wos; Dakota Clinic, Fargo, ND: K. Sen; University of Nebraska Medical Center, Omaha, NE: E.C. Reed; Portsmouth Regional Hospital, Portsmouth, NH: E.M. Bonnem; South Jersey Healthcare, Vineland, NJ: D.H. Blom; New York University Medical Center, New York, NY: A.D. Tiersten; Albert Einstein College/Medicine, Bronx, NY: C.M. Pellegrino; Roswell Park Cancer Institute, Buffalo, NY: E.G. Levine; Geisinger Medical Center, Danville, PA: G.D.A. Padula; Greenville CCOP, Greenville, SC: J.K. Giguere; Sioux Valley Clinic - Oncology, Sioux Falls, SD: M.A. Mazurczak; University of Vermont, Burlington, VT: S. Burdette-Radoux; Mountainview Medical, Berlin, VT: S. Burdette-Radoux; Swedish Hospital Medical Center, Seattle, WA: S.E. Rivkin; University of Washington Medical Center, Seattle, WA: S.E. Rivkin; Aspirus Wausau Hospital Center, Wausau, WI: U. Gautam; Oncology Alliance-Glendale, Glendale, WI: R.D. Hart; West Virginia University, Morgantown, WV: J. Abraham.