Gel Tamoxifen effective for breast cancer without dangerous side effects

July 15, 2014, Northwestern University - A gel form of tamoxifen applied to the breasts of women with noninvasive breast cancer reduced the growth of cancer cells to the same degree as the drug taken in oral form but with fewer side effects that deter some women from taking it, according to new Northwestern Medicine® research.

Tamoxifen is an oral drug that is used for breast cancer prevention and as therapy for non-invasive breast cancer and invasive cancer.

Because the drug was absorbed through the skin directly into breast tissue, blood levels of the drug were much lower, thus, potentially minimizing dangerous side effects -- blood clots and uterine cancer.

The gel was tested on women diagnosed with the non-invasive cancer ductal carcinoma in situ (DCIS) in which abnormal cells multiply and form a growth in a milk duct. Because of potential side effects, many women with DCIS are reluctant to take oral tamoxifen after being treated with breast-saving surgery and radiation even though the drug effectively prevents DCIS recurrence and reduces risk of future new breast cancer.

The paper was published July 15 in the journal Clinical Cancer Research.

“Delivering the drug though a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it,” said lead author Seema Khan, M.D., a Northwestern Medicine® surgical oncologist. “For breast cancer prevention and DCIS therapy, effective drug concentrations are required in the breast. For these women, high circulating drug levels only cause collateral damage.”

Khan is a professor of surgery and the Bluhm Family Professor of Cancer Research at Northwestern University Feinberg School of Medicine. She also is a surgeon at Northwestern Memorial Hospital and co-leader of the breast cancer program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University

“The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed,” Khan said. “There was very little drug in the bloodstream which should avoid potential blood clots as well as an elevated risk for uterine cancer.”

Women who have completed surgery and radiation are given oral tamoxifen for five years to reduce the risk of the DCIS recurring at the same place and of new breast cancer appearing elsewhere in the same breast or the other breast. Tamoxifen is an anti-estrogen therapy for a type of breast cancer that requires estrogen to grow.

Khan and colleagues conducted a phase II clinical trial to compare the effects of the gel, 4-OHT, with oral tamoxifen. They found after six to 10 weeks of gel application that the reduction in a marker for cancer cell growth, Ki-67, in breast tissue was similar to that of oral tamoxifen. The scientists also found equal amounts of 4-OHT present in the breast tissue of patients who used the gel or took the oral drug, but the blood levels of 4-OHT were more than five times lower in those who used the gel.

The reduction in the levels of 4-OHT in the blood also was correlated with a reduction in proteins that cause blood clots.

The study involved 26 women, ages 45 to 86, who had been diagnosed with DCIS that was sensitive to estrogen (estrogen-receptor-positive DCIS). Half the women received the gel, which they applied daily, and half the oral drug, which they took daily.

The gel application may also be more effective for some women. Oral tamoxifen doesn’t help all women who take it because it needs to be activated in the liver by specific enzymes and about a third of women lack these enzymes, Khan said. These women may not receive full benefits from the pill.

Other Northwestern authors on the paper include first author Oukseub Lee, Katherine Page, David Ivancic, Irene Helenowski, Vamsi Parini, Megan E. Sullivan, Robert T. Chatterton Jr., Borko Jovanovic, Julia Shklovskaya, Silvia Skripkauskas, Piotr Kulesza, David Green, Nora M. Hansen, Kevin P. Bethke, Jacqueline S. Jeruss and Raymond Bergan.

The research is supported by the grant N01-CN-35157 from the National Cancer Institute of the National Institutes of Health and BHR Pharma, LLC.

New treatment option for young women with hormone-sensitive breast cancer

June 2014, National Cancer Institute - A drug used for treating breast cancer, known as exemestane, is more effective than a common breast cancer prevention drug, tamoxifen, in preventing breast cancer recurrence in young women who also receive post-surgical treatment to suppress ovarian function. The findings from this trial were in women who had a form of early breast cancer that was sensitive to hormonal treatment.

The study was conducted by the International Breast Cancer Study Group (IBSCG), in partnership with the Breast International Group (BIG) and the North American Breast Cancer Group, and funded by the U.S. National Cancer Institute (NCI), IBSCG, and the pharmaceutical companies Pfizer and Ipsen. The combined results of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) were presented today at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (late breaking abstract #1) and published online in the New England Journal of Medicine.

Treatment with exemestane plus ovarian function suppression reduced the risk of any invasive cancer by 28 percent, and reduced the risk of invasive breast cancer recurrence by 34 percent, compared to treatment with tamoxifen plus ovarian function suppression. At five years from study entry, 92.8 percent of women remained free from breast cancer after treatment with exemestane plus ovarian function suppression; 88.8 percent were breast cancer-free after receiving tamoxifen plus ovarian function suppression.

Treatment with an aromatase inhibitor, such as exemestane, has previously been demonstrated to benefit postmenopausal breast cancer patients compared to treatment with tamoxifen. Aromatase inhibitors prevent the formation of estradiol, a female hormone, by interfering with an aromatase enzyme. Both trials were conducted to determine whether this benefit could be extended to premenopausal women by combining exemestane with ovarian function suppression. Hormone-sensitive breast cancer, defined as estrogen and/or progesterone receptor-positive breast cancer, represents 79 percent of breast cancers diagnosed in women under age 50 in the United States.

The TEXT and SOFT trials were phase III, randomized clinical trials that enrolled 2,672 and 3,066 premenopausal women with hormone receptor-positive early breast cancer, respectively, between November 2003 and April 2011. Over 500 medical institutions from 27 countries enrolled women in the trials. In the two trials, 4,690 women were randomly assigned to 5 years of adjuvant, or post-surgical, treatment with exemestane plus ovarian function suppression or assigned to tamoxifen plus ovarian function suppression. SOFT included a third treatment assignment, tamoxifen alone, which will be analyzed in late 2014. The women may also have received chemotherapy as part of adjuvant treatment.

Ball and stick image of exemestane moleculeThe two trials were designed to be complementary. They were conducted over the same time period, in the same general population, and have the two treatments in common. Combining them brought the results to doctors and patients sooner than if they were presented separately.

Ovarian function suppression has been used for decades as a breast cancer treatment for premenopausal women, though whether it adds benefit when combined with other treatments was still uncertain. In these trials ovarian function suppression was combined with either tamoxifen or exemestane. In premenopausal women use of an aromatase inhibitor such as exemestane requires suppression of estrogen produced by the ovaries. In TEXT and SOFT, ovarian function suppression was achieved by use of monthly injections of the GnRH agonist triptorelin, surgical removal of both ovaries, or radiation therapy to the ovaries.

“These results provide a new treatment option for young women with hormone-sensitive breast cancer. The trials demonstrate that an aromatase inhibitor, previously recommended only for postmenopausal women, is also effective for premenopausal women when combined with ovarian function suppression,” said study co-chair Olivia Pagani, M.D., Breast Unit Clinical Director at the Oncology Institute of Southern Switzerland in Bellinzona, Switzerland. “As a physician who routinely recommends ovarian function suppression as adjuvant therapy for some young patients, these results will change my practice. I will combine ovarian function suppression with an aromatase inhibitor rather than with tamoxifen.”

Support from NCI enabled American and Canadian participation in the TEXT and SOFT trials through the North American Breast Cancer Group (NABCG). NABCG contributed one-third of all patient enrollments in the TEXT and SOFT trials, whereas two-thirds enrolled from cooperative oncology groups affiliated with the Breast International Group (BIG) network. Led by Alliance (formerly CALGB), North American involvement accelerated trial recruitment, permitting earlier reporting of findings and faster access to these practice-changing results.

In addition to assessing the effectiveness of the treatments at reducing recurrence, patient-reported quality of life assessments were collected throughout the five years as well as physician-reported side effects. “As clinicians we should be reassured that, in the two treatments studied, the patient-reported quality of life results were similar overall, as was the frequency of severe side effects,” said study co-chair Barbara Walley, M.D., Medical Oncologist at the Tom Baker Cancer Centre in Calgary, Canada and executive member of the Breast Disease Site Committee, National Cancer Institute of Canada-Clinical Trials Group. “The side effects reported in this premenopausal population are similar to those in postmenopausal women in which tamoxifen and aromatase inhibitors are widely prescribed.” Follow-up of the young women participating in the trials continues to assess long-term prognosis, tolerability, and side effects.

“These results underscore the importance of international research collaboration in improving patient outcomes in North America and beyond, such as for the young women in this study,” said Richard Gelber, Ph.D., professor, Harvard Medical School and director, IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston. “This partnership between NCI and IBCSG represents a successful model for future clinical research advances.”

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Reference: Pagani O, et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. NEJM early online. June 1, 2014. ASCO late breaking abstract #1. TEXT: Clinicaltrials.govNCT00066703. SOFT: Clinicaltrials.govNCT00066690.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

The International Breast Cancer Study Group (IBCSG) is a Swiss nonprofit cooperative breast cancer research organization that has conducted clinical research in adjuvant endocrine therapy and chemotherapy, timing and duration of adjuvant therapies, and quality of life for over 35 years.

Experimental blood test can spot recurrent breast cancers

April 15, 2014 – Johns Hopkins Kimmel Cancer Center reported they have developed a blood test that accurately detects the presence of advanced breast cancer. They also believe it can be used to monitor responses to breast cancer treatment.

In the study, the researchers used a test, called cMethDNA assay. “It accurately detected the presence of cancer DNA in the blood of patients with metastatic breast cancers up to 95% of the time in laboratory studies.” The findings were described in the April 15 issue of Cancer Research.

This new blood test was developed by a research team led by Dr. Sara (Saraswati) Sukumar, a professor of oncology and pathology, as well as a co-director of the Breast Cancer Program at Johns Hopkins. It can monitor 10 breast cancer-specific genes in a patients’ blood that are altered in those with breast cancer.  They selected 10 genes specifically altered in breast cancers, including newly identified genetic markers AKR1B1, COL6A2, GPX7, HIST1H3C, HOX B4, RASGRF2, as well as TM6SF1, RASSF1, ARHGEF7, and TMEFF2, which Sukumar's team had previously linked to primary breast cancer. Oncology NurseAdvisor, April 30, 2014.

To see whether a patient is at risk for breast cancer recurrence, the test determines whether hypermethylation – a process that silences genes that keep cancers in check – has occurred in any of the breast cancer genes. Signs of hypermethylation in the breast cancer genes indicate that the cancer is likely to recur.” Honor Whiteman, Medical News Today, April 15, 2014. 

Besides being 95% accurate, here’s more potentially good news according to Sukumar: “Using cMethDNA, we were able to detect a drop in methylation levels as early as 2 weeks, and weeks before traditional imaging methods can detect a recurrence. Detecting early on whether or not the treatment is working for a patient can greatly help prevent unnecessary exposure to highly toxic agents, save time and help indicate other treatments more likely to be beneficial.”

In one set of experiments, the researchers tested the assay's ability to detect methylated tumor DNA in blood samples from patients with breast cancer and from healthy women without breast cancer. The blood test was up to 95% accurate in distinguishing patients with metastatic breast cancer from healthy women.

According to an article in OncologyNurseAdvisor, the investigators also studied the assay's potential to monitor response to chemotherapy. They evaluated 58 blood samples from 29 patients with metastatic breast cancer, some taken before the initiation of therapy and some taken 18 to 49 days after starting a new chemotherapy regimen. In as little as 2 weeks, the test detected a significant decrease in DNA methylation in patients with stable disease or in those who responded to treatment; this decrease was not found in patients whose disease progressed or who did not respond to treatment. 

The researchers also found that the cMethDNA assay could be used to detect recurrent lung and colorectal cancers.