In the Journals

Clinical-risk stratification shows prognostic utility among women with breast cancer

Joseph A. Sparano, MD
Joseph A. Sparano

Adding clinical-risk stratification based on tumor size and histologic grade to the 21-gene breast cancer recurrence score yielded prognostic information that could help identify younger women who may benefit from more effective antiestrogen therapy than a course of tamoxifen, according to results of a prospective study published in The New England Journal of Medicine.

However, this approach was not predictive of chemotherapy benefit.

“In women with hormone receptor-positive, HER2-negative early breast cancer, the 21-gene recurrence score assay provides prognostic information that is independent of clinicopathological features, and a high-score indicates a higher rate of distant recurrence and is predictive of chemotherapy benefit,” Joseph A. Sparano, MD, clinical oncologist at Montefiore Medical Center and professor of medicine and obstetrics, gynecology and women’s health at Albert Einstein College of Medicine, and colleagues wrote. “Here, we report the results of secondary analyses of the TAILORx trial that were designed to determine whether clinical risk ... adds prognostic information to the 21-gene recurrence score and predictive information regarding the benefit of chemotherapy.”

Study results

Sparano and colleagues analyzed 9,427 women with hormone receptor-positive, HER2-negative, axillary node-negative early breast cancer who underwent testing with the 21-gene Oncotype DX (Genomic Health) assay and evaluation of clinical risk for recurrence based on tumor size and histological grade.

Researchers evaluated the effect of clinical risk by calculating HRs for distant recurrence using Cox proportional-hazards models.

Most of the women (70.2%) had low clinical risk, defined as having tumors no larger than 3 cm in diameter and with a low histologic grade, no larger than 2 cm with an intermediate grade, or no larger than 1 cm with a high grade. The remainder of the women (29.8%) had high clinical risk based on failure to meet these criteria.

Distribution between the risk groups appeared similar according to age (50 years or younger vs. older than 50 years). The majority of premenopausal women aged 50 years and younger received tamoxifen alone as initial endocrine therapy.

Results showed that the level of clinical risk appeared prognostic of distant recurrence among women with a 21-gene recurrence score of 11 to 25, considered intermediate risk, who were randomly assigned to endocrine therapy (HR = 2.73; 95% CI, 1.93-3.87) or chemotherapy plus endocrine therapy (HR = 2.41; 95% CI, 1.66-3.48), as well as among women with a recurrence score of 26 to 100, considered high risk, who were assigned chemotherapy plus endocrine therapy (HR = 3.17; 95% CI, 1.94-5.19).

A model of distant recurrence that included clinical risk and the recurrence score for patients with an intermediate recurrence score showed significant prognostic information from the clinical-risk level (HR for high vs. low risk = 2.42; P < .001) and the continuous recurrence score (HR for an increase of 1 point in the recurrence score = 1.08; P < .001).

Researchers then estimated treatment HRs for 6,496 women with an intermediate recurrence score who were randomly assigned to endocrine therapy alone or with chemotherapy. The level of clinical risk did not predict chemotherapy benefit in all women who had an intermediate recurrence score, nor when researchers looked at women aged older or younger than 50 years. Researchers observed a trend toward chemotherapy benefit among women aged younger than 50 years with a recurrence score of 21 to 25, but these trends did not vary according to clinical risk.

Age-stratified Kaplan-Meier estimates showed similar rates of distant recurrence at 9 years among women aged older than 50 years with an intermediate risk score, regardless of chemotherapy use or clinical risk.

Women aged 50 years or younger who received only endocrine therapy demonstrated an estimated rate of distant recurrence at 9 years of 5% with a low recurrence score, regardless of clinical risk category, and 4.7 ± 1% with an intermediate recurrence score and low clinical risk.

The estimated rate of distant recurrence at 9 years topped 10% among women aged 50 years or younger who received endocrine therapy alone and had a high clinical risk and an intermediate recurrence score (12.3 ± 2.4%) and those who received chemotherapy and endocrine therapy and had a high recurrence score (15.2 ± 3.3%).

Conclusions

From these data, researchers concluded that younger women with a recurrence score of 11 to 25 and high clinical risk may be undertreated with endocrine therapy alone. Researchers also observed risk differences in the subgroups of women with a recurrence score of 16 to 20 and 21 to 25, as well as the potential of a chemotherapy benefit for women at low clinical risk with a recurrence score of 21 to 25.

Adding ovarian suppression and an aromatase inhibitor might give a reduction in risk equivalent to that observed using adjuvant chemotherapy, according to the researchers.

“Given the incremental benefits observed with ovarian suppression plus tamoxifen or an aromatase inhibitor as compared with tamoxifen alone in premenopausal women, and the low percentage of premenopausal women who received ovarian suppression in TAILORx, it is possible that similar incremental benefits observed in younger women who received chemotherapy and had a recurrence score of 16 to 25 could be achieved with ovarian suppression and an aromatase inhibitor, as observed in other trials,” they wrote. “... For patients who are approaching menopause, a strategy of an initial 2-to-5-year course of tamoxifen followed by a switch to an aromatase inhibitor at the time of natural menopause is another reasonable approach.”

Overall, researchers concluded that the binary clinical risk stratification based on tumor size and histologic grade added prognostic information to the 21-gene recurrence score, but was not predictive of a large chemotherapy benefit.

“The addition of this information enabled more precise identification of subgroups of younger women who may derive some benefit from more effective antiestrogen therapy than a course of tamoxifen,” they added.

Tumor genetic analysis has contributed substantially to treatment strategies for certain types of cancers, including breast cancer, lung cancer, colon cancer and melanoma. Deriving polygenic risk scores from germline genotyping has not yet had a clinical impact, but that could change soon, David J. Hunter, MBBS, MPH, professor of cancer prevention and epidemiology at Harvard T.H. Chan School of Public Health, and Dan L. Longo, MD, professor of medicine at Harvard Medical School, wrote in an accompanying editorial.

“Distinguishing between results that warrant a change in practice and those that do not will not be a ‘precise’ process,” Hunter and Longo wrote. “Medicine in the molecular era will be no more precise than in private eras — evidence synthesis, clinical judgement, and patient preferences all factor in.”– by John DeRosier

Disclosures: Sparano reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Hunter reports employment with The New England Journal of Medicine. Longo reports editorial roles with The New England Journal of Medicine.

Joseph A. Sparano, MD
Joseph A. Sparano

Adding clinical-risk stratification based on tumor size and histologic grade to the 21-gene breast cancer recurrence score yielded prognostic information that could help identify younger women who may benefit from more effective antiestrogen therapy than a course of tamoxifen, according to results of a prospective study published in The New England Journal of Medicine.

However, this approach was not predictive of chemotherapy benefit.

“In women with hormone receptor-positive, HER2-negative early breast cancer, the 21-gene recurrence score assay provides prognostic information that is independent of clinicopathological features, and a high-score indicates a higher rate of distant recurrence and is predictive of chemotherapy benefit,” Joseph A. Sparano, MD, clinical oncologist at Montefiore Medical Center and professor of medicine and obstetrics, gynecology and women’s health at Albert Einstein College of Medicine, and colleagues wrote. “Here, we report the results of secondary analyses of the TAILORx trial that were designed to determine whether clinical risk ... adds prognostic information to the 21-gene recurrence score and predictive information regarding the benefit of chemotherapy.”

Study results

Sparano and colleagues analyzed 9,427 women with hormone receptor-positive, HER2-negative, axillary node-negative early breast cancer who underwent testing with the 21-gene Oncotype DX (Genomic Health) assay and evaluation of clinical risk for recurrence based on tumor size and histological grade.

Researchers evaluated the effect of clinical risk by calculating HRs for distant recurrence using Cox proportional-hazards models.

Most of the women (70.2%) had low clinical risk, defined as having tumors no larger than 3 cm in diameter and with a low histologic grade, no larger than 2 cm with an intermediate grade, or no larger than 1 cm with a high grade. The remainder of the women (29.8%) had high clinical risk based on failure to meet these criteria.

Distribution between the risk groups appeared similar according to age (50 years or younger vs. older than 50 years). The majority of premenopausal women aged 50 years and younger received tamoxifen alone as initial endocrine therapy.

Results showed that the level of clinical risk appeared prognostic of distant recurrence among women with a 21-gene recurrence score of 11 to 25, considered intermediate risk, who were randomly assigned to endocrine therapy (HR = 2.73; 95% CI, 1.93-3.87) or chemotherapy plus endocrine therapy (HR = 2.41; 95% CI, 1.66-3.48), as well as among women with a recurrence score of 26 to 100, considered high risk, who were assigned chemotherapy plus endocrine therapy (HR = 3.17; 95% CI, 1.94-5.19).

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A model of distant recurrence that included clinical risk and the recurrence score for patients with an intermediate recurrence score showed significant prognostic information from the clinical-risk level (HR for high vs. low risk = 2.42; P < .001) and the continuous recurrence score (HR for an increase of 1 point in the recurrence score = 1.08; P < .001).

Researchers then estimated treatment HRs for 6,496 women with an intermediate recurrence score who were randomly assigned to endocrine therapy alone or with chemotherapy. The level of clinical risk did not predict chemotherapy benefit in all women who had an intermediate recurrence score, nor when researchers looked at women aged older or younger than 50 years. Researchers observed a trend toward chemotherapy benefit among women aged younger than 50 years with a recurrence score of 21 to 25, but these trends did not vary according to clinical risk.

Age-stratified Kaplan-Meier estimates showed similar rates of distant recurrence at 9 years among women aged older than 50 years with an intermediate risk score, regardless of chemotherapy use or clinical risk.

Women aged 50 years or younger who received only endocrine therapy demonstrated an estimated rate of distant recurrence at 9 years of 5% with a low recurrence score, regardless of clinical risk category, and 4.7 ± 1% with an intermediate recurrence score and low clinical risk.

The estimated rate of distant recurrence at 9 years topped 10% among women aged 50 years or younger who received endocrine therapy alone and had a high clinical risk and an intermediate recurrence score (12.3 ± 2.4%) and those who received chemotherapy and endocrine therapy and had a high recurrence score (15.2 ± 3.3%).

Conclusions

From these data, researchers concluded that younger women with a recurrence score of 11 to 25 and high clinical risk may be undertreated with endocrine therapy alone. Researchers also observed risk differences in the subgroups of women with a recurrence score of 16 to 20 and 21 to 25, as well as the potential of a chemotherapy benefit for women at low clinical risk with a recurrence score of 21 to 25.

Adding ovarian suppression and an aromatase inhibitor might give a reduction in risk equivalent to that observed using adjuvant chemotherapy, according to the researchers.

“Given the incremental benefits observed with ovarian suppression plus tamoxifen or an aromatase inhibitor as compared with tamoxifen alone in premenopausal women, and the low percentage of premenopausal women who received ovarian suppression in TAILORx, it is possible that similar incremental benefits observed in younger women who received chemotherapy and had a recurrence score of 16 to 25 could be achieved with ovarian suppression and an aromatase inhibitor, as observed in other trials,” they wrote. “... For patients who are approaching menopause, a strategy of an initial 2-to-5-year course of tamoxifen followed by a switch to an aromatase inhibitor at the time of natural menopause is another reasonable approach.”

PAGE BREAK

Overall, researchers concluded that the binary clinical risk stratification based on tumor size and histologic grade added prognostic information to the 21-gene recurrence score, but was not predictive of a large chemotherapy benefit.

“The addition of this information enabled more precise identification of subgroups of younger women who may derive some benefit from more effective antiestrogen therapy than a course of tamoxifen,” they added.

Tumor genetic analysis has contributed substantially to treatment strategies for certain types of cancers, including breast cancer, lung cancer, colon cancer and melanoma. Deriving polygenic risk scores from germline genotyping has not yet had a clinical impact, but that could change soon, David J. Hunter, MBBS, MPH, professor of cancer prevention and epidemiology at Harvard T.H. Chan School of Public Health, and Dan L. Longo, MD, professor of medicine at Harvard Medical School, wrote in an accompanying editorial.

“Distinguishing between results that warrant a change in practice and those that do not will not be a ‘precise’ process,” Hunter and Longo wrote. “Medicine in the molecular era will be no more precise than in private eras — evidence synthesis, clinical judgement, and patient preferences all factor in.”– by John DeRosier

Disclosures: Sparano reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Hunter reports employment with The New England Journal of Medicine. Longo reports editorial roles with The New England Journal of Medicine.