Stockholm Tamoxifen Trial: Clinical Biomarkers Predict Long-Term Survival in ER-positive, ERBB2-Negative Breast Cancer

Tumor size and tumor grade were the most significant clinical biomarkers associated with long-term survival in women with estrogen-receptor (ER)-positive, ERBB2-negative breast cancer, a secondary analysis of a subset of women who were originally enrolled in the Stockholm Tamoxifen (STO-3) trial has shown.

In contrast, neither progesterone receptor (PR) nor Ki-67 status was significantly associated with long-term survival in the same patient cohort, although patients with larger tumors, lower tumor grades, and PR-positive tumors had significant, long-term treatment benefit with tamoxifen, the same secondary analysis indicated.

In a subgroup of 565 postmenopausal women (mean age 62 years) originally enrolled in the STO-3 trial, there was a 69% reduction in the long-term risk of distant recurrence among patients with smaller tumors (T1a/b) compared to those with larger tumors (T2) at a Hazard Ratio (HR) of 0.31 (95% CI, 0.17-0.55), Huma Dar, MSc, Karolinska Institute and University Hospital, Stockholm, Sweden, and colleagues reported in JAMA Network Open. Similarly, a 42% reduction in the long-term risk of distant recurrence was observed among patients with a T1c tumor compared to those with T2 tumors at a HR of 0.58 (95% CI, 0.38-0.88), investigators added.

Patients with grade 1 tumors were also 52% less likely to develop distant recurrence at 25-years compared with patients with grade 3 tumors (HR 0.48 [95% CI, 0.24-0.95]), the study authors reported.

In contrast, no significant difference in the disease recurrence-free interval (DRFI) again at 25 years was seen between patients with grade 2 and those with grade 3 tumors. Nor were any significant differences seen in long-term DRFI by either PR or Ki-67 status.

“Clinically used breast cancer markers are known to be associated with patient survival for up to 10 years after diagnosis,” Dar and colleagues wrote. “The STO-3 clinical trial follow-up data now enable DRFI outcome assessment for up to 25 years after primary diagnosis as well as examination of outcomes among those who received adjuvant tamoxifen therapy,” investigators added.

The STO-3 clinical trial originally enrolled 1,780 postmenopausal women with lymph node-negative breast cancer and tumors with a diameter of 30 mm or less. Women were enrolled between 1976 and 1990 and patients were randomized to receive adjuvant tamoxifen at a dose of 40 mg a day or no endocrine therapy.

“In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy,” the investigators wrote.

Looking at long-term treatment benefit with tamoxifen, they found a significant 47% reduction in the risk of long-term distant recurrence in patients with larger T1c tumors treated with tamoxifen (HR 0.53 [95% CI, 0.32-0.89]) compared to those who did not receive adjuvant treatment. There was also a 66% reduction in the risk of distant recurrence among patients with T2 tumors who received tamoxifen (HR 0.34 [95% CI, 0.16-0.73]) compared with patients who did not receive adjuvant tamoxifen. The same risk reduction was not seen, however, among those with the smallest tumors regardless of adjuvant treatment, investigators noted.

Similarly, patients with grade 1 tumors who received adjuvant treatment had a 76% lower risk of distant recurrence compared to those who did not receive adjuvant treatment (HR 0.24 [95% CI, 0.07-0.82]) while for those with grade 2 tumors, the risk of long-term distant recurrence was 50% lower (HR 0.50 [95% CI, 0.31-0.80]) compared to those who did not receive adjuvant treatment. In contrast, no significant treatment benefit from adjuvant tamoxifen was seen among patients with grade 3 tumors.

Patients with both PR-positive disease as well as those who had median to high Ki-67 expression also benefited from adjuvant tamoxifen.

For those with PR-positive disease, tamoxifen recipients had a 62% reduction in the risk of long-term distant recurrence compared with those who did not receive endocrine treatment at a HR of 0.38 (95% CI, 0.24-0.62).

Patients who had median to high Ki-67 expression levels had a similar, 61% reduction in the risk of long-term distant recurrence with adjuvant treatment (HR 0.39 [95% CI, 0.17-0.92]), the authors noted.

Even patients with low levels of Ki-67 expression had a 55% lower risk of distant recurrence when treated with adjuvant tamoxifen (HR 0.45 [95% CI, 0.29-0.71]) compared to the untreated arm.

Commenting on the findings, Robert Charles Burton, MD, PhD, Monash School of Public Health and Preventive Medicine, Melbourne, Australia, pointed out that life-long follow-up of breast cancer patients began with the International Breast Cancer Study Group (IBCSG) clinical trials I to V which included follow-up of participants since 1978.

“The IBCSG reported in 2016 that the duration of breast cancer-free interval, the primary outcome measure, from diagnosis and attempted curative treatment for women with ER-positive operable breast cancer remained significantly higher than that of women with ER-negative breast cancer for a median follow-up of 24 years,” Burton observed.

Burton went on to note that Dar et al’s study, like the IBCSG trials, “was also performed in the context of increasing recognition that breast cancer is a very complex cancer and that mammographic screening, which is based on the assumption that breast cancer can be detected by a radiographic technique that depends on the density of potentially neoplastic tissue versus general breast density: however, this approach does not take into account molecular genetic studies of all the major forms of breast cancer, including sporadic, familial, and inherited.”

He noted that the complexity of the disease is currently being studied by the Women Informed to Screen Depending on Measures of Risk (WISDOM) clinical trial, “which incorporates integrated and integral biomarkers, including single and polygenic risk factors, into a pragmatic clinical trial in which the participating women can choose their randomization arm,” and added that the current study is an important addition to the research.

Dar et al noted that patients with ER-positive tumors have a continuous long-term risk of distant recurrence and death compared with patients with ER-negative tumors. Indeed, the authors pointed out that roughly half of patients with ER-positive disease do not benefit from endocrine therapy and that approximately one-quarter of them develop distant metastasis and die of breast cancer.

Burton suggested that a priority for breast cancer screening is to measure breast cancer stage at diagnosis over a decade or more in patients undergoing screening mammography in order to evaluate whether screening leads to downstaging of the disease from advanced to more curable stages. “If it does not, then screening is harmful rather than beneficial,” he suggested.

Burton also noted that this issue is “particularly relevant” in the treatment of early breast cancer where adjuvant external beam radiotherapy has been used for decades for women with early breast cancer undergoing anything other than a mastectomy. “Unfortunately, this radiotherapy has been associated with a significant increase in all-cause mortality from myocardial infarction and lung cancers,” Burton wrote. “In future studies, Dar and colleagues may wish to consider ascertaining all-cause mortality among participants in the Stockholm tamoxifen clinical trial who received adjuvant external beam radiotherapy.”

1. Tumor size and grade were key clinical biomarkers that predicted long-term survival in women with ER-positive, ERBB2-negative breast cancer.

2. Women with larger tumors, lower tumor grades, and PR-positive tumors gained significant treatment benefit from adjuvant tamoxifen.

Pam Harrison, Contributing Writer, BreakingMED™

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Topic ID: 78,22,730,22,691,192,925