Long-term outcomes of preventing premature menopause during chemotherapy

Compared with receiving chemotherapy alone, women with breast cancer who also received the hormonal drug triptorelin to achieve ovarian suppression had a higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate or disease-free survival, according to a study published in JAMA.

The majority of young women with invasive breast cancer are candidates to receive both chemotherapy and endocrine therapy. Loss of ovarian function and impaired fertility are possible consequences of anticancer treatments. Fertility concerns can affect treatment decisions of young women with breast cancer. Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy, according to background information in the article.

Lucia Del Mastro, M.D., of the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy and colleagues randomly assigned 281 premenopausal women (median age, 39 years) with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer to receive chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). The trial was conducted at 16 Italian sites. Women were enrolled between October 2003 and January 2008; last annual follow-up was June 2014. Median follow-up was 7.3 years.

The 5-year cumulative incidence estimate of menstrual resumption was 73 percent among the 148 patients in the LHRHa group and 64 percent among the 133 patients in the control group. Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1 percent) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6 percent) in the control group. Five-year disease-free survival was 80.5 percent in the LHRHa group and 84 percent in the control group. This increased but statistically nonsignificant risk appeared specific to the patients with hormone receptor-negative tumors.

The authors write that these results, together with the findings of another study (POEMS-SWOG S0230), “indicate that, in addition to fertility preservation strategies such as embryo and oocyte cryopreservation, temporary ovarian suppression with LHRHa is an option to preserve ovarian function in premenopausal women with early stage breast cancer receiving adjuvant chemotherapy.”

Lambertini et al. Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival. A Randomized Clinical Trial. JAMA. 2015;314(24):2632-2640. doi:10.1001/jama.2015.17291 [Abstract]

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Why does tamoxifen work better in some women?

The anti-hormone therapy tamoxifen can reduce breast cancer recurrence by about half in women with hormone-sensitive breast cancer. But it works better in some women than others. Researchers are not sure why.

We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes,” says Daniel L. Hertz, Pharm.D., Ph.D., an assistant professor in the University of Michigan College of Pharmacy and member of the U-M Comprehensive Cancer Center.

These tumor have found pathways to overcome anti-estrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics,” Hertz says.

One theory is that in some patients, tamoxifen is not activated to the more potent estrogen inhibitor endoxifen. Patients with low levels of endoxifen may have worse outcomes on tamoxifen.
A meta-analysis by the International Tamoxifen Pharmacogenetics Consortium points to genetic variants. Researchers found patients with certain variants on the gene CYP2D6 had worse survival. Later analyses of prospective clinical trials, however, did not find the same link.

New research presented by Hertz at the San Antonio Breast Cancer Symposium examined these prior studies to assess whether errors in genotyping – how they identify the genetic variants – could have accounted for the differing findings. Statistical deviations seen in the original meta-analysis had been attributed to genotyping error. But their secondary analysis revealed that statistical deviations were linked to enrolling patients from multiple institutions, not genotyping error.

Furthermore, advanced statistical modeling from Hertz and colleagues confirms that genotyping error would introduce negligible bias to the analyses of the prospective trials.

Genotyping from the tumor in these prospective clinical trials is not the reason these analyses are negative,” Hertz says. “Either there is some other reason that the later studies were negative or the initial study suggesting CYP2D6 as a marker was falsely positive.”

This leaves more questions than answers about tamoxifen efficacy.

In another study presented in San Antonio, Hertz and colleagues found that variants in CYP2D6 and another gene, CYP2C9, contribute to endoxifen exposure. Hertz suggests that it may not be one single marker that predicts whether tamoxifen works.

At this point we still have a hypothetical association between genotype and efficacy that has not been validated,” he says. “For now, there is no clinical benefit to using CYP2D6 to inform tamoxifen treatment decisions. We need to validate these hypotheses.”

San Antonio Breast Cancer Symposium, Dec. 8-12, 2015

Thyroid cancer patients report poor quality of life despite ‘good’ diagnosis

Thyroid cancer survivors report poor quality of life after diagnosis and treatment compared with other patients who are diagnosed with more lethal cancers, according to new research from the University of Chicago Medicine.

The findings, published  in the journal Thyroid, shed light on a rarely studied outcome for a growing group of patients who are expected to soon account for 10 percent of all of American cancer survivors.

Thyroid cancer patients have a nearly 98 percent five-year survival rate, according to the National Cancer Institute. More than 95 percent survive a decade, leading some to call it a “good cancer.” But those successful outcomes mean few thyroid cancer survivorship studies have been conducted.
UChicago Medicine researchers Briseis Aschebrook-Kilfoy, PhD, assistant research professor in epidemiology, and Raymon Grogan, MD, assistant professor of surgery, are trying to address that data gap. Together, they lead the North American Thyroid Cancer Survivorship Study (NATCSS).

For their most recent research, Aschebrook-Kilfoy and Grogan recruited 1,174 thyroid cancer survivors – 89.9 percent female with an average age of 48 – from across the U.S. and Canada. Participants were recruited through the thyroid cancer clinics at UChicago Chicago Medicine, the clinics of six other universities, as well as through thyroid cancer survivor support groups and social media.

The researchers then used City of Hope’s Quality of Life thyroid tool, a questionnaire that assesses physical, psychological, social and spiritual wellbeing to measure patient-reported quality of life. They found that thyroid cancer survivors reported an average of 5.56 out of 10 on the scale. That was worse than the mean quality of life score of 6.75 that was reported by survivors of other cancer types (including colorectal and breast cancer) that have poorer prognoses and more invasive treatments.

I think we all have this fear of cancer that has been engrained in our society,” Grogan said. “So, no matter what the prognosis is, we’re just terrified that we have a cancer. I think this shows that.”

After treatment, thyroid cancer survivors face a lifetime of cancer surveillance and an anxiety-inducing high rate of recurrence, which could contribute to their findings.

Aschebrook-Kilfoy and Grogan also found that patients who were younger, female, and less educated, as well as those who participated in survivorship groups, all reported even worse quality of life than other study participants. However, after the five-year mark, quality of life gradually starts to increase over time for both male and female thyroid cancer survivors.

The researchers will continue to track participants to further understand this data.

The goal of this study is to turn it into a long-term, longitudinal cohort,” said Grogan, who hopes to develop a tool that physicians can use to assess the psychological wellbeing of thyroid cancer survivors. “But, there was no way to do that with thyroid cancer because no one had ever studied quality of life or psychology of thyroid cancer before.”

Psychological wellbeing is part of the Institute of Medicine’s recommended survivorship care plans.
Thyroid cancer rates have increased dramatically in the past several decades, climbing about 5 percent a year. A 2011 study by Aschebrook-Kilfoy and Grogan found that thyroid cancer, which is most common in women, will double in incidence by 2019.

The increase that we’ve seen in the U.S. we’ve also seen in a number of countries worldwide,” Aschebrook-Kilfoy said. “And, even in lower incidence countries, you see a similar gender disparity.”
Thyroid cancer is the 8th most-common cancer in the U.S., with about 62,000 new cases diagnosed this year, according to NCI data.

Both researchers believe the rise in thyroid cancer rates could be due in part to more advanced imaging tools that catch cases that might have otherwise gone undiagnosed. They also attribute it to emerging environmental and lifestyle risk factors.

Radiation exposure is one of the main risk factors that is known to cause cancer of the thyroid,” Grogan said. “One environmental hypothesis is that ultra-low doses of radiation over decades could cause some type of change in the thyroid.”

Another common environmental hypothesis: pesticides and other chemicals in the environment have been shown to affect thyroid hormone levels, an area where Aschebrook-Kilfoy has focused much of her research.

Along with that there is literature that shows there’s an increased risk of thyroid cancer with people who are obese,” she said.

Other studies have even shown that proximity to volcanic activity (living in a certain region on the Italian island of Sicily, for example) correlates with an increased risk for the disease. Scientists are still not sure why.

Aschebrook-Kilfoy and Grogan have begun to collect biospecimens and DNA samples from patients, which can be used to further study environmental and genetic risk factors that may account for the increase.

Both researchers hope this study will demonstrate the importance of studying survivorship, especially in thyroid cancer, which may have better patient outcomes but is far from “good.”

Aschebrook-Kilfoy et al. Risk Factors for Decreased Quality of Life in Thyroid Cancer Survivors: Initial Findings from the North American Thyroid Cancer Survivorship Study. Thyroid. 2015; doi:10.1089/thy.2015.0098 [Abstract]