Should We Be Worried If Patients Tolerate Endocrine Therapy Well?

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N. Lynn Henry, MD, PhD

More research is required to fully understand the association between symptom development and benefit from treatment, and analyses that include the patient’s perspective will be invaluable.

—N. Lynn Henry, MD, PhD
More research is required to fully understand the association between symptom development and benefit from treatment, and analyses that include the patient’s perspective will be invaluable.

—N. Lynn Henry, MD, PhD

When meeting with patients to discuss adjuvant endocrine therapy for breast cancer, the question often arises, “How will I know that the treatment is working?” While the efficacy of these treatments has been demonstrated for the majority of patients in multiple large randomized clinical trials, they are ineffective for others. We remain unable to determine whether the treatment will be, or is, effective for the individual patient sitting in front of us in the clinic.

Researchers have sought to identify predictors of response to adjuvant endocrine therapy that can be used to guide treatment decisions, either between different classes of endocrine therapy—ie, selective estrogen receptor modulators and aromatase inhibitors—or among different aromatase inhibitors. Studies assessing standard cancer-related factors, including pathologic characteristics of the tumor, have not yet identified a useful predictive marker for endocrine therapy selection.

Patient-Reported Outcomes

Evaluation of other outcomes that are potential surrogates for adjuvant endocrine therapy activity and that could be used as predictors of response has therefore been considered. One such outcome that has been assessed retrospectively in multiple clinical trials is patient-reported symptoms.

The first reported finding was from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) randomized trial of anastrozole vs tamoxifen for adjuvant endocrine therapy in postmenopausal women with newly diagnosed breast cancer.1 This retrospective analysis concluded that patients who developed hot flashes and/or arthralgias within the first 3 months of treatment were less likely to experience breast cancer recurrence compared with those who did not report either symptom.

Similar findings were reported from other large clinical trial cohorts, including the Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multinational (TEAM) trials.2-4 There has been some discordance in the findings, however, since not all symptoms (vasomotor, arthralgia, and vulvovaginal) have been associated with improved survival in every study.

In contrast to these findings, the recent report by Stearns et al from the MA.27 randomized trial of anastrozole vs exemestane, reviewed in this issue of The ASCO Post, did not identify any associations between development of symptoms during therapy and improvement in breast cancer disease outcomes.5 The investigators examined associations between worsening of symptoms at 6 and 12 months following treatment initiation and event-free survival, with a median follow-up of 4.1 years. No differences in event-free survival were noted, regardless of whether symptoms were present at baseline.

One of the key limitations of all these studies is the lack of validated patient-reported outcomes. The trials used physician-reported toxicity or obtained data from patients in a nonstandardized manner. Reliance on physician reporting of toxicity has been shown to result in underestimation of symptom burden in aromatase inhibitor–treated women.6 Therefore, the data used for the analyses of associations between treatment-emergent toxicity and breast cancer outcomes are likely incomplete, which could affect the findings.

There are other potential limitations, as discussed by Stearns et al, including exclusion of patients with baseline symptoms; omission of symptom severity information; and lack of information about concomitant medications, including analgesics. Patients treated with aromatase inhibitor therapy are postmenopausal and generally have a baseline symptom burden that is fairly high due to arthritis and other age-related conditions.

The lack of data about the effect of baseline symptoms on the findings and the omission of concomitant medication data influence the findings and, more importantly, limit the applicability of the results to the typical patient population. Overall, these concerns about the quality and completeness of data used for the various retrospective analyses could account for the discordance in findings among studies.

Future Directions

There is a movement afoot to increase the patient voice in oncology trials. Symptom presence and severity are subjective, not objective, and the patient’s perception of his or her symptoms is vital. Ethan Basch and colleagues have called for the incorporation of patient-reported outcomes into clinical trials to improve the accuracy of clinician-reported adverse events.7

One argument against collection of patient-reported outcomes in trials is the cost and inconvenience. In response, the National Institutes of Health has developed tools such as the Patient-Reported Outcomes Measurement Information System ­(PROMIS) in order to facilitate collection of patient-reported ­outcomes.8

The PROMIS short-form questionnaires are being used in the ongoing ECOG-ACRIN E1Z11 observational clinical trial of anastrozole, which is specifically assessing toxicity of aromatase inhibitor therapy ( NCT01824836). It will be interesting to see both the uptake of electronic reporting of patient-reported outcomes, which would streamline data collection, and the concordance between patient- and physician-reported symptoms in this prospective clinical trial.

The ability to accurately predict the efficacy of adjuvant endocrine therapy for an individual patient is crucial to optimizing the benefit-risk ratio of treatment. For now, it remains uncertain whether we should be concerned if a patient fails to develop toxicity from adjuvant endocrine therapy. More research is required to fully understand the association between symptom development and benefit from treatment, and analyses that include the patient’s perspective will be invaluable. ■

Disclosure: Dr. Henry reported no potential conflicts of interest.


1. Cuzick J, Sestak I, Cella D, et al: Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: A retrospective analysis of the ATAC trial. Lancet Oncol 9:1143-1148, 2008.

2. Fontein DB, Houtsma D, Hille ET, et al: Relationship between specific adverse events and efficacy of exemestane therapy in early postmenopausal breast cancer patients. Ann Oncol 23:3091-3097, 2012.

3. Fontein DB, Seynaeve C, Hadji P, et al: Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: An international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol 31:2257-2264, 2013.

4. Huober J, Cole BF, Rabaglio M, et al: Symptoms of endocrine treatment and outcome in the BIG 1-98 study. Breast Cancer Res Treat 143:159-169, 2014.

5. Stearns V, Chapman JA, Ma CX, et al: Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. J Clin Oncol 33:265-271, 2015.

6. Oberguggenberger A, Hubalek M, Sztankay M, et al: Is the toxicity of adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs). Breast Cancer Res Treat 128:553-561, 2011.

7. Basch E, Bennett A, Pietanza MC: Use of patient-reported outcomes to improve the predictive accuracy of clinician-reported adverse events. J Natl Cancer Inst 103:1808-1810, 2011.

8. Cella D, Riley W, Stone A, et al: The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 63:1179-1194, 2010.


Dr. Henry is Associate Professor, Internal Medicine, University of Michigan Medical School, Ann Arbor.

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