Study: Does extending hormonal therapy impact risk of breast cancer recurrence?

IN-DEPTH REVIEW OF RESEARCH

Study background:

Researchers of this study attempted to identify women whose long-term risk of recurrence was so small that any additional benefit from extended therapy would not be outweighed by added side effects.  Hongchao Pan, PhD, and colleagues conducted a meta-analysis of 88 trials involving 62,923 women with ER-positive breast cancer who were disease free after 5 years of endocrine therapy.  They used data on recurrence, tumor diameter and nodal status (TN), tumor grade and other factors during 5 to 20 years after standard endocrine therapy ended.  Results were published in the November 9, 2017 edition of the New England Journal of Medicine.

Researchers of this study wanted to know:

Whether they could identify women with early-stage, ER-positive breast cancer who were disease free following 5 years of standard endocrine therapy for whom additional benefit from extended therapy would not outweigh added side effects.  However, they revealed factors that may help to guide patients and healthcare providers when considering who would benefit from extended hormonal therapy. 

Population(s) looked at in the study:

Researchers analyzed data from 88 clinical trials involving 62,923 women with ER-positive breast cancer.

• All of the women received endocrine therapy for 5 years and were free of cancer when therapy ended. 
• Half of the women received a diagnosis of breast cancer before 2000 (from 1976 to 2011).
• Data was available on: 
  • Age, tumor size and nodal status for all the women
  • Tumor grade for 43,590 (69%) of the patients
  • Progesterone-receptor status for 54,115 (86%)
  • HER-2 status for 24,145 (38%) 
  • A tumor marker called Ki-67—a protein that is a marker for cell division—status for 7692 (12%)

Study findings: 

The cumulative risk and annual rates of distant recurrence and death from breast cancer in each 5-year period from year 0 to year 20, was subdivided according to lymph node status at the time of diagnosis. In each category, distant recurrence occurred steadily throughout the 20-year period. Annual risk was strongly related to nodal status.

• The 20-year risk of distant recurrence was:
  • 22% in those with no positive nodes
  • 31% in those with 1 to 3 positive nodes
  • 52% in those with 4 to 9 positive nodes

The annual rates of death from breast cancer, as would be predicted in a population that was disease free following 5 years of endocrine therapy, was low during the first 5 years. However, starting at year 5, the annual rates of death increased. These risks were not significantly lower than the 20-year risk of distant recurrence.

• The 20 year risks of death from breast cancer were:
  • 15% in women with no positive nodes
  • 28% in women with 1 to 3 positive nodes
  • 49% in women with 4 to 9 positive nodes

However, even women with small, node-negative (T1N0) low-grade tumors had risk of distant recurrence.  For these women (T1N0) risk of recurrence was:

• 10% for patients with low-grade disease
• 13% for patients with moderate-grade disease
• 17% for patients with high-grade disease

The corresponding risk of any recurrence or contralateral breast cancer for these women (T1N0) was:

• 17% for patients with low-grade disease
• 22% for patients with moderate-grade disease
• 26%for patients with high-grade disease

When other factors were taken into account, tumor grade and Ki-67 status were moderate independent predictive indicators for recurrence. Progesterone receptor and HER2 receptor status did not predict recurrence. 

Limitations:

• Noncompliance (patients stopping medications early) is a big concern with long-term hormonal treatment due to side effects. The recurrence rates reported here are among women who were scheduled to receive 5 years of hormonal therapy, not in those who actually completed 5 years of treatment.
• Researchers could not reliably look at the effect of chemotherapy after year 5, since the extent of lymph node involvement differed between women who received chemotherapy and those who did not.
• The analysis included a significant number of patients who were diagnosed before the year 2000, and therefore may not be completely relevant to today’s population that has better screening, diagnostic methods, staging and systemic therapy.

Conclusions:

The risk for recurrence steadily rose among women who were diagnosed with early-stage ER-positive breast cancer, received 5 years of hormonal therapy and were disease-free when their therapy ended. Risk of recurrence was strongly associated with the original size of the tumor and the patient’s nodal status at the time of diagnosis.  These findings impact long-term follow-up strategies and the need for new approaches to reduce the long-term risk of recurrence. For some patients, risk may be reduced by extending the duration of hormonal therapy; however, additional side effects of extended therapy must be taken into consideration.  Tumor size and lymph node involvement at the time of diagnosis may help to identify those who would benefit the most from extended endocrine therapy.

Posted 12/21/17

Share your thoughts on this XRAYS article by taking our brief survey
 

References

Pan H, Gray R, Braybrooke J, et al. “20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.” New England Journal of Medicine 2017;377:1836-46. 
 

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.