Allie Strickler

Whereas the androgen receptor (AR) is a common target in the treatment of prostate cancer, Michael F. Press, M.D., Ph.D., shed light on the role of the receptor in breast cancer in a presentation during the 2017 Miami Breast Cancer Conference.

“The reason people are particularly interested in the possibility of using the AR in breast cancer has to do with the category of triple-negative breast cancers [TNBCs],” said Press, the Harold E. Lee Chair for Cancer Research in the Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California.

At present, no targeted therapies are approved for the treatment of patients with TNBC and new treatment approaches are critically needed. “One of the potential targets is AR,” Press said. “A proportion of breast cancers that lack ER, PR and HER2 do show AR expression.”

Androgens are classified as male hormones, although they can also be expressed in the female body. Furthermore, they can be expressed in the breast epithelium. The hope is that AR blockers, most commonly used in the treatment of prostate cancer, could be used on breast cancers that express ARs.

“Since there are Food and Drug Administration-approved drugs that block the androgen receptor in men, the hope is that, if one could come up with a strategy that would demonstrate the effectiveness of these drugs in some women, that they could become clinically available for use in the clinic pretty quickly. This is under active investigation,” said Press. Current efforts to employ ARs in breast cancer are focused on three prostate cancer drugs.

A phase II study, presented at the 2015 ASCO Annual Meeting (MDV3100-11 trial), evaluated single-agent Xtandi (enzalutamide) — an AR inhibitor that impairs nuclear localization of AR &mdash; in patients with advanced AR-positive (IHC ≥10 percent and ≥1 post-baseline tumor assessment) TNBC. The clinical benefit rate (CBR) at 16 weeks served as the study’s primary endpoint.

Among the 75 evaluable patients, the CBR was 35 percent (n = 26) at 16 weeks (95 percent CI, 0.24-0.46) and 29 percent (n = 22) at 24 weeks (95 percent CI, 0.20-0.41). Six patients showed a complete or partial response (response rate of eight percent). The researchers found a median progression-free survival (PFS) of 14.7 weeks in the evaluable population (95 percent CI, 8.1-19.3).

The median age of patients in the intent-to-treat population (n = 118; those who received >1 dose of enzalutamide) was 57 years. The 16-month CBR for these patients was 25 percent, and the 24-month CBR was 20 percent. The response rate was six percent, and the median PFS was 12.6 weeks. Additionally, the median overall survival was 12 months.

Overall, 61 percent of patients (n = 72) experienced treatment-related adverse events (AEs), the most common of which were fatigue (30 percent), nausea (22 percent), and decreased appetite (11 percent).

Thus far, this study is the largest prospective trial to date of an AR inhibitor in TNBC. Xtandi represents one of the most promising agents evaluated in this space. The drug is currently being explored in the phase III ENDEAR trial, which will evaluate Xtandi in combination with paclitaxel or as a monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC.

In another study looking at Xtandi, which was published in Breast Cancer Research, the AR antagonist was used to elucidate the role of AR in preclinical models of ER-positive and ER-negative breast cancer.

The study authors examined a cohort of 192 women with ER-positive breast cancers, assessing their nuclear AR to ER protein ratios in primary breast cancers, in relation to response to treatment with endocrine therapy. The effects of AR inhibition with Xtandi were examined in vitro and in preclinical models of ER-positive and ER-negative breast cancers with AR expression.

The AR to ER ratio was an independent predictor of disease-free survival (HR, 4.04; 95 percent CI, 1.68-9.69; 

 = .002) and disease-specific survival (HR, 2.75; 95 percent CI, 1.11-6.86; 

 = .03). The findings demonstrated that the AR to ER ratio might influence a patient’s response to traditional endocrine therapy when being treated for breast cancer.

Casodex (bicalutamide), another hormone-based AR antagonist, was evaluated in a phase II trial involving patients with AR-positive, ER-negative metastatic breast cancer.

The study, published in Clinical Cancer Research, tested tumors from patients with ER/progesterone receptor (PgR)-negative advanced breast cancer for AR by IHC (>10 percent nuclear staining considered positive). If either the primary or a metastatic site was positive, patients were then eligible to receive Casodex at a dose of 150 mg daily. The primary endpoint was CBR, defined as the total number of patients who showed a complete response, partial response or stable disease more than six months. Secondary endpoints in the study included PFS and toxicity.

Of 424 patients with ER/PgR-negative breast cancer, 12 percent were found to have AR-positive disease. The six-month CBR was 19 percent (95 percent CI, 0.07-0.39) for Casodex and the median PFS was 12 weeks (95 percent CI, 11-22 weeks). The AR antagonist was well tolerated with no observable grade 4/5 treatment-related AEs.

These findings demonstrate proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. An ongoing study at Memorial Sloan Kettering Cancer Center is looking at Casodex in combination with the CDK4/6 inhibitor Ibrance (palbociclib) for women with AR-positive metastatic breast cancer (NCT02605486).

 evaluated the activity of Zytiga (abiraterone acetate), a second-generation AR inhibitor, in the treatment of postmenopausal women with ER-positive metastatic breast cancer. A total of 297 patients were randomized to receive abiraterone and prednisone (n = 89); abiraterone, prednisone, and exemestane (n = 106); or exemestane alone (n = 102). The primary endpoint of the trial was PFS.

Although the results showed that the overall response rate was higher among patients who received abiraterone, prednisone and exemestane (12.1 percent), compared with exemestane alone (6.3 percent), the benefit was not statistically significant (P = .366). Additionally, the clinical benefit rate was higher among patients who received abiraterone, prednisone and exemestane (22.7 percent) compared with exemestane alone (12.7 percent). Again, the data were not statistically significant (

 = .137). The median PFS with exemestane alone was 3.7 months, compared with 4.5 months with abiraterone, prednisone and exemestane (HR, 0.96; 95 percent CI, 0.70-1.32; 

 = .795) and 3.7 months with abiraterone plus prednisone (HR, 1.1; 95 percent CI, 0.82- 1.60; 

Articles

Michael F. Press, M.D., Ph.D., shed light on the role of the receptor in breast cancer in a presentation during the 2017 Miami Breast Cancer Conference.

Using Androgen Receptor Blockers to Treat Triple-Negative Breast Cancer

A small subset of patient may be prone to be misclassified and receive the wrong treatment after new guidelines were set for the way that patients with breast cancer should be classified, said Michael F. Press, M.D., Ph.D., a member of the College of American Pathologists (CAP).

He has recommended changes to updated ASCO-CAP guidelines on assessment of 

 amplification by fluorescence in situ hybridization (FISH).

What is controversial about the HER2 oncogene right now in breast cancer?

Press, the Harold E. Lee Chair for Cancer Research in the Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, discussed the new ASCO-CAP guidelines for HER2 FISH testing at the 2017 Miami Breast Cancer Conference. Although the updates have resulted in no changes for approximately 90 percent to 95 percent of cases, they will result in potential disagreements for approximately 5 percent of HER2 breast cancer cases, according to Press.

The guidelines were published in 2013 and 2014 and did not recommend many changes related to testing for the HER2 protein using immunohistochemistry [IHC]. Some minor revisions were made, but they didn’t substantially impact the way in which HER2 is evaluated by IHC. On the other hand, the ASCO-CAP guidelines committee did make a number of changes in the way the 

gene is evaluated by FISH for gene amplification. These changes have created confusion about whether or not some FISH subgroups are 

 amplified, known as in situ hybridization (ISH)-positive, or 

 not amplified, known as ISH-negative. This confusion impacts approximately 5 percent of women with breast cancer.

Approximately 20 percent to 25 percent of breast cancers in women have the 

 gene alteration, also known as gene amplification. This means that the cancer cells have increased the number of copies of the 

 gene in each tumor cell. Whereas normal cells have two copies of the 

 gene, cancer cells often have greater than 20 copies per tumor cell. This leads to a great increase in such things as cell migration, cell invasion, and increased cell division. It stimulates the production of new blood vessels, and these cancer cells are much more aggressive than cancers that lack this particular alteration.

The good news is that there are several different HER2-targeted therapies that interfere with the actions of the overexpressed protein on the cell surface. And one class of these would be monoclonal antibodies that are directed against the extracellular domain, such as Herceptin (trastuzumab) and Perjeta (pertuzumab). There are also antibody—drug conjugates (ADCs). There’s Kadcyla (trastuzumab emtansine; T-DM1), which is linked to a biological toxin, so that the drug is directed to tumor cells that overexpress HER2. When the membrane is internalized, the poison that’s linked to Herceptin damages and destroys the tumor cells. Another class of agents is anti-HER2 small molecule inhibitors. Either one of these classes of drugs prevent the continuous stimulation of HER2 in tumor cells.

How are these definitions changing, and what makes them so problematic?

Because there are drugs that are aimed at 

 gene amplification and overexpression, it’s important to know who among patients with breast cancers has this alteration and who doesn’t. In the absence of gene amplification, there is no HER2 overexpression. The ASCO-CAP guidelines for HER2 testing by FISH have created new definitions of what is HER2-positive and what is HER2-negative. And I think these new definitions are problematic. 

In the past, women were enrolled in clinical trials of HER2-targeted drugs if they had HER2-positive breast cancers. The definition of HER2-positive by FISH in the past referred to a ratio between the number of copies of the 

 gene, compared with a control gene on the same chromosome arm that was greater than 2. The centromere is the usual control gene for calculation of this ratio. When the ratio of the 

 gene compared with the centromere (CEP17) is greater than 2, these breast cancers are referred to as 

The current ASCO-CAP guidelines for HER2 testing by FISH require consideration of both the 

 gene copy number per tumor cell. Because the clinical trials used for FDA approval of HER2-targeted therapies did not use this definition, it was not clear how the current ASCO-CAP guidelines definitions correspond to the previous definition of

 amplification used for enrollment in the clinical trials.

In order to address this issue, we reanalyzed the 

 gene amplification status of more than 10,000 women previously enrolled in three Breast Cancer International Research Group clinical trials using the current ASCO-CAP guidelines. We found that the HER2 status for approximately 95 percent of these women’s breast cancers was not changed by the new guidelines. However, the HER2 status of approximately 5 percent of these women was different than the status originally assigned to their cancers.

Do oncologists in this space share your dissatisfaction with the newer guidelines?

Our study was published last year in the 

, and it reported that difference. Although this change in HER2 FISH scoring affects only a minority of the breast cancer population, these 5 percent of cases constitute three of five FISH scoring categories created by the new ASCO-CAP guidelines. Our findings indicate all three of these subgroups are mislabeled by the guidelines and should be revised.

Many medical oncologists treating patients with breast cancer are dismayed about the uncertainty the current guidelines create for some of their patients. The ASCO-CAP guidelines FISH group that has created the most confusion is the group classified as ISH-equivocal. These women represent about 4 percent of all breast cancers. Because a HER2-targeted therapy “treat” or “not treat” decision must be made, assignment to an equivocal category is not acceptable for either the patient or her oncologist. Our findings indicate that the breast cancers in this equivocal category are not amplified and women with these cancers have a clinical outcome similar to that of other women whose cancers are considered ISH-negative or 

 not amplified. Some of these women with ASCO-CAP equivocal breast cancers are, nevertheless, currently receiving HER2-targeted therapy.

The equivocal group has represented a problem that comes up in about one out of every 20 patients. For medical oncologists treating patients frequently, this issue arises with great regularity.

 The additional problem with this is that the ASCO-CAP guidelines recommend that these patients’ breast cancers can be analyzed with alternative control genes. As I explained before, there’s a numerator of 

 copy number divided by the chromosome 17 centromere copy number. That ratio in this equivocal category is less than two. But they [ASCO-CAP guidelines] have also permitted, or even suggested, that alternative genes on the same chromosome could be used in that denominator as comparison controls.

 gene is located on the long arm of chromosome 17, the q arm. One could choose other genes that are on that arm for comparison. Retinoic acid receptor alpha is a frequently used gene on that arm. The opposite arm, the p arm, which is the short arm of chromosome 17, has a number of other genes that are used, including the 

 gene, and the Smith-Magenis Syndrome region—which is a birth defect in children that’s on that arm&mdash;and there are a couple of other genes that are used and recommended, for example, by the Mayo Clinic and the Cleveland Clinic, as alternative control genes. Many large laboratories are using all of these controls, and when any one of them produces a ratio greater than two, they’re recommending that these patients be considered HER2-positive by ISH. Our review in our lab would be, and has been for a long time, that this is not warranted, because many of those genes on the p arm of the chromosome are deleted.

Breast cancers can increase gene copy number, or they can reduce gene copy number. On the p arm, I mentioned that 

 is a gene that’s present on that arm, and it’s mutated in about 20 percent of human breast cancers. In that setting where it’s mutated, the normal copy of TP53 is frequently lost or deleted. So that whole arm of chromosome 17 has relatively frequent deletions of portions of that arm. If you have, say, a numerator that’s just a normal value, and you lose one of the two comparator genes that’s in the denominator, suddenly your ratio, instead of being, say, one, goes to two, simply because half of your denominator is lost. It doesn’t really reflect that the HER2 gene has increased in copy number. There’s a loss of the comparison gene, the control gene.

In that setting, a lot of large commercial laboratories and large institutional laboratories are reporting a ratio greater than two and suggesting that these patients are HER2-positive. The patients are then being subjected to a course of chemotherapy and Herceptin that is consistent with HER2-positive disease. We’re suggesting that this is inappropriate, and the data we have on clinical outcomes in our paper also suggest that this is not warranted.

New guidelines may result in a small percentage of patients with breast cancer being misclassified and not receiving proper treatment, Michael F. Press, M.D., Ph.D., says. 

Some Breast Cancer Patients May Be Misclassified, Expert Explains

For postmenopausal women, especially those with obesity, intentional weight loss was associated with a lower endometrial cancer risk, according to the results of a recent study published in the 

These findings — which draw from the Women’s Health Initiative (WHI) study data &mdash; suggest that weight loss could decrease the risk of developing endometrial cancer in postmenopausal patients by as much as 29 percent to 56 percent.

“Many older adults think it’s too late to benefit from weight loss, or think that because they are overweight or obese, the damage has already been done. But our findings show that’s not true,” lead study author Juhua Luo, Ph.D., an associate professor of Epidemiology and Biostatistics at the Indiana University School of Public Health, said in a statement. “It’s never too late, and even moderate weight loss can make a big difference when it comes to cancer risk.”

Compared with women who had stable weight, women with weight loss had a significantly lower endometrial cancer risk. This correlation was strongest among obese women who intentionally lost weight. Weight gain (at least 10 pounds) was associated with a higher endometrial cancer risk than was stable weight, especially among women who had never used hormone therapy.

The trial evaluated over 35,000 women from the WHI Observational Study, which originally enrolled postmenopausal women between the ages of 50 and 79 and was initially designed to address major causes of morbidity and mortality in this specific patient population.

The investigators measured patients’ weight at the beginning of the study and then again three years later to assess changes over time. The patients who lost weight were asked via self-report at the three-year follow-up mark whether their weight loss was intentional or unintentional. Weight change was categorized as stable (change within +/- 5 percent), loss (change of at least 5 percent), and gain (change at least 5 percent).

The researchers then followed these women for an average of 11.4 years to identify those who were diagnosed with endometrial cancer (566 patients).

The results showed that, among women who lost 5 percent or more of their body weight after age 50, the risk of developing endometrial cancer was 29 percent lower, regardless of their age or how much weight they lost.

The greatest reduction of endometrial cancer risk was observed in patients who were obese and intentionally lost weight. Women who were obese and voluntarily lost 5 percent or more of their body weight saw a 56 percent reduction in their endometrial cancer risk.

Additionally, women who were overweight or obese and achieved a normal body mass index (BMI) after intentional weight loss were found to have the same risk as women who maintained a stable BMI.

Women who gained more than 10 pounds had a 26 percent higher risk of being diagnosed with endometrial cancer.

Given that endometrial cancer is known to be highly hormone-related, the study authors also analyzed their findings to determine the influence of hormone use. However, they found no significant difference in risk between women who used hormone therapy and those who did not.

“There have been more than a thousand studies linking obesity to an increased risk of endometrial and other cancers, but almost none that look at the relationship between weight loss and cancer risk,” Jennifer Ligibel, M.D., ASCO Expert in Cancer Prevention, said in a statement. “This study tells us that weight loss, even later in life, is linked to a lower risk of endometrial cancer.”

These findings also support the development of weight loss programs that could potentially be embedded within a cancer prevention strategy in overweight and obese adults, explained Ligibel.

According to Karen H. Lu, M.D., chair of ASCO’s Cancer Prevention Committee, this study demonstrates the potential role of weight loss in the reduction of cancer risk, as well as the notion that it is never too late to improve one’s health.

“We hope these findings will encourage individuals who may be overweight to change their behaviors to reduce the amount of food eaten and increase their physical activity,” said Lu, chair of ASCO’s Cancer Prevention Committee.

Lowering weight may lead to lowering the risk for developing endometrial cancer, according to recent findings.

Weight Loss Lowers Endometrial Cancer Risk

Survival was improved in patients with recurrent prostate cancer when hormone therapy was added to radiation treatment following surgery, according to a recent study published in 

In the multicenter trial — which initially enrolled 760 men with biochemical recurrence after radical prostatectomy &mdash; patients were randomly assigned to treatment with bicalutamide or placebo for two years, along with 6.5 weeks of radiation therapy.

After a median follow-up of 13 years, the actuarial rate of overall survival (OS) at 12 years was 76.3 percent for patients treated with bicalutamide, compared with 71.3 percent for patients in the placebo group. The 12-year incidence of death from prostate cancer was 5.8 percent versus 13.4 percent, respectively. The cumulative incidence of metastatic prostate cancer at 12 years was 14.5 percent in the bicalutamide group and 23.0 percent in the placebo group.

“Our study indicates that hormonal treatments should be incorporated into the management of men who need radiation therapy after surgery for prostate cancer," senior author Howard Sandler, M.D., chair of the Department of Radiation Oncology at the Samuel Oschin Comprehensive Cancer Institute at Cedar's Sinai, said in a statement.

The double-blind, placebo-controlled trial was conducted between 1998 and 2003 and enrolled patients who had had their prostate gland removed for localized disease. Patients’ disease was originally assessed, on the basis of pathological testing, as tumor stage T2 or T3 without nodal involvement.

Eligible patients were also required to have a detectable PSA level of 0.2 to 4.0 ng/ml at least eight weeks after surgery. Additionally, patients could not participate in the study if they had previously received chemotherapy, radiation therapy, or hormone therapy (other than preoperative short-term hormonal therapy for two to six months in some patients [6.4 percent of those enrolled]) for prostate cancer.

Salvage radiation therapy began within 12 weeks after randomization. A total dose of 64.8 Gy was administered in 36 daily fractions of 1.8 Gy at a rate of five sessions per week. Beginning at the initiation of radiation therapy, patients were given, on a daily schedule, either 150 mg of bicalutamide or one placebo tablet. Patients received their respective treatments for 24 months.

At the beginning and end of radiation therapy, the researchers evaluated patients’ clinical history, physical examination, Karnofsky performance status score, complete blood count, PSA level, serum alanine aminotransferase level, bilirubin level, and reports of any treatment-related adverse events. Subsequent follow-up evaluations were done every three months for two years, then every six months for three years, and then on a yearly basis. Bone and CT scans were performed at subsequent biochemical recurrence. Maximum androgen blockade was recommended if metastatic disease was present or if the serum PSA level rose to over 4.0 ng/ml.

The two groups of patients were well balanced in terms of demographic and tumor-related characteristics. The median age of patients was 65 years, and the median PSA level at study entry was 0.6 ng/ml. The median interval between surgery and the first detectable PSA level was 1.4 years, and the median interval between surgery and trial entry was 2.1 years.

The primary endpoint was the rate of OS. Prespecified secondary endpoints included disease-specific death, distant metastases, local disease progression, non—disease-specific death, any disease progression including a second biochemical recurrence, and adverse events.

A total of 21 patients treated with bicalutamide died from prostate cancer, compared with 46 patients in the placebo group. The cumulative incidence of a second biochemical recurrence at 12 years was 44.0 percent in the bicalutamide group, compared with 67.9 percent in the placebo group.

In terms of toxicity, the incidence of late adverse events associated with radiation therapy was similar between the two treatment arms. Gynecomastia was observed in 69.7 percent of the patients in the bicalutamide group, compared with 10.9 percent of patients in the placebo group.

"This study's findings—that adding antiandrogen therapy to the radiation typically used against recurrence reduces the incidence of metastasis, death from prostate cancer and overall deaths - will change the standard of care for patients experiencing a postoperative recurrence," study author William U. Shipley, M.D., Massachusetts General Hospital Department of Radiation Oncology, said in a statement.

Adding hormone therapy to radiation therapy after surgery showed significant survival improvements in a recent study involving men with recurrent prostate cancer.

Allie Strickler

Using Androgen Receptor Blockers to Treat Triple-Negative Breast Cancer

Some Breast Cancer Patients May Be Misclassified, Expert Explains

Weight Loss Lowers Endometrial Cancer Risk

The Addition of Hormone Therapy Improves Survival in Recurrent Prostate Cancer

Latest News