Tag Archives: Anti-Estrogen Therapy

Estrogen Replacement Therapy Speeds Growth of ER+ Ovarian Cancer & Increases Risk of Lymph Node Metastasis

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Estrogen therapy used by menopausal women causes “estrogen receptor positive” (ER+) ovarian cancer to grow five times faster, according to a new study being published by researchers at the University of Colorado Cancer Center in the November 1 issue of Cancer Research.

Estrogen therapy used by menopausal women causes so-called “estrogen receptor positive” (ER+) ovarian cancer to grow five times faster, according to a new study being published tomorrow by researchers at the University of Colorado Cancer Center.

Menopausal estrogen replacement therapy (ERT) also significantly increases the likelihood of the cancer metastasizing to the lymph nodes, according to the study, which will be published in the November 1 issue of Cancer Research. The study was released online on Oct. 19, 2010. Cancer Research, published by the American Association for Cancer Research, is the world’s largest (based upon circulation) medical journal devoted specifically to cancer research.

The effect of ERT was shown in mouse models of estrogen receptor positive (ER+) ovarian cancer, which accounts for about 60 percent of all human ovarian cancer cases. Ovarian cancer is one of the deadliest cancers affecting women. This year alone, nearly 22,000 women will be newly diagnosed with ovarian cancer and an estimated 13,850 women will die from the disease, according to the National Cancer Institute.

Monique Spillman, M.D., Ph.D., Gynecologic Oncologist, University of Colorado Hospital; Assistant Professor, Obstetrics & Gynecology, University of Colorado School of Medicine.

“We showed that estrogen replacement substantially increases proliferation and risk of distant lymph node metastasis in ER+ tumors,” says Monique Spillman, M.D., Ph.D., the study’s lead researcher, a gynecologic oncologist at University of Colorado Hospital and assistant professor at of obstetrics and gynecology at the University of Colorado School of Medicine.

For the first time, Spillman and her team measured ovarian cancer growth in the abdomen of mice using novel techniques for visualizing the cancer. In mice with ER+ ovarian cancer cells, which were tagged with a firefly-like fluorescent protein that allowed them to be tracked, the introduction of estrogen therapy made the tumors grow five times faster than in mice that did not receive the ERT. The risk of the cancer moving to the lymph nodes increased to 26 percent in these mice compared with 6 percent in mice that did not receive ERT.

The team also found that the estrogen-regulated genes in ovarian cancer reacted differently than ER+ genes found in breast cancer, helping to explain why current anti-estrogen therapies used with breast cancer, such as tamoxifen, are largely ineffective against ovarian cancer.

“Breast cancer and ovarian cancer are often linked when talking about hormone replacement therapy, but we found that only 10 percent of the ER+ genes overlapped,” Spillman says. “We were able to identify estrogen-regulated genes specific to ER+ ovarian cancer that are not shared with ER+ breast cancers. We believe these genes can be specifically targeted with new anti-estrogen therapies that could more effectively treat ER+ ovarian cancers.”

“Breast cancer and ovarian cancer are often linked when talking about hormone replacement therapy, but we found that only 10 percent of the ER+ genes overlapped.  We were able to identify estrogen-regulated genes specific to ER+ ovarian cancer that are not shared with ER+ breast cancers. We believe these genes can be specifically targeted with new anti-estrogen therapies that could more effectively treat ER+ ovarian cancers.”

— Monique Spillman, M.D., Ph.D., Gynecologic Oncologist, University of Colorado Hospital; Assistant Professor, Obstetrics & Gynecology, University of Colorado School of Medicine.

Spillman and her team now will begin to screen current anti-estrogen therapies against the newly identified ovarian cancer genes to identify the [biological] pathways and compounds relevant to the treatment for ER+ ovarian cancer.

This study looked at the effect of estrogen replacement therapy in mice that already possessed ER+ ovarian cancer cells. It did not test whether the estrogen replacement actually could cause the development of these cancer cells. The study also dealt only with estrogen replacement, which is linked to higher risks of ovarian cancer, not combined estrogen/progesterone therapy that is used with women who retain their uteruses.

This research is too early to draw implications for use of estrogen replacement therapy in women, Spillman cautions. “We cannot make clinical recommendations based on what is happening in mice,” says Spillman, one of just eight gynecological oncologists in Colorado. “Every woman is different and needs to talk to her doctor about the decision to use hormone replacement therapy.”

The study was funded by a Gynecologic Cancer Foundation Career Development Award and the Liz Tilberis Scholars Award from the Ovarian Cancer Research Foundation. This competitive award, a $450,000 three-year grant, is given to early-career researchers who are developing techniques for early diagnosis and improved care for women with ovarian cancer.

About the University of Colorado Cancer Center

The University of Colorado Cancer Center is the Rocky Mountain region’s only National Cancer Institute-designated comprehensive cancer center. NCI has given only 40 cancer centers this designation, deeming membership as “the best of the best.” Headquartered on the University of Colorado Denver Anschutz Medical Campus, UCCC is a consortium of three state universities (Colorado State University, University of Colorado at Boulder and University of Colorado Denver) and five institutions (The Children’s Hospital, Denver Health, Denver VA Medical Center, National Jewish Health and University of Colorado Hospital). Together, our 440+ members are working to ease the cancer burden through cancer care, research, education and prevention and control. Learn more at www.uccc.info.

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Small Phase II Study Tests the Use of Fulvestrant in the Treatment of Recurrent Epithelial Ovarian Cancer

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… University of Minnesota researchers evaluated the use of fulvestrant [Faslodex®] in women with recurrent ovarian or primary peritoneal cancer. …Using modified-RECIST criteria 13 patients (50%) achieved SD …[T]he University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

It is well-known that the goal of treating recurrent ovarian cancer is disease control while minimizing toxicity. Previously, Fulvestrant (Faslodex®), a novel estrogen receptor (ER) antagonist, was proven clinically beneficial and well-tolerated in treating recurrent breast cancer. If a pathologist determines that a women’s ovarian cancer biopsy is estrogen receptor positive (ER+), there is a possibility that she may respond to anti-estrogen therapy.

On this basis, University of Minnesota researchers evaluated the use of fulvestrant in women with recurrent ovarian or primary peritoneal cancer. Patients with ER+, multiply recurrent ovarian or primary peritoneal carcinoma were eligible for trial enrollment if (i) they had measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria, or (ii) an abnormal and rising CA-125 blood test measurement. Treatment consisted of single agent fulvestrant, 500 mg IM (intramuscular) on Day 1, 250 mg IM on Day 15, and 250 mg IM on Day 29 and every 28 days thereafter until the patient experienced intolerance or disease progression. Disease response was assessed by monthly physical exams and CA-125 levels as well as bimonthly CT scans. The clinical trial primary endpoint was “clinical benefit” (CB) (i.e., CB=complete response (CR) + partial response (PR) + stable disease (SD)) at 90 days).

Pursuant to the phase II fulvestrant clinical trial, the study researchers reported the following:

  • Thirty-one women were enrolled and 26 women (median age of 61) met inclusion criteria and received at least one dose;
  • Patients received a median of 5 prior chemotherapeutic regimens (range: 2-13) prior to enrollment;
  • One patient experienced CR (4%), one patient experienced PR (4%), and 9 patients experienced SD (35%) using modified-Rustin criteria (CA-125 level);
  • Using modified-RECIST criteria 13 patients (50%) achieved SD;
  • The median time to disease progression was 62 days (mean 86 days); and
  • Grade 1 toxicity included headache (1 patient) and bromidrosis (2 patients).

Based upon the foregoing results, the University of Minnesota researchers concluded that fulvestrant is well-tolerated and efficacious. The researchers also noted that objective response rates are low, but disease stabilization was common.

Primary Source:  A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer; Argenta PA, Thomas SG, Judson PL et. al., Gynecol Oncol. 2009 Feb 22. [Epub ahead of print]

European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer

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“… ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Abstract:

“Amplification of the gene encoding estrogen receptor-alpha occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases.

To study a potential role of estrogen receptor-alpha gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization [FISH] for estrogen receptor-alpha gene amplification and immunohistochemistry [IHC] for estrogen receptor expression. The estrogen receptor-alpha gene status was successfully determined in 243 of 428 arrayed cancers.

Estrogen receptor gene amplification was found in 5 of 243 (2%) of tumors. Amplification levels were usually low, with 4-8 estrogen receptor-alpha gene copies. However, one case had a high-level amplification, with more than 30 estrogen receptor-alpha gene copies. All five amplified tumors were estrogen receptor positive, with 3 of 5 tumors showing highest (Allred score, 7-8) estrogen receptor levels. The data demonstrate that estrogen receptor-alpha amplification occurs only rarely in ovarian cancer.”

Article Discussion Points:

  • “The results of this study show that ESR1 amplification is rare in ovarian cancers (2.1%). More than one-third of ovarian tumors showed immunohistochemically detectable estrogen receptor protein expression, most abundant in serous and endometroid subtypes. This is in line with previous studies done on the classical paraffin blocks. The good concordance between our data and previous studies demonstrates the representation of our tumor tissue microarray data obtained on a 0.6 mm tissue spot per tumor and enhances the results of other studies used in this method.”
  • “A small subset of ESR1 [gene] amplified estrogen receptor-positive cases was indeed found in ovarian cancers. In comparison, some other genes showed higher rates of amplifications in these cancers. For example, the amplification of ERBB2 ranges (0-66%),  EGFR (3.65-12%),  CCND1 (0-19%), C-MYC up to 54.5,  and KRAS (31%).”
  • “The significant frequency of estrogen receptor positivity in ovarian cancers had prompted treatment efforts using hormonal therapy early on. In addition their relatively little toxicity was another provoking factor to continue going on to achieve more advance in this therapeutic field. Monotherapy studies using tamoxifen, aromatase inhibitors, and GnRH analogues had yielded variable results with objective response rates ranging between 0 and 56%.  Combinatorial treatment regimens combining tamoxifen and goserelin or tamoxifen and Gefitinib had obtained results with objective response rates of up to 11.5%.”
  • “The role of estrogen receptor expression for response prediction to anti-hormonal drugs has been much better studied in breast cancer, where a strong association between estrogen receptor positivity and response to anti-hormonal drugs is well established. … More than 20% of breast cancers had amplified or at least elevated ESR1 [gene] copy number. Possible explanations for the predictive effect of ESR1 [gene] amplification could be a particularly high expression of amplified as compared to non-amplified cancers. Alternatively, it could be speculated, that ESR1 [gene] amplified are more dependent on the estrogen receptor pathway than other tumors that express estrogen receptors together with many other growth receptors. If this latter hypothesis was true, visualization of ESR1 [gene] amplification would pinpoint toward an ‘Achilles tendon‘ of a tumor that could be most successfully targeted.”
  • “The frequency of ESR1 [gene] amplified ovarian cancers (2.1%) is much lower than that in breast cancer. Interestingly, this fraction somehow parallels the percentage of ovarian cancers reported to show strong responses to hormonal therapies.”
  • “For example, in retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer,
    • Karagol et al found that out of 29 eligible patients included in the study, there were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease.
    • Papadimitriou et al have studied response rate in 27 patients treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n=21) and those with only increasing CA-125 serum levels (n=6) were eligible. Among the 21 patients with measurable or evaluable disease, 1 complete response (5%) and 2 partial responses were observed (10%) for an objective response rate of 15%.
    • Other studies, in which the combined regiment had been implicated, patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. In total, 26 patients entered this study, of which 17 had platinum–resistant disease, using the definition of endocrine response that included patients with stable disease of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (3.8%), two partial responses (7.7%), and 10 patients with stable disease (38.5%).”
  • “In summary, ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Quoted Source:  Estrogen receptor gene amplification occurs rarely in ovarian cancer, Issa RM et. al., Mod Pathol. 2009;22(2):191-196, reprinted in From Modern Pathology, Medscape Today, February 18, 2009. [Free Medscape subscription required to view full text article.]

Comment:  This study indicates that the occurrence of estrogen positivity (ER+)/ESR1 gene amplification with respect to ovarian cancer is significantly lower than such occurrence in the breast cancer area.  Nevertheless, it is prudent to request your doctor to have your ovarian cancer tumor tissue tested by a pathologist for estrogen positivity or ESR1 gene amplification (through IHC or FISH testing, respectively).  If your ovarian cancer tissue tests ER+, you may respond to anti-estrogen drugs.  Although this type of pathology testing is commonplace in the breast cancer area, it is not in the ovarian cancer area due to the much lower percentage of ER+ ovarian cancer tumors.  As the study above notes, further research of anti-estrogen therapy use within the area of ovarian cancer is needed, especially given the potential high effectiveness and low toxicity of such therapies.