Progress Emerging With Optimal Adjuvant Therapy in Young Women With Breast Cancer

Mark Robson, MD

Determining the optimal adjuvant therapy in young women with breast cancer remains challenging, but some clarity is beginning to emerge. Younger women benefit from the addition of chemotherapy to tamoxifen and ovarian suppression may enhance survival rates, “but ovarian suppression provides a relatively small benefit and can come with significant treatment burdens,” Mark Robson, MD, said in a talk at the 2018 Lynn Sage Breast Cancer Symposium.

Robson, chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center in New York, began by reminding colleagues that breast cancer patients under age 40 have worse outcomes overall. Recent studies suggest this is largely due to increases in estrogen receptor (ER)-positive disease. “This implies that clinicians should apply a lower threshold when choosing chemotherapy in young estrogen receptor-positive patients, but not in young patients with triple negative or HER2-positive breast cancer,” he said.

Robson examined the issue of how genomic profiling can guide treatment in young ER-positive patients using the TAILORx trial.¹ He noted that, of the trial’s 6711 patients with intermediate recurrence scores (RS), only 311 (4.6%) were aged 40 or younger.

Robson reviewed the trial’s invasive disease-free survival (IDFS) data at 5 years and 9 years among women younger than 50. Those who had an RS of 11 to 15 saw only a 0.8% increase in IDFS among patients who received chemotherapy with endocrine therapy versus endocrine therapy alone. Patients with an RS of 16 to 20 who also received chemotherapy saw a 1.6% increase in the IDFS rate. But those with an RS of 21 to 25 who also received chemotherapy saw a slightly larger IDFS rate of 6.5%. “This is the point at which adding chemotherapy becomes reasonably clinically meaningful, although we probably need a longer follow-up to fully parse out the meaning,” Robson said.

Younger patients generally do not derive greater benefit from chemotherapy than patients in their 50s and 60s, Robson said. “Younger patients also do not derive greater benefit from more aggressive therapy than older patients,” he said. “But younger patients do derive greater benefit from the addition of chemotherapy to tamoxifen. This could be the result of ovarian suppression.”

Robson also considered the role of BRCA1/2 mutation status in this decision. “At this time, there is no evidence to support incremental adjuvant or neoadjuvant carboplatin specifically because of BRCA1/2 mutations, or mutations in other genes,” he said.

Finally, Robson discussed the issue of ovarian function suppression and whether it increases the benefits of tamoxifen. He noted that in combined results from the SOFT and TEXT trials, a total of 5738 patients were randomized.² Of these, 3066 underwent randomization in SOFT and were stratified according to nonreceipt of chemotherapy or receipt before randomization. This trial had 3 arms: tamoxifen alone, tamoxifen with ovarian suppression, or exemestane plus ovarian suppression. The primary analysis was tamoxifen with ovarian suppression versus tamoxifen alone. The secondary analysis was exemestane with ovarian suppression versus tamoxifen alone. For the combined SOFT/TEXT analysis, researchers considered the efficacy of exemestane with ovarian suppression versus tamoxifen with ovarian suppression.

In the SOFT comparisons, the researchers found that ovarian suppression improved disease-free survival (DFS) compared to tamoxifen alone, especially among patients who had received prior chemotherapy. Additionally, these patients had better DRFS and overall survival (OS).

In a separate SOFT/TEXT analysis, which examined tamoxifen with ovarian suppression versus exemestane with ovarian suppression, researchers found that ovarian suppression provided a relatively small benefit and came at a cost of significant toxicity.³ “About 20% of younger women discontinued treatment due to the treatment burden ovarian suppression created,” Robson said.

In 2016 ASCO convened a guideline panel, which attempted to parse the benefits of ovarian suppression based on clinical risk.⁴ The panel determined that higher-risk patients should receive ovarian suppression with endocrine therapy, whereas lower-risk patients should not.

For example, that means that patients with stage II and stage III disease who would receive chemotherapy should receive ovarian suppression and endocrine treatment, Robson said. Patients with high-risk stage I and stage II disease who might consider chemotherapy may also be offered a combination of ovarian suppression and endocrine function.

In contrast, patients with stage I cancers that do not warrant chemotherapy should receive endocrine therapy, but not ovarian suppression. Patients with node-negative tumors 1 cm or less in size should receive endocrine therapy, but not ovarian suppression, Robson said.

He also offered some qualifying statements on the ASCO guidelines, noting that the trials’ standard duration of ovarian suppression was only 5 years. “There were no data to assess ovarian suppression versus tamoxifen over a 10-year period,” Robson said. “Then there is the issue that no existing studies compare ovarian suppression with endocrine therapy versus chemotherapy with endocrine therapy.”

References

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.
2. Francis PA, Pagani O, Fleming GF, et al. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137. doi: 10.1056/NEJMoa1803164.
3. Saha P, Regan MM, Pagani O, et al. Treatment efficacy, adherence, and quality of life among women younger than 35 years in the international breast cancer study group TEXT and SOFT adjuvant endocrine therapy trials. J Clin Oncol. 2017;35(27):3113-3122. doi: 10.1200/JCO.2016.72.0946.
4. Rugo HS, Rumble RB, Macrae E, et al. Endocrine therapy for hormone receptor—positive metastatic breast cancer: American Society of Clinical Oncology guideline. J Clin Oncol. 2016;34(25):3069-3103. doi: 10.1200/JCO.2016.67.1487.

View more from the 2018 Lynn Sage Breast Cancer Symposium