'Unrelenting': 20-Year Recurrence Risks in Breast Cancer

Nick Mulcahy

November 08, 2017

The risk of breast cancer returning continues long after the initial treatment has been completed. A new analysis shows that in the 20 years after initial diagnosis, there is an ongoing, steady risk of the cancer recurring in the form of deadly metastatic disease.

The absolute, cumulative risk for metastatic or distant recurrence among women with estrogen receptor–positive (ER+) breast cancer ranged from 10% to 41% over that time span, depending on various disease characteristics.

The findings about women with ER+ disease, which is the most common form of breast cancer, were published online November 8 in the New England Journal of Medicine.

The data come from a meta-analysis that included 88 clinical trials involving 62,923 women who were disease free after 5 years of scheduled endocrine therapy with tamoxifen or aromatase inhibitors.

Thus, all of the recurrences happened after that initial 5 years.

The women all had stage T1 (≤2 cm) or T2 (>2 cm to 5 cm) breast cancers (of varying grades) with fewer than 10 positive lymph nodes and no distant metastases. The patients were followed for up to 15 years after the 5-year treatment period, which generated 20-year data.

What is "surprising" about the findings is the "unrelenting risk over 20 years" and that metastases occur even among patients with the best prognoses, senior author Daniel Hayes, MD, of the University of Michigan Cancer Center in Ann Arbor, told Medscape Medical News.

The main aim of the study was to identify subgroups of patients for whom endocrine therapy could be stopped (thereby avoiding the side effects) after 5 years because their risk for long-term distant recurrence was "so small," say Dr Hayes and his international team of coauthors.

But they found that even among women with the least-threatening profile of small tumors (T1) who had no lymph node involvement (N0), there was a cumulative recurrence risk of 13% over a 20-year period. (The risk was 10% for the less aggressive, low-grade cancers; 13% for moderate-grade cancers; and 17% for high-grade.)

Notably, the annual rate of distant recurrence for these patients was about 1% for a period of 5 to 20 years (ie, after treatment ended), resulting in the 13% cumulative risk.

The new study "quantifies the 20-year risk more reliably than previous studies," owing to size, length of follow-up, and the quality of clinical trial-only evidence, say the authors.

The data "can help women and their health care professionals decide whether to extend therapy beyond 5 years and whether to persist if adverse events occur," they conclude.

An expert not involved with the study welcomed it but called attention to the concept of data reliability.

"This is a very important study because it provides some guidance how to select early-stage breast cancer patients for long-term, extended endocrine therapy," said Lajos Pusztai, MD, DPhil, of the Yale Cancer Center in New Haven, Connecticut.

However, the long-term follow-up means that study patients were treated 2 to 4 decades earlier "with therapies that we now consider suboptimal," Dr Pustzai added.

In addition, during the past 30 years, diagnostic, staging, and tumor assessment strategies and accuracy have dramatically changed, he noted. The majority of breast cancers are now detected through screening. Such cancers are associated with better prognoses than clinically apparent cancers.

"For these reasons, it is likely that the risk estimates presented in the paper do not completely apply to contemporary patients, particularly to screen-detected T1N0 cancers," Dr Pusztai told Medscape Medical News.

The newly reported 10% distant recurrence rate for low-grade T1N0 tumors "contradicts the remarkably good survival results seen in randomized trials in the past 15 years," he added.

It is likely that the risk estimates presented in the paper do not completely apply to contemporary patients. Dr Lajos Pusztai

In short, some of the risks reported in the new study are probably higher than those seen currently, he suggested.

Nevertheless, Dr Pusztai agreed with the study authors that the major predictor of distant recurrence risk was status of the tumor stage and lymph node involvement at diagnosis.

Table 1. Distant Recurrence Risk to 20 Years

Stage at Diagnosis Nodes Involved Cumulative Risk
T1 0 13%
  1 - 3 20%
  4 - 9 34%
T2 0 19%
  1 - 3 26%
  4 - 9 41%


The main massage for me is that clinical stage matters. Dr Lajos Pusztai

The study authors state, "The risk of distant recurrence was strongly correlated with the original TN status." They also report that tumor grade and Ki-67 status were of only moderate independent predictive value for recurrence and that HER2 status was not predictive (however, only 2% of the women received trastuzumab).

Talking With Patients

Dr Pusztai said that the new data raise "a pressing clinical question: who are the patients who really need 10 years of endocrine treatment and who are cured with 5 years?"

He explained that several randomized clinical trials have demonstrated that 10 years of adjuvant antiestrogen therapy is more efficacious than 5 years of therapy. However, "the improvement is small, with 2% to 3% fewer distant recurrences, and the costs and potential side effects of taking a pill for 10 years are not negligible," he observed.

"Useful" molecular diagnostic tests, including the Breast Cancer Index and the Prosigna assay, can now help identify patients who are both at risk for recurrence and remain endocrine sensitive and therefore benefit from extended endocrine therapy, he added.

Another expert who was approached for comment, Virginia Kaklamani, MD, of the Unitersity of Texas Health Science Center, San Antonio, said the new study "changes the conversation with patients.

"Extended endocrine therapy becomes an important part of the discussion, given the fact that [distant] recurrence after 5 years is higher than recurrence during the first 5 years," she told Medscape Medical News.

Extended endocrine therapy becomes an important part of the discussion. Dr Virginia Kaklamani

This is a reference to the fact that the study analyzed recurrence and disease-specific mortality risks in 5-year increments. And for each subgroup analysis, the same pattern was seen: a steady increase of associated risk over time, up to 20 years.

Steven Vogl, MD, a private practitioner in New York City, said the study was "good to have" and that he would look at it "again and again" with patients.

"What's nice about this paper is that they give you what you need to know ― the risk of distant metastases and death from breast cancer," he told Medscape Medical News.

He explained that breast cancer is only deadly once it spreads to distant vital organs.

Overall, the risk for breast cancer mortality "looks identical to distant recurrence except with lower percentages at each time point," summarized Dr Hayes.

Table 2. Cancer Mortality Risk to 20 Years

Stage at Diagnosis Nodes Involved Cumulative Risk
T1 0 7%
  1 - 3 13%
  4 - 9 22%
T2 0 13%
  1 - 3 20%
  4 - 9 29%


The new meta-analysis has several limitations, including that it involved women who were scheduled to receive 5 years of endocrine therapy ― not who completed it. In six of the trials that investigated only tamoxifen, a "substantial minority" (11% to 31%) of women did not complete treatment.

That fact may lead to higher rates of recurrence risk in the study, just as 100% completion would lead to lower risk.

However, the authors also suspect that the rate of distant recurrence would have been 5% to 10% higher had the data not been tamped down by unreported breast-cancer events.

The team also could not "reliably assess" the relevance of chemotherapy to prognosis after the treatment period ended at 20 years. They acknowledged that the risk for recurrence after 5 years may be lower for women who receive contemporary chemotherapy compared to the risk for women in the study, echoing Dr Pusztai's comments.

The study was funded by Cancer Research UK, the British Heart Foundation, and the Medical Research Council at the University of Oxford. Dr Pusztai has worked with Biotheranostic to assess use of their Breast Cancer Index. Dr Hayes, and Dr Kaklamani, and Dr Vogl have disclosed no relevant financial relationships.

N Engl J Med. Published online November 9, 2017. Abstract

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.