Determining Which Breast Cancer Patients Can Skip Chemotherapy

CHICAGO—The overwhelming majority of women with invasive breast cancer who are node-negative, both those with positive and negative estrogen receptors, routinely receive chemotherapy today. "But it’s worthwhile to step back and ask whether we can define groups of women who should not routinely receive chemotherapy," Monica Morrow, MD, said at the Lynn Sage Breast Cancer Conference.

Dr. Morrow is professor of surgery and director of the Lynn Sage Comprehensive Breast Center, Northwestern University Medical School.

"Potentially, there are three such groups," she noted. The first includes patients with an extremely favorable prognosis who are unlikely to experience any meaningful prolongation of survival from a treatment that could be both toxic and costly.

She would also exclude patients in whom clear evidence of benefit from chemotherapy is lacking and those in whom toxicity would outweigh benefits.

Extremely Favorable Prognosis

The "extremely favorable prognosis" group includes subsets of node-negative breast cancer patients with tumors no larger than 1 cm. Survival rates (at 5 to 10 years, depending on the study) in these women exceed 90%, according to a number of reliable databases, she said.

In the Breast Cancer Diagnosis and Demonstration Project (BCDDP), stage I cancers had an 8-year survival of 90%; those less than 1 cm were associated with a 95% survival rate. Surveillance, Epidemiology, and End Results (SEER) data from the same period are similar. In 5,479 women, stage I cancer carried a 92% 5-year survival rate.

Age appears to have little effect on this subpopulation. "We have the idea that breast cancer in young women may be different. But in the BCDDP study, for tumors less than 1 cm, the 8-year survival for all age groups between 40 and 65 was extremely high," she said.

In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-21 study of women with invasive carcinomas 1 cm or smaller with negative axillary nodes, 5-year survival was 97%, regardless of treatment, although there was some difference in local failure rate.

Rosen et al have noted a 20-year survival of 88% among women with tumors 1 cm and smaller vs 72% in tumors 1.1 to 2 cm in size (J Clin Oncol 11:2090, 1993). That particular series also found that ipsilateral cancer as a cause of death was overlapped by cardiovascular disease. Furthermore, the risk of developing another type of cancer (non-breast) was identical to the risk of dying of breast cancer during that same time period.

"So multiple other forces of mortality are equal to that of breast cancer in these women with very small tumors," Dr. Morrow pointed out, "though this is not so for the T1C group [tumors 1.1 to 2 cm]. Breast cancer remains for them the overwhelming source of mortality."

Tumor Grade

Histologic tumor grade does not appear to be influential in these small tumors, she said. In the National Cancer Data Base of 22,288 patients with tumors less than 1 cm, 5-year survival was 96% with grade 3 lesions and 98% with grade 1 lesions.

"So there does not appear to be a poor-prognosis group in these small tumors. Tumor size less than 1 cm is associated with an extremely favorable prognosis in basically any subset of patients," she emphasized.

The addition of histologic grade does help select patients who may receive only minimal benefit from chemotherapy in larger tumors (T1C).

Grade 1 tumors clearly have a statistically different outcome than tumors of higher grade, regardless of the stage of disease. All stage I breast cancers up to 2 cm carry a 10-year survival rate of 95% if they are histologic grade 1, she noted, reminding listeners that virtually all grade 1 tumors are hormone-receptor positive.

"What becomes particularly important about this is that the likelihood of having a grade 1 tumor is related to the size of the tumor," she pointed out. "The smaller the tumor, the more likely it is to be low grade. So with screening mammography detecting more tumors at small sizes, the likelihood is increased of seeing grade 1 tumors. If one does not recognize the favorable prognostic implications of grade 1 tumors, there is a significant likelihood of overtreatment in a subset of women with extremely good prognosis."

Tumor Type

Several special histologic types, even up to 3 cm, are associated with good prognosis. These include tubular, mucinous, papillary, and adenocystic tumors, and possibly medullary tumors. The 20-year disease-free survival rate has been noted to be 87% for these special subtypes, which account for about 4% of all breast cancers.

"For tumors up to 3 cm, there remains a good prognosis for these special subtypes," Dr. Morrow said. "It is difficult to find anyone in the literature who has ever died of node-negative tubular carcinoma, regardless of size." Similarly, she said, for mucinous carcinomas, the risk of dying is about one third the risk of dying of infiltrating ductal carcinoma, stage for stage.

Benefit vs Toxicity

There are a few other subsets of patients whose prognosis is so favorable that cytotoxic chemotherapy may not be warranted, she said.

The NSABP B-20 trial randomized ER-positive, node-negative women to tamoxifen (Nolvadex) or chemotherapy plus tamoxifen, and established that chemotherapy reduced breast-cancer-related events. However, all of the statistically significant benefit occurred in women under the age of 49.

"Not surprisingly, the addition of chemotherapy and the magnitude of benefit is related to the risk of relapse in the first place," she pointed out.

For tumors 2 cm or smaller, the number of events per 100 patients per year with tamoxifen alone was 2.75; the reduction with chemotherapy is from 2.75 down to a maximum of 1.9, "not an enormous benefit," she said. "You pay for this small benefit with toxicity—the risk of thromboembolic events associated with tamoxifen triples with the addition of chemotherapy."

Elaborating on the influence of age, Dr. Morrow added that the risk of breast cancer deaths is lower in ER-positive women over age 50, compared with younger women.

"So what we can say about the use of chemotherapy plus tamoxifen in receptor-positive node-negative postmenopausal women is that the benefits are small, there is definitely a toxicity trade-off, and it should be reserved for high-risk node-negative women, not routine use," she stated.

For patients age 70 and older with ER-negative, node-negative cancers, evidence of a survival benefit from adjuvant chemotherapy is less clear; several studies have suggested that there is not much gain from chemotherapy. Since comorbidity has an enormous impact in this group, Dr. Morrow recommended that chemotherapy not be urged for these patients. In contrast, in node-positive disease, there is a significant survival benefit from adjuvant chemotherapy, in spite of comorbid conditions, she said.