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NEWS New Hope for Young Breast Cancer Patients By Judy Peres A dding a hormone-suppressing drug to chemotherapy helps avert premature menopause—one of the most distressing side effects of treatment—in hormone-insensitive breast cancer patients, according to a recent clinical trial that some oncologists called practice-changing. “Preserving fertility is a common and important concern among younger women diagnosed with cancer, and these findings offer a simple, new option for women with breast cancer, or possibly other cancers,” said lead study author Halle Moore, M.D., of the Cleveland Clinic in Cleveland, Ohio, who presented the findings at the 2014 annual meeting of the American Society of Clinical Oncology. In the phase III intergroup trial known as SWOG S0230, or POEMS (Prevention of Early Menopause Study), women with early breast cancer who received the luteinizing hormone-releasing hormone (LHRH) goserelin in addition to chemotherapy were 64% less likely to develop premature ovarian failure than women who received chemotherapy alone, and they were more likely to get pregnant. Unexpectedly, women who received goserelin were also 50% more likely to be alive and well 4 years later. In the study, 257 premenopausal women with stage I–IIIA estrogen receptor (ER)– negative and progesterone receptor (PR)– negative breast cancer were randomized to treatment with cyclophosphamide-containing chemotherapy alone or chemotherapy plus goserelin. Goserelin (Zoladex) was given as monthly injections starting 1 week before the first chemotherapy treatment. Two years after starting treatment, 8% of women in the goserelin arm had ovarian failure (defined as cessation of menstrual periods and postmenopausal levels of folliclestimulating hormone), compared with 22% of women in the control arm. Twenty-two women assigned to goserelin plus chemotherapy became pregnant, whereas only 12 assigned to chemotherapy alone became jnci.oxfordjournals.org pregnant. Sixteen patients in the goserelin arm delivered at least one healthy baby, compared with eight in the control arm. Goserelin was not associated with increased risk of miscarriage or pregnancy termination. “Premenopausal women beginning chemotherapy for early breast cancer sho uld consider this new option to prevent premature ovarian failure,” said Kathy Albain, M.D., of Loyola University Medical Center in suburban Chicago, the study’s senior author. “I think it will be practicechanging, not just to preserve fertility but to prevent premature menopause, which can be debilitating.” Chemotherapy-induced menopause tends to come on suddenly, so symptoms—including vaginal dryness, hot flashes, sleep disturbance, and mood changes—may be more intense. “Preserving fertility is a common and important concern among younger women diagnosed with cancer, and these findings offer a simple, new option for women with breast cancer, or possibly other cancers.” Since most women survive breast cancer, “survivorship issues have become paramount,” said Claudine Isaacs, M.D., codirector of the breast cancer program at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. For younger patients, “preservation of fertility is key. Anything we can do to allow these women to live a normal life is the goal.” Patricia Ganz, M.D., director of cancer prevention and control research at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, said, “Preserving fertility is an important component of quality survivorship care. This study provides strong evidence for a safe and effective strategy for younger women with breast cancer to preserve ovarian function and the possibility of pregnancy.” George Sledge, M.D., chief of oncology at Stanford University, agreed: “If I had a young ER-negative patient who wanted to have children, I’d offer it to her, sure.” Sledge noted that the trial’s primary endpoint had a wide confidence interval, because the study was statistically underpowered. (Its original accrual target was 416.) But “it’s as good as we’re going to get,” Sledge said. “It’s hard to randomize patients in this setting. This was an international Halle Moore, M.D. effort, and it still didn’t get all the patients it wanted. But even so, they showed a significantly reduced likelihood of premature menopause.” Albain stressed that the impact of the trial goes beyond fertility preservation. “We have not yet had a trial of anything to prevent a major toxicity” caused by chemotherapy intended to cure cancer, she said. “In this case, the toxicity is that of sudden menopause and all the symptoms that come with it that often make women miserable. To prevent that in a substantial number of women is an advance that will improve quality of life for thousands of premenopausal women with ER-negative disease embarking on adjuvant or neoadjuvant chemotherapy.” About 25% of breast cancers—approximately 58,000 per year in the U.S. (68,000, if one includes in situ cases)—occur in women younger than 50 years. Overall, about one-quarter of all breast cancer cases JNCI | News 1 of 8 NEWS are hormone receptor negative, but the proportion is greater in younger women. Almost all women taking chemotherapy stop menstruating, at least temporarily. The risk of permanent premature menopause varies widely depending on age and treatment regimen, among other variables. LHRH analogues temporarily shut down ovarian function, which is believed to protect follicles from chemotherapy damage, but the mechanism of action is unknown. Breast cancer researcher Peter Ravdin, M.D., Ph.D., noted that other researchers have looked at the same question, and some have reported strikingly similar results. An Italian group led by Lucia Del Mastro, M.D., of the National Institute for Cancer Research in Genoa, randomized 281 early breast cancer patients to receive standard chemotherapy or chemotherapy plus triptorelin, an LHRH analogue similar to goserelin. They reported in JAMA (July 20, 2011) that 12 months after the last cycle of chemotherapy, the rate of early menopause was 25.9% in the control arm and 8.9% in the triptorelin arm. In that trial, which included hormone-sensitive patients, only about 20% were hormone receptor negative. Two years later, Del Mastro and colleagues published a meta-analysis of similar trials of LHRH analogues (also called gonadotropin-releasing hormone agonists). They included nine randomized trials evaluating the efficacy of ovarian suppression to prevent premature ovarian failure in cancer patients undergoing chemotherapy. Six were in breast cancer, one in ovarian cancer, and two in lymphoma. Although several trials were negative, the overview still found a statistically significant reduction in risk of premature menopause (odds ratio = 0.43) in patients receiving LHRH analogues. “So I would expect the LHRH to help prevent early menopause,” Ravdin said. “The unexpected result in the POEMS trial was that goserelin seemed to have a powerful adjuvant effect in hormone receptor– negative patients. And the effect is so large that I think it is unlikely to be a statistical fluke.” After 4 years, 12 patients who received goserelin had relapsed or died, compared with 24 of those receiving standard chemotherapy. Overall survival at 4 years was 92% (97/105) in the goserelin group, compared with 82% (96/113) in the control group. “There may very well be a direct anticancer effect of the LHRH analogue in combination with chemotherapy,” Albain said. “LHRH receptors are present in most triple-negative breast cancers.” Forthcoming results could clarify this question. The British OPTION trial, which began enrolling hormone-insensitive breast cancer patients 10 years ago, is due to report its results. And Del Mastro’s group should update their results soon. Another researcher eager to see what new information these results can provide is Mitchell Rosen, M.D., director of the fertility preservation program at the University of California, San Francisco. Rosen called the survival advantage reported by the POEMS investigators awesome. “Mechanistically, I don’t understand it,” he said. “But it’s provocative. We need to do further studies to determine whether it’s true. It will be interesting to see what it looks like with hormone receptor–positive patients and with longer-term results.” The POEMS trial gives more confidence that using an LHRH analogue can increase a woman’s odds of resuming menstruation after chemotherapy, Rosen said. “But we still have only preliminary data that these women can get pregnant. We know people can have [menstrual] cycles and still have trouble getting pregnant. So I wouldn’t use an LHRH analogue to replace fertility preservation [i.e., harvesting and freezing the patient’s eggs or embryos before chemotherapy]. You can say it’s an adjunct treatment, to be used in addition to fertility preservation treatment.” One unanswered question, Rosen said, is how long restored menstruation will last. “A 28-year-old breast cancer patient who takes goserelin during chemotherapy may be able to get pregnant when she’s 30,” he said, “but can she still get pregnant at age 35? The reproductive window may not be the same.” Another question is whether a woman with fewer eggs will get the same protection as one who has more eggs. Rosen stressed that treatment needs to be individualized, and a multidisciplinary team including both oncologists and reproductive endocrinologists can best do that. “Each patient of reproductive age needs to be evaluated,” he said. “She needs to understand her risk, and we need a better understanding of what she wants. Then we can lay out the options.” © Oxford University Press 2014. DOI:10.1093/jnci/dju308 First published online September 11, 2014 Alleviating the Crisis in Cancer Care By Cathryn M. Delude A 2013 Institute of Medicine (IOM) report warned that U.S. cancer care is in a state of crisis, for reasons that will worsen in coming decades. The population is aging and, since cancer is primarily a disease of 2 of 8 News | JNCI aging, so is the population of cancer patients, whose age-associated health conditions complicate treatment. Cancer care is becoming more complex, making it harder for patients to make informed decisions about treatment options, while oncologists often have little incentive or time to discuss an individual’s values and preferences. The cancer workforce is shrinking at all levels—and among potential partners in primary care and geriatrics. Vol. 106, Issue 9 | September 10, 2014