HR+, HER2- Early Breast Cancer

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Interpreting Adjuvant Breast Cancer Clinical Trials

Patients with early breast cancer (EBC) are treated with curative intent1

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With access to more treatment options, mortality risk in patients with breast cancer has been significantly reduced.2-4 For this reason, it is not practical to rely on overall survival (OS) in adjuvant breast cancer clinical trials, as it can take decades before OS is reliably measured.5
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Defining surrogate endpoints

To observe efficacy outcomes for patients with EBC, it has become essential to define surrogate endpoints for OS. This is especially crucial in the adjuvant setting.5 To ensure the use of standardized endpoints, careful consideration should be taken across the clinical trial life cycle.5

Three human figures with center one highlighted
Before trial initiation
Pills
During the trial
Round bottom flask
At analysis
Clipboard with a check mark
At publication
Through the development of the Standardized Definitions for Efficacy End Points (STEEP) system and other global initiatives, time-to-event endpoints have been largely standardized to mitigate inconsistencies in endpoint definitions that may confound interpretation of clinical trial results.2,5
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Invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) are surrogate endpoints for OS

Recurrence of breast cancer can be local, regional, or distant.6 Risk of recurrence peaks early in patients at ~2 years after primary diagnosis.6,7 IDFS is a composite endpoint that includes local, regional, and distant recurrence. DRFS emphasizes distant recurrence or metastasis in a vital organ.5,8

Local recurrence is in the breast. Regional recurrence is in the lymph nodes. Examples of distant recurrences are in the brain, lung, liver, or bone.

IDFS and DRFS: composite endpoints used in adjuvant breast cancer clinical trials

Both IDFS and DRFS are standardized, clinically meaningful endpoints in adjuvant breast cancer clinical trials.2,5

  • IDFS provides information on local invasive recurrence, regional invasive recurrence, distant recurrence, death of any cause, invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, and second primary nonbreast invasive cancer
  • DRFS provides information on distant recurrence and death of any cause
  • Ductal carcinoma in situ (DCIS) includes both ipsilateral and contralateral DCIS
  • IDFS Endpoint
    • Local invasive recurrence: yes
    • Regional invasive recurrence: yes
    • Distant recurrence: yes
    • Death of any cause: yes
    • Invasive ipsilateral breast tumor recurrence: yes
    • Invasive contralateral breast cancer: yes
    • DCIS: no
    • Second primary non-breast invasive cancer: yes
  • DRFS Endpoint
    • Local invasive recurrence: no
    • Regional invasive recurrence: no
    • Distant recurrence: yes
    • Death of any cause: yes
    • Invasive ipsilateral breast tumor recurrence: no
    • Invasive contralateral breast cancer: no
    • DCIS: no
    • Second primary non-breast invasive cancer: no
Ten human figures with 3 highlighted

Implications for patients with high-risk disease

Because ~30% of patients with high-risk, HR+, HER2- EBC may experience disease recurrence in 5 years,8 IDFS and DRFS are very meaningful clinical endpoints. Improvement in IDFS or DRFS means fewer recurrences and fewer instances of incurable metastatic disease, which are critically important in practice.

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Woman with pill

Understanding the Carryover Effect of Oral Endocrine Therapy

Adjuvant endocrine therapy (ET), such as tamoxifen and aromatase inhibitors (AIs), is the current standard of care for patients with hormone receptor–positive (HR+) EBC.9-11 Carryover effect is the term used to describe the long-lasting benefit of ETs in reducing the risk of recurrence after stopping the initial treatment.12,13

Timeline showing a carryover effect of adjuvant tamoxifen beyond 5 years of adjuvant treatment

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5 years

5 years of adjuvant tamoxifen:

  • Significantly lowered disease recurrence throughout the first 15 years (recurrence ratio [RR], 0.61; standard error [SE], 0.03)
  • Reduced mortality by 30% throughout the first 15 years (RR, 0.77; SE, 0.05)

Arrow pointing down. ET extending beyond 5 years produces a further reduction in recurrence and mortality.

10 years

Extending adjuvant tamoxifen to 10 years:

  • Continued to lower disease recurrence (RR, 0.90; 95% confidence interval [CI], 0.79-1.02) and mortality (RR, 0.97; 95% CI, 0.79-1.18) during years 5-9
  • Reduced the risk of recurrence (RR, 0.75; CI, 0.62-0.90) and mortality (RR, 0.71; 95% CI, 0.58-0.88) after year 10
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AIs also have a carryover effect

In patients with ER+ disease, 5 years of adjuvant AI when compared with no ET17:

Calendar with a pill indicating a dosing schedule

A minimum of 5 years of ET is recommended for women with stage 1-3 ER+ EBC. Up to 10 years of extended therapy is recommended for women with higher-risk, node-positive disease.

Doctor discussing risk of recurrence with a patient

Understanding the carryover effect

As healthcare providers, it is important to understand the carryover effect of ET for patients with HR+ EBC and how treatment duration, ET adherence, and choice of therapy may influence these effects.

Developing an individualized treatment plan for each patient can help to optimize patient care and reduce risk of disease recurrence.

Downloadable PDFs

INFOGRAPHIC: The Importance of Surrogate Endpoints for Adjuvant Breast Cancer Clinical Trials: IDFS and DRFS (PDF)

INFOGRAPHIC: High-Risk HR+, HER2- EBC: Carryover Effect of Oral Endocrine Therapy (PDF)

https://main--lusa-lillymeded-aem-us--elilillyco.aem.page/medical/fragments/figure-captions/clinical-trials-page-video1

IDFS: a clinically meaningful endpoint in adjuvant breast cancer clinical trials

Watch Dr. O’Shaughnessy describe why Invasive Disease-Free Survival (IDFS) is an important clinical trial endpoint used in high-risk, HR+, HER2- early breast cancer studies.

https://main--lusa-lillymeded-aem-us--elilillyco.aem.page/medical/fragments/figure-captions/clinical-trials-page-video2

Defining DRFS as an endpoint in adjuvant breast cancer clinical trials

Dr. O’Shaughnessy defines distant relapse-free survival (DRFS) explains why it is an important endpoint in high-risk HR+, HER2- early breast cancer trials.

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References

  1. Yung R, et al. Breast Cancer Res Treat. 2020;180(3):747-757.
  2. Gourgou-Bourgade S, et al. Ann Oncol. 2015;26(5):873-879.
  3. Garutti M, et al. Cancers. 2022;14(1898):1-17.
  4. Giaquinto AN, et al. CA Cancer J Clin. 2022;72(6):524-541.
  5. Hudis CA, et al. J Clin Oncol. 2007;25(15):2127-2132.
  6. Colleoni M, et al. J Clin Oncol. 2016;34(9):927-935.
  7. Cheng L, et al. Cancer Epidemiol Biomarkers Prev. 2012;21(5):800-809.
  8. Sheffield KM, et al. Future Oncol. 2022;18(21): 2667-2682.
  9. Cardoso F, et al. Ann Oncol. 2019;30(8):1194-1220.
  10. Korde LA, et al. J Clin Oncol. 2021;39(13):1485-1505.
  11. Burstein HJ, et al. Ann Oncol. 2021;32(10):1216-1235.
  12. Chumsri S, Thompson EA. Lancet. 2020;395(10218):91-92.
  13. EBCTCG. Lancet. 2005;365(9472):1687-1717.
  14. EBCTCG. Lancet. 2011;378(9793):771-784.
  15. Davies C, et al. Lancet. 2013;381(9869):805-816.
  16. Burstein HJ, et al. J Clinic Oncol. 2019; 37(5):423-438.
  17. EBCTCG. Lancet. 2015;386(10001):1341-1352.

VV-MED-154879

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