Analysis of Adjuvant Endocrine Therapy in Practice From Electronic Health Record Data of Patients With Breast Cancer

Purpose Adjuvant endocrine therapy is a long-term drug therapy prescribed to prevent recurrence of hormone receptor–positive breast cancer. Data on adjuvant endocrine therapy are reported though clinical trials, which may differ from treatment practice and outcomes in the general population of patients with breast cancer. With secondary use of electronic health record (EHR) data, we summarize adjuvant endocrine treatment practice and outcomes in real-world settings. Methods We analyzed treatment data derived from EHR data on 1,587 patients with stage I to III breast cancer at a National Cancer Institute–designated comprehensive cancer center to learn the frequencies of real-world adjuvant endocrine drug switches and discontinuation and to explore the potential cause for drug switches and discontinuation from medical records. We measured rates of drug use, drug switches, early drug discontinuation, adverse events, recurrence, and death. We also measured adverse events and change in menopause status as potential causes for drug switch and discontinuation. Results Within the study population, approximately 49% of patients were lost to follow-up or did not complete adjuvant treatment through 5 years. Fifty-two percent of patients switched to a different endocrine therapy drug during their treatment. We found that age is correlated with drug switches and that adverse events are correlated with drug switches and discontinuation. We also found that patients who switched to an alternative endocrine therapy during treatment were more likely to complete 5 years of treatment. Conclusion This study describes long-term adjuvant endocrine treatment in real-world settings and demonstrates the ability to leverage longitudinal EHR data to characterize oral medication treatment patterns in patients with cancer.

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Evolution in the risk of adverse events of adjuvant endocrine therapy in postmenopausal women with early-stage breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-020-05715-1 ◽

2020 ◽

Vol 182 (2) ◽

pp. 259-266

Author(s):

Daniel Reinhorn ◽

Rinat Yerushalmi ◽

Assaf Moore ◽

Alexandra Desnoyers ◽

Ramy R. Saleh ◽

...

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Postmenopausal Women ◽

Endocrine Therapy ◽

Early Stage ◽

Adjuvant Endocrine Therapy ◽

Early Stage Breast Cancer

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SAT-418 Finding the Needles in the Haystack: Harnessing the Electronic Health Record to Find Thyroid Immune Related Adverse Events

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.127 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Zoe Quandt ◽

Laura Trupin ◽

Michael Evans ◽

Gabriela Schmajuk ◽

Mark Stuart Anderson ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Electronic Health Record ◽

Real World ◽

Immune Checkpoint ◽

Thyroid Disease ◽

Thyroid Dysfunction ◽

Health Record ◽

The Real ◽

New Onset

Abstract Background: Immune checkpoint inhibitors (CPIs) are being used to effectively treat a growing number of cancers but can cause immune related adverse events (irAE). Thyroid dysfunction is the most common endocrine irAE. A meta-analysis of clinical trials estimated that following CPI exposure, 6.6% will become hypothyroid and 2.9% will have hyperthyroidism1. It is unclear if this reflects the real-world incidence of these irAEs. We used electronic health record (EHR) data to identify patients who developed thyroid dysfunction after CPI to estimate the real-world incidence of these irAEs. Methods: Data were derived from the EHR of a large U.S. academic center. We identified subjects treated with CPIs between 2012 and 2018 and excluded those with thyroid cancer or pre-existing thyroid disease. Thyroid dysfunction was identified as either a TSH > 10, an abnormal free T4 or a prescription for thyroid hormone replacement or anti-thyroid medication. Those with thyroid dysfunction were then categorized as having pre-existing disease or a new-onset thyroid irAE based on the timing of CPI initiation. Logistic regression was used to evaluate the association of thyroid irAE with age, gender, CPI and type of cancer. Results: In total, 1146 individuals without pre-existing thyroid disease that received CPIs were assessed. Pembrolizumab was the most common treatment (45%), followed by nivolumab (20%). Less than 10% of subjects received atezolizumab, durvalumab, ipilimumab monotherapy, combined ipilimumab/nivolumab, or other combinations of CPIs. Melanoma was the most common cancer treated (32%), followed by non-small cell lung cancer (13%). The prevalence of any other cancer was < 10% each. Overall, 19% developed thyroid irAEs. After adjustment for gender and age, the type of cancer was significantly associated with new onset thyroid dysfunction (p=0.01). The rates of thyroid irAEs ranged from 10% in glioblastoma to 40% in renal cell cancer. Although there was no significant association between irAEs and specific CPIs in the overall analysis, thyroid irAEs were more common in subjects who received combined ipilimumab/ nivolumab (31%) compared to pembrolizumab (18%, p=0.03), nivolumab (18%, p<0.01) and ipilimumab (15%, p=0.02). Conclusion: Thyroid irAEs are much more common in real world practice than in clinical trials and there is emerging evidence that certain cancer types incur a higher risk of thyroid irAEs even after adjustment for CPI exposure. Clinicians and patients should be educated about these risks. Future work should focus on exploring the reasons underlying the differing rates of thyroid irAEs among different cancers including effect on cancer outcomes. 1Barroso-Sousa et al. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens. JAMA Oncol. 2017; 02215: 1–10.

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Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.7102 ◽

2007 ◽

Vol 25 (7) ◽

pp. 820-828 ◽

Cited By ~ 223

Author(s):

Michael F.X. Gnant ◽

Brigitte Mlineritsch ◽

Gero Luschin-Ebengreuth ◽

Stephan Grampp ◽

Helmut Kaessmann ◽

...

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Loss ◽

Endocrine Therapy ◽

Premenopausal Women ◽

Adjuvant Endocrine Therapy ◽

Phase Iii ◽

Endocrine Treatment ◽

Mineral Density ◽

T Score

Purpose Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients. Patients and Methods This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) ± zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin ± zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months. Results Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, −14.4% after 36 months; mean T score reduction, −1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, −17.3%; mean T score reduction, −2.6) compared with patients receiving tamoxifen/goserelin (BMD, −11.6%; mean T score reduction, −1.1). In contrast, BMD remained stable in zoledronic acid–treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted. Conclusion Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.

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The Optimal Duration and Selection of Adjuvant Endocrine Therapy for Breast Cancer: How Long Is Enough?

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2014.34.e16 ◽

2014 ◽

pp. e16-e24 ◽

Cited By ~ 7

Author(s):

Ian E. Smith ◽

Belinda Yeo ◽

Gaia Schiavon

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Prognostic Significance ◽

Indirect Evidence ◽

Late Recurrence ◽

Term Treatment ◽

Adjuvant Endocrine Therapy ◽

Risk Of Recurrence ◽

Long Term Treatment

Women with estrogen receptor (ER)+ early breast cancer (BC) are at continuing risk of relapse up to at least 15 years after diagnosis, despite being on adjuvant endocrine therapy for approximately 5 years. Extended adjuvant endocrine therapy with an aromatase inhibitor (AI) after 5 years of tamoxifen further reduces the risk of recurrence in postmenopausal women. More recently, continuing tamoxifen for 10 years has also been shown to further reduce the risk of recurrence compared with 5 years. There are no direct comparative data on the relative merits of extended tamoxifen compared with an AI; indirect evidence suggests that an AI may have increased efficacy but a greater adverse effect on quality of life. Results are awaited on the need for continuing front-line adjuvant AIs for more than 5 years. The next challenge is to determine which patients will benefit from this long-term treatment. Currently, tumor size, nodal involvement, and gene expression profile as measured by the PAM50 Risk of Recurrence (ROR) score have all been shown to have prognostic significance for late recurrence beyond 5 years.

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Specific Adverse Events Predict Survival Benefit in Patients Treated With Tamoxifen or Aromatase Inhibitors: An International Tamoxifen Exemestane Adjuvant Multinational Trial Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2012.45.3068 ◽

2013 ◽

Vol 31 (18) ◽

pp. 2257-2264 ◽

Cited By ~ 41

Author(s):

Duveken B.Y. Fontein ◽

Caroline Seynaeve ◽

Peyman Hadji ◽

Elysée T.M. Hille ◽

Willemien van de Water ◽

...

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Endocrine Therapy ◽

Proportional Hazards ◽

Disease Free Survival ◽

Distant Metastases ◽

Cox Proportional Hazards ◽

Endocrine Treatment ◽

Survival Outcomes ◽

Cox Proportional Hazards Models

Purpose Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Patients and Methods Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. Results A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Conclusion Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

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Long term effects of extended adjuvant endocrine therapy on quality of life in breast cancer patients

The Breast ◽

10.1016/j.breast.2015.01.010 ◽

2015 ◽

Vol 24 (3) ◽

pp. 224-229 ◽

Cited By ~ 6

Author(s):

M. Kool ◽

D.B.Y. Fontein ◽

E. Meershoek-Klein Kranenbarg ◽

J.W.R. Nortier ◽

E.J.T. Rutgers ◽

...

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Cancer Patients ◽

Endocrine Therapy ◽

Adjuvant Endocrine Therapy ◽

Breast Cancer Patients ◽

Long Term Effects

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Progesterone Receptor Status Significantly Improves Outcome Prediction Over Estrogen Receptor Status Alone for Adjuvant Endocrine Therapy in Two Large Breast Cancer Databases

Journal of Clinical Oncology ◽

10.1200/jco.2003.09.099 ◽

2003 ◽

Vol 21 (10) ◽

pp. 1973-1979 ◽

Cited By ~ 442

Author(s):

Valerie-Jeanne Bardou ◽

Grazia Arpino ◽

Richard M. Elledge ◽

C. Kent Osborne ◽

Gary M. Clark

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Progesterone Receptor ◽

Endocrine Therapy ◽

Multivariate Analyses ◽

Adjuvant Endocrine Therapy ◽

Endocrine Treatment ◽

Receptor Status ◽

Risk Of Death ◽

Er Positive

Purpose: To determine whether progesterone receptor (PgR) status provides additional value to estrogen receptor (ER) status and improves prediction of benefit from endocrine treatment among patients with primary breast cancer. Patients and Methods: Clinical outcomes of patients in two large databases were analyzed as a function of steroid receptor status. The first database (PP), contained 3,739 patients who did not receive any systemic adjuvant therapy and 1,688 patients who received adjuvant endocrine therapy but no chemotherapy. The second database (SPORE), contained 10,444 patients who received adjuvant endocrine therapy but no chemotherapy. Biochemical ER and PgR assays were identically performed in two different central laboratories. Results: In univariate and multivariate analyses, the prognostic significance of PgR status among systemically untreated patients is modest. Among endocrine-treated patients, however, multivariate analyses, including lymph-node involvement, tumor size, and age, demonstrate that PgR status is independently associated with disease-free and overall survival. For recurrence, the reduction in relative risk (RR) was 25% for ER-positive/PgR-negative patients and 53% for ER-positive/PgR-positive patients, compared with ER-negative/PgR-negative patients (P < .0001, PP patients). Patients with ER-positive/PgR-negative tumors have a reduction in RR of death of 30% (SPORE patients) and 38% (PP patients), compared with patients with ER-negative/PgR-negative tumors (P < .0001). For ER-positive/PgR-positive tumors, the reduction of the risk of death was greater than 46% in SPORE patients and 58% in PP patients, indicating that ER-positive/PgR-positive patients derive more benefit from endocrine therapy (P < .0001). Conclusion: When accurately measured, PgR status is an independent predictive factor for benefit from adjuvant endocrine therapy. Therefore, PgR status should be taken into account when discussing RR reductions expected from endocrine treatment with individual patients.

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Adverse effects of adjuvant endocrine therapy

Medical Council ◽

10.21518/2079-701x-2018-10-64-69 ◽

2018 ◽

pp. 64-69

Author(s):

E. I. Kovalenko ◽

I. B. Kononenko ◽

A. V. Snegovoi ◽

O. P. Grebennikova ◽

L. V. Manzyuk

Keyword(s):

Breast Cancer ◽

Quality Of Life ◽

Side Effects ◽

Adverse Effects ◽

Adverse Events ◽

Endocrine Therapy ◽

Aromatase Inhibitors ◽

Hormonal Therapy ◽

Adjuvant Endocrine Therapy

Hormonal therapy is a highly effective and well tolerable treatment of hormone-responsive breast cancer. However, it has some side effects that can affect quality of life and lead to treatment discontinuation. Common side effects of tamoxifen and aromatase inhibitors are discussed in this article: menopausal, gynecological symptoms, cardiovascular and musculoskeletal adverse events. Some of them are preventable and manageable. In order to maintain good quality of life during treatment the oncologists should pay more attention to the side effects that lead to it’s deterioration and not be too anxious about insignificant ones.

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Cardiovascular Adverse Events During Adjuvant Endocrine Therapy for Early Breast Cancer Using Letrozole or Tamoxifen: Safety Analysis of BIG 1-98 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2007.12.1665 ◽

2007 ◽

Vol 25 (36) ◽

pp. 5715-5722 ◽

Cited By ~ 86

Author(s):

Henning Mouridsen ◽

Aparna Keshaviah ◽

Alan S. Coates ◽

Manuela Rabaglio ◽

Monica Castiglione-Gertsch ◽

...

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Endocrine Therapy ◽

Early Breast Cancer ◽

Aromatase Inhibitors ◽

Safety Analysis ◽

Adjuvant Endocrine Therapy ◽

Double Blind ◽

Significant Difference ◽

Grade 3

Purpose Previous analyses of adjuvant studies of aromatase inhibitors versus tamoxifen, including the Breast International Group (BIG) 1-98 study, have suggested a small numerical excess of cardiac adverse events (AEs) on aromatase inhibitors, a reduction in the incidence of hypercholesterolemia on tamoxifen, and significantly higher incidence of thromboembolic AEs on tamoxifen. The purpose of the present study is to provide detailed updated information on these AEs in BIG 1-98. Patients and Methods Eight thousand twenty-eight postmenopausal women with receptor-positive early breast cancer were randomly assigned (double-blind) between March 1998 and May 2003 to receive 5 years of adjuvant endocrine therapy with letrozole, tamoxifen, or a sequence of these agents. Seven thousand nine hundred sixty-three patients who actually received therapy are included in this safety analysis, which focuses on cardiovascular events. AE recording ceased 30 days after therapy completion (or after switch on the sequential arms). Results Baseline comorbidities were balanced. At a median follow-up time of 30.1 months, we observed similar overall incidence of cardiac AEs (letrozole, 4.8%; tamoxifen, 4.7%), more grade 3 to 5 cardiac AEs on letrozole (letrozole, 2.4%; tamoxifen, 1.4%; P = .001)—an excess only partially attributable to prior hypercholesterolemia—and more overall (tamoxifen, 3.9%; letrozole, 1.7%; P < .001) and grade 3 to 5 thromboembolic AEs on tamoxifen (tamoxifen, 2.3%; letrozole, 0.9%; P < .001). There was no significant difference between tamoxifen and letrozole in incidence of hypertension or cerebrovascular events. Conclusion The present safety analysis, limited to cardiovascular AEs in BIG 1-98, documents a low overall incidence of cardiovascular AEs, which differed between treatment arms.

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