Quicker Fertility Rebound in Young Women With Breast Cancer

M. Alexander Otto, PA, MMS

April 16, 2021

For a young woman diagnosed with breast cancer, the prospect that the treatment needed for the cancer may irreversibly impair fertility piles on distress.

A new study from China raises the hope that the standard chemotherapy regimen can be changed to preserve fertility without compromising survival.

Researchers found that removing cyclophosphamide from the adjuvant chemotherapy regimen (leaving epirubicin and placlitaxel) increased the likelihood of an early return of menses, and there was a trend toward improved disease-free survival.

The phase 3 SPECTRUM trial involved 521 women with ER-positive, HER2-negative breast cancer who had undergone definitive surgery. The average age of the patients was 34 years.

Cyclophosphamide is a standard component of adjuvant chemotherapy, but it's strongly associated with premature ovarian failure and infertility, a devastating possibility for young patients.

"For the first time, we demonstrate that a cyclophosphamide-free regimen [can] increase the rate of menses recovery without compromising survival," say the researchers, led by Ke-Da Yu, MD, PhD, of the Fudan University Shanghai Cancer Center, Shangai, China.

They also report that among the women who tried to conceive at a later date, there was a higher pregnancy success rate among those who did not take cyclophosphamide.

"Our findings can be extrapolated to patients with other subtypes of breast cancer, such as triple-negative or HER2-enriched, because the effect of paclitaxel and cyclophosphamide on menstrual resumption is not subtype-specific," the investigators comment.

The results were published online April 2 in the Journal of the National Cancer Institute.

This is the first prospective trial specifically designed to find an adjuvant breast cancer regimen less toxic to the ovaries. The "investigators...should be applauded," say Matteo Lambertini, MD, PhD, a medical oncologist at the University of Genova, Genova, Italy, and medical oncologist Ann Partridge, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, in an accompanying editorial.

Although promising, there are a few caveats, say the editorialists. They note that in a past trial of doxorubicin and docetaxel in lieu of a cyclophosphamide regimen, disease outcomes were inferior. There is also a question as to whether these SPECTRUM results apply to non-Asian women.

The editorialists also note that enrollment in this trial ended in 2016, before it was recommended that ovarian suppression be used in conjunction with adjuvant chemotherapy to prevent premature menopause.

"[It's] notable that the absolute benefit in reducing [premature ovarian insufficiency] rates with the use of a cyclophosphamide-free regimen is similar to the effect demonstrated with the administration of a gonadotropin-releasing hormone agonist during cyclophosphamide-based chemotherapy," they comment. It's possible that combining the two approaches might have an additive effect, but for now the possibility remains unknown.

In addition, the SPECTRUM trial predates the widespread use of genetic testing to guide treatment, the editorialists point out.

"Therefore, caution should be taken in adopting wholesale such regimens," Lambertini and Partridge say.

Switch to Paclitaxel

The Chinese team was inspired by previous reports that swapping out cyclophosphamide for paclitaxel did not reduce adjuvant efficacy in the general breast cancer population.

The SPECTRUM trial randomly assigned 260 women to receive a cyclophosphamide-free regimen of epirubicin (75 mg/m2) and paclitaxel (175 mg/m2) every 3 weeks for four cycles followed by weekly paclitaxel (80 mg/m2) for 12 weeks.

Another 261 women were randomly assigned to receive cyclophosphamide (600 mg/m2) and epirubicin (75 mg/m2) every 3 weeks for four cycles followed by weekly paclitaxel (80 mg/m2) for 12 weeks. These patients constituted the control group.

A year after completing chemotherapy, 63.1% of the cyclophosphamide-free arm, vs 48.3% of the control group, had resumed menses, defined as having two consecutive menstrual cycles or one cycle but with premenopausal levels of estradiol and follicle-stimulating hormone (P < .001).

Another caveat of the study is that assessments of women who resumed menses were conducted at the 1-year point; rates may have been higher in the cyclophosphamide arm had the investigators conducted the assessments at 2 years, the editorialists say.

Five-year disease-free survival was 84.7% in the cyclophosphamide-free arm, vs 78.3% in the control group, an absolute difference of 14.8% (P = 0.07).

Patients with node-positive disease appeared to benefit the most from cyclophosphamide sparing.

There were no statistically significant differences in overall or distant disease-free survival.

Higher Pregnancy Rates

Almost 18% of women in the experimental arm reported trying to conceive, and 9.6% of them did so. About 10% of women in the cyclophosphamide arm tried to conceive, but only 2.7% did so (P = .03).

The median interval between randomization and pregnancy was 42 months.

For all of the women who became pregnant, endocrine therapy was interrupted. "Women who temporarily interrupt endocrine therapy due to pregnancy should be reminded to resume endocrine therapy following attempted or successful pregnancy," the investigators said.

The patients were taking tamoxifen at least 5 years after receiving chemotherapy, most often as monotherapy. Five percent of the patients underwent upfront ovarian suppression with an aromatase inhibitor, which is a current standard option.

The study was supported by the National Natural Science Foundation of China and other organizations. The investigators have disclosed no relevant financial relationships. Lambertini has consulted for and/or has received speakers fees from Roche, AstraZeneca, Lilly, Novartis, and other companies.

J Natl Cancer Inst. Published online April 2, 2021. Abstract, Editorial

M. Alexander Otto is a physician assistant and award-winning medical journalist who has previously worked for several major news outlets, including McClatchy and Bloomberg BNA. He is a former MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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