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San Antonio Breast Cancer Symposium

The CLEOPATRA trial marks the first time that dual inhibitors have demonstrated value in the treatment of HER2-positive metastatic breast cancer, and the dramatic findings likely will result in a “sea change” in the way the disease is treated, according to the lead investigator.

The study found that combining pertuzumab with trastuzumab (Herceptin) and docetaxel chemotherapy reduced the risk of progression by 38% in women with metastatic HER2-positive disease. The combination is now under study in patients with early-stage disease.

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital in Boston, said the study “is perhaps the formal demonstration that dual tumor blockade is superior to single blockade.”

“This is likely to become the new standard of therapy for this patient population,” Baselga said in an interview. “It’s a sea change in that way. It’s a new concept.  I think this will gain strength as we move along with other studies.

“This is, I think, the key proof that we were looking for in support of dual blockade as a better approach to targeting HER2-positive tumors,” he added.

As a result of the positive findings, Genentech, the San Francisco-based company developing the drug, said an application has been submitted with the FDA for pertuzumab to be used for patients with previously untreated HER2-positive metastatic breast cancer.

Both pertuzumab and trastuzumab are monoclonal antibodies. Trastuzumab targets HER2, while pertuzumab is the first in a new class of HER2 dimerization inhibitors that prevents HER2 receptor proteins from linking to other HER receptors, according to Genentech.

Baselga detailed the results of the international phase III study during a press briefing at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium in Texas on Thursday. The study enrolled 808 women with confirmed HER2-positive, locally recurrent, unresectable, or metastatic disease who had not undergone >1 hormonal regimen.

At median follow-up of 19.3 months, the findings show that patients who received pertuzumab (402 patients) experienced a median progression-free survival (PFS) of 18.5 months.  By comparison, patients who received trastuzumab, docetaxel, and a placebo (406 patients) demonstrated a median PFS of 12.4 months. (Hazard ratio = 0.62; confidence interval, 0.51-0.75; 

In addition, the objective response rate (tumor shrinkage ≥30%) was 80.2% in the pertuzumab group as opposed to 69.3% in the placebo arm.

Based on a 3-week cycle, patients in the pertuzumab arm received an 840-mg loading dose followed by a 420-mg maintenance dose. Patients in both arms received an 8-mg/kg loading dose of trastuzumab followed by a 6-mg/kg maintenance dose and 75 mg/m

Baselga said more time is needed before survival data are determined, but he said early indications are quite positive.

Concerning adverse events, the results indicate that patients taking the pertuzumab combination experienced higher rates of diarrhea, rash, mucosal inflammation, and febrile neutropenia than those in the placebo arm but that most of the effects were grades 1-2. Significantly, Basegla said, patients in the pertuzumab arm did not experience cardiac dysfunction.

Commenting on the data, Lisa A. Carey, MD, a professor in breast cancer research at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill, said during the press briefing that the study explored the dual blockade strategy explored in earlier, less definitive trials to demonstrate a “marked advance” in the concept.

She said the challenges for researchers going forward include identifying which patients benefit from the targeted therapies and chemotherapy. 

>>>Return to the main conference coverage page.

The CLEOPATRA trial marks the first time that dual inhibitors have demonstrated value in the treatment of HER2-positive metastatic breast cancer.

Dual Therapy With Pertuzumab Slows Advanced Breast Cancer

Gabriel N. Hortobagyi, MD, professor of medicine, chair, Department of Breast Medical Oncology, director, Multidisciplinary Breast Cancer Research Program, University of Texas MD Anderson Cancer Center, discusses the BOLERO-2 trial that examined everolimus (Afinitor) plus exemestane (Aromasin) in hormone receptor-positive (HR+) breast cancer.

The trial was a prospective, double blind, placebo-controlled, phase III trial examining 724 postmenopausal women with HR+ metastatic breast cancer that had previously been treated with an aromatase inhibitor such as anastrozole or letrozole. Patients were randomized 2:1 to receive exemestane plus everolimus or exemestane plus placebo.

At the median follow-up of 12.5 months the progression-free survival (PFS) was 7.4 months for the everolimus arm and 3.2 in the control arm. The hazard ratio was 0.44 with a highly significant 

-value. At this point it is too early to determine an overall-survival benefit.

Dr. Gabriel Hortobagyi from the MD Anderson Cancer Center Discusses the BOLERO-2 Trial

Dr. Hortobagyi Discusses the BOLERO-2 Everolimus Trial

Although hormonal therapy can delay or prevent disease progression in hormone receptor-positive (HR+) breast cancer, resistance develops over time. Updated results of BOLERO-2 suggest that the addition of everolimus to hormonal therapy can overcome that resistance in patients whose disease progressed despite being treated with hormonal therapy.

Adding everolimus to exemestane extends progression-free survival (PFS) in postmenopausal women with HR+ breast cancer, as demonstrated in the original results and updated results of the phase III BOLERO-2 trial. Results were first presented at ECCO/ESMO in September 2011. Data based on an additional 5 months of follow-up were presented at the CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) on December 8, 2011. Study results were published online in the 

 to coincide with the formal presentation at SABCS.

“The addition of everolimus to exemestane markedly improves the duration of disease control. The difference between the two arms in PFS was highly significant in favor of the addition of everolimus. The trial was based on the original hypothesis that the combination would be of benefit, based on compelling preclinical experiments and preliminary results of earlier, smaller clinical trials. These results establish exemestane and everolimus as a new standard of care for postmenopausal HR+ breast cancer,” stated Gabriel N. Hortobagyi, MD, professor of medicine and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, TX.

Experts found the results of this trial exciting. In fact, when asked about FDA approval for everolimus in this setting, Jose Baselga, MD, Massachusetts General Hospital, Boston, MA, stated, “I’m looking forward to having everolimus [approved for this indication] to treat patients as soon as possible.”

The prospective, double-blind, placebo-controlled, phase III BOLERO-2 trial enrolled 724 postmenopausal women with HR+ metastatic breast cancer who had progressed on anastrozole or letrozole. Patients were randomized 2:1 to exemestane plus everolimus (n=485) versus exemestane plus placebo (n=279). At baseline, median age was 62 years, 56% had visceral metastases, and 84% had documented benefit from previous endocrine therapy with letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%).  

At a median follow-up of 12.5 months, median PFS was 7.4 months for the combination versus 3.2 months for exemestane plus placebo. The rate of clinical benefit (complete response, partial response, stable disease, amount of pain, and overall benefit of the drug) was 50.5% for the combination versus 25.5% for exemestane plus placebo.

Overall survival data are not yet available. The combination of exemestane plus everolimus was well tolerated; the most common grade 3 or higher adverse events were stomatitis (8% for the combination versus 1% for exemestane plus placebo, respectively), anemia (7% versus 1%, respectively), hyperglycemia (5% versus <1%, respectively), dyspnea (4% versus 1%, respectively), and fatigue (4% versus 1%, respectively). Hortobagyi said that although adverse events were higher in the combination arm, they were manageable with dose interruption and/or reduction and did not appear to affect quality of life.

Everolimus inhibits the mTOR pathway, which is activated in hormone-resistant advanced breast cancer.  Phase II clinical trials showed promise for everolimus as monotherapy and in combination with endocrine therapy in patients with estrogen-receptor advanced breast cancer.

“These results highlight the progress being made in understanding the evolving mechanisms of resistance to standard therapies,” Hortobagyi said. 

The BOLERO-2 trial suggests that adding everolimus to hormonal therapy can overcome resistance in patients whose disease progressed.

Exemestane Plus Everolimus New Standard of Care for Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer

A large study of HER2-positive (HER2+) breast cancer patients shows that obese patients with this type of breast cancer had worse outcomes than normal weight or overweight patients. These included: larger tumors, greater lymph-node involvement, and worse long-term outcomes compared with normal weight counterparts. However, when obese patients were treated with trastuzumab, the negative prognostics of obesity appeared to be abrogated.

“We knew that obesity was a risk factor for breast cancer. However, we had not explored the relationship between body mass and how patients respond to treatment and disease-free survival (DFS),” said Jennifer A. Crozier, MD, medical resident at The Mayo Clinic in Jacksonville, FL, who presented this study at CTRC-AACR San Antonio Breast Cancer Symposium. This is the first study to examine the relationship between obesity and HER2+ breast cancer, she noted.

The North Central Cancer Treatment Group N9831 study included 3017 patients with early-stage, HER2+ breast cancer classified according to World Health Organization body mass index (BMI) guidelines as: obese (BMI >30) or normal weight (BMI <30). BMI was measured at the start of chemotherapy in this 3-arm, randomized, Phase III clinical trial. Patients were randomized to chemotherapy alone (Arm A); chemotherapy followed by trastuzumab for 1 year (sequential trastuzumab, Arm B); chemotherapy plus trastuzumab followed by trastuzumab for 1 year (concurrent trastuzumab, Arm C). Obese patients were more likely to be older and postmenopausal compared with normal-weight patients (

<.0001 for both). No significant association was present between BMI and estrogen or progesterone receptor status or histological tumor grade.

Across all 3 treatment arms, obese patients had worse outcomes compared with normal-weight patients, but these trends were not statistically significant. Obese and overweight patients who were treated with chemotherapy alone had lower rates of 7-year disease-free survival (DFS); 70.6% for obese patients and 65.9% for overweight patients, versus 74.7% among normal-weight patients. When trastuzumab was added to chemotherapy, either sequentially or concurrently, these differences were attenuated; in the two trastuzumab-containing arms, 5-year DFS were 85% for normal-weight and overweight patients and 82.6% for obese patients.

Disease-free survival rates were similar among all patients who received concurrent trastuzumab as part of therapy, regardless of BMI, Crozier said. In the sequential trastuzumab arm, normal-weight patients appeared to have more benefit than obese patients. Those patients who were treated with chemotherapy alone had the worst DFS of all 3 treatment arms. According to Crozier, these results underscore the importance of using trastuzumab as part of the treatment regimen for HER2+ breast cancer. She and her colleagues believe that this research alleviates the concern that hormonal differences associated with obesity could interfere with trastuzumab’s effect.

“This study supports weight loss intervention for obese women with early-stage HER2+ breast cancer. Overall, we can see that weight management should be an important strategy in management of HER2+ breast cancer. The next step [In our research] will be to examine how weight management during different stages of treatment affects outcomes,” Crozier said.

Senior investigator of this trial, Edith Perez, MD, Mayo Clinic, Jacksonville, FL, said: “We are continually searching for approaches that will help our patients have the best outcome possible after their diagnosis of breast cancer, and this study suggests that excess body weight may make a difference.”

A large study of HER2+ breast cancer patients shows that obese patients had worse outcomes than normal weight or overweight patients.

Obese Patients With HER2-Positive Breast Cancer Have Worse Outcomes but Trastuzumab Equalizes Weight Differences

Edith A. Perez, MD, deputy director, Mayo Clinic Cancer Center, Florida, director, Breast Program, Serene M. and Frances C. Durling Professor of Medicine, Mayo Medical School, expresses that in order to increase the outcomes for breast cancer patients there has been a push toward targeted approaches, such as those used in the CLEOPATRA trial.

The CLEOPATRA trial, a phase III double-blind study of 808 women, included patients that were eligible to receive a first-line treatment for HER2-positive metastatic breast cancer. The trial randomly added placebo or pertuzumab, an inhibitor of HER2 dimerization, to docetaxel and trastuzumab (Herceptin).

The addition of pertuzumab helped delay tumor progression. The pertuzumab arm experienced a median progression-free survival (PFS) of 18.5 months, compared to 12.4 months in the placebo group. Perez adds the increase in PFS did not entail any additional adverse events and potentially resulted in an overall survival (OS) benefit. She remarks the OS benefit will require further study in order to determine if this is indeed the case.

Dr. Edith Perez from the Mayo Clinic Cancer Center Discusses the CLEOPATRA Pertuzumab Trial

Dr. Perez Discusses the CLEOPATRA Pertuzumab Trial

The results of 2 studies likely to have a significant impact upon the treatment of women with metastatic breast cancer were released Wednesday evening at the CTRC-AACR San Antonio Breast Cancer Symposium, generating optimism about the potential for dramatic strides in 2 types of the disease.

Both studies will be discussed in press briefings and panel sessions as the symposium unfolds this week at the Henry B. Gonzalez Convention Center. Here is an advance summary of the research:

Findings from the CLEOPATRA trial indicate that combining pertuzumab with trastuzumab (Herceptin) and docetaxel chemotherapy reduced the risk of progression by 38% in women with metastatic HER2-positive disease.

The international, double-blind, phase III trial involved 808 women randomly assigned to receive a regimen in which pertuzumab was added to trastuzumab and docetaxel, versus placebo plus trastuzumab and docetaxel.

Those who received pertuzumab, which included 402 patients, experienced a median progression-free survival (PFS) of 18.5 months, compared with a median PFS of 12.4 months among the 406 patients in the placebo group (hazard ratio = 0.62; 

 = <0.0001).  In addition, the objective response rate (tumor shrinkage ≥30%) was 80.2% in the pertuzumab group as opposed to 69.3% in the placebo arm.

 “Most metastatic patients with HER2-positive breast cancer eventually stop responding to trastuzumab, so the fact that we now have an agent that can be added to current treatment to delay progression is very exciting,” said José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital in Boston, in an SABCS press release. He is the senior researcher on the trial.

The regimen employs a dual HER2 inhibition strategy. Trastuzumab targets HER2, while pertuzumab is the first in a new class of HER2 dimerization inhibitors that prevents HER2 receptor proteins from linking to other HER receptors, according to Genentech, which is developing the drug.

Genentech, a San Francisco-based company that is a member of the Roche Group, said an application has been submitted with the FDA for pertuzumab to be used for patients with previously untreated HER2-positive metastatic breast cancer. 

Longer-term data from the BOLERO-2 trial continue to demonstrate that combining everolimus (Afinitor) with exemestane significantly enhances PFS for postmenopausal women with estrogen receptor-positive metastatic disease.

The phase III, double-blind trial included 724 patients who had experienced disease progression after receiving previous endocrine therapy consisting of either anastrozole or letrozole, in treatment plans that variously included tamoxifen, fulvestrant, and chemotherapy.  Participants were randomized 2:1 to receive either everolimus plus exemestane or exemestane alone with a placebo.

The latest data indicate a median PFS of 7.4 months for the 485 patients treated with the everolimus combination versus a median PFS of 3.2 months for the 239 patients in the placebo group.

In addition, patients treated with the everolimus regimen experienced a 50.5% clinical benefit rate as opposed to 25.5% for those in the placebo arm. The benefit rate combines complete response, partial response, or stable disease >6 months.

“These results establish a new standard of care for this group of patients,” said Gabriel N. Hortobagyi, MD, chair of the Department of Breast Medical Oncology and director of the Multidisciplinary Breast Cancer Research Program at the University of Texas MD Anderson Cancer Center in Houston, in an SABCS press release. He is the lead researcher.

Afinitor, an inhibitor of the mTOR pathway, is FDA-approved for the treatment of advanced renal cell carcinoma, subependymal giant cell astrocytoma associated with tuberous sclerosis, and progressive neuroendocrine tumors of the pancreas.

Novartis Pharmaceuticals Corporation, which is based in East Hanover, New Jersey, said it plans to file regulatory submissions with the FDA based on the BOLERO-2 results by the end of this year. 

The results of 2 studies likely to have a significant impact upon the treatment of women with metastatic breast cancer.

The CLEOPATRA and BOLERO-2 Studies are Stirring Excitement at SABCS

Benjamin D. Smith, MD, Assistant Professor, Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, discusses a clinical trial that compared whole-breast irradiation (WBI) to accelerated partial breast brachytherapy (APBI-brachy) for women that were diagnosed with incident-invasive breast cancer after lumpectomy.

The study looked at 130&thinsp;535 Medicare patients age 66 and older that were diagnosed with invasive breast cancer between 2000 and 2007. Compared to WBI the patients receiving APBI-brachy had a much higher incidence of mastectomy within 5 years of treatment, postoperative infections, breast pain, and fat necrosis.

Smith describes the trial as being novel and intriguing because of the unexpected illustration of outcomes demonstrated between the two therapies. A complex trade-off between the two therapies has been revealed and an appreciation of the differences will help clinicians and patients determine the best radiation treatment approach.

Dr. Benjamin Smith from MD Anderson Cancer Center Discusses the Brachytherapy Breast Cancer Trial

Dr. Smith on the Brachytherapy Breast Cancer Trial

A new 12-gene assay for predicting risk of recurrence for patients with ductal carcinoma 

 (DCIS) was validated by a study presented at the CTRC-AACR San Antonio Breast Cancer Symposium, and the test (developed by Genomic Health) will be available for clinical use in a matter of weeks. Test results can be used to identify low-risk patients who do not require further radiation, as well as high-risk patients who should be treated more aggressively.

“The DCIS score [derived from the multigene RT-PCR assay] can identify patients at low, intermediate, and high risk for recurrence. The test can be used to quantify an individual patient’s 10-year risk of developing a recurrence (ie, ipsilateral breast event [IBE]). The score provides independent information on recurrence risk beyond clinical and pathological variables. We are not just reinventing the wheel here,” said Lawrence J. Solin, MD, chair of radiation oncology at Einstein Medical Center in Philadelphia, PA.

“The study is important because DCIS is a common diagnosis due to increased use of screening mammography, and it is not clear which patients will go on to recur. Many patients are treated with radiation. So far, we haven’t been able to identify clinical characteristics of patients with DCIS who can avoid it,” said Jennifer Ligibel, MD, assistant professor at Dana-Farber Cancer Institute in Boston, MA, who moderated a press conference where this study was discussed.

The validation study was based on tumor samples from 327 patients enrolled in ECOG 5194, a multi-institutional study of patients with low-, intermediate-, or high-grade DCIS who had been treated with breast conservation, had wide negative margins, and did not receive any radiation; tamoxifen was optional.

 DX 21-gene assay was used to study the tumor samples. Patients were categorized as low-, intermediate-, or high-risk according to prespecified characteristics.

Three-quarters of patients were low risk, Solin said.

The DCIS score on the 12-gene assay was a highly significant and strong predictor of local recurrence (

Solin did not know what the cost of the 12-gene array would be once it is made available. “The cost of the study will be determined by Genomic Health. If we can use this test to spare patients from other adjuvant therapies, the test will be cost effective,” he stated.

Test results will be helpful in sparing low-risk patients from having unnecessary therapy and in selecting radiation (and tamoxifen) for high-risk patients, but treatment selection is not clear for intermediate-risk patients. “That group is always challenging, but at least this test allows us to provide patients information on their individual risk level. The numbers of patients in the intermediate-risk group is actually very small. Most patients with DCIS are low risk,” Solin said.

A new 12-gene assay for predicting risk of recurrence for patients with ductal carcinoma in situ (DCIS).

New Test Predicts Recurrence Risk in Patients With Ductal Carcinoma in Situ

Lawrence J. Solin, MD, chair, Department of Radiation Oncology, Einstein Medical Center, discusses a new multigene assay designed to predict recurrence risk in patients with ductal carcinoma 

 (DCIS). The new test labeled the DCIS Score uses the Onco

 DX breast cancer assay and an optimized gene expression algorithm to sort patients into the three groups low-, intermediate-, or high-risk.

The treatment decision for patients with DCIS is currently based upon clinical and pathological parameters such as the size and grade of the tumor. From this initial inspection many patients are able to receive a lumpectomy, or a lumpectomy in addition to radiation.

Predicting the individual risk will provide a more tailored treatment for each patient and will reduce the amount of unneeded radiation received. Read more about the study >>> 

Dr. Lawrence Solin from Einstein Medical Center Discusses the DCIS Score Recurrence Test

Dr. Solin Discusses the DCIS Score Recurrence Test

It may be possible to predict which women with hormone receptor-positive (HR+) invasive breast cancer will experience recurrence despite treatment with tamoxifen by using a series of gene expression profiles; these profiles appear to distinguish between women who will experience early recurrence (within less than 3 years) versus later recurrence (more than 10 years), according to results of a preliminary study presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

“There are clear biological differences within the supposedly unified group of hormone receptor-positive [HR+] breast cancers, and these differences distinguish subtypes relative to the time at which they recur. Our study confirms what many have suspected — that there are biological drivers present at the time of tumor development that define whether or not breast cancer will recur early, late, or not at all. Now we need to validate these findings and move to the next step,” said lead researcher Minetta C. Liu, MD, associate professor of medicine and oncology and director of translational research at Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Research is ongoing to validate selected genes as biological drivers of metastasis, she explained.

Specifically, the study showed that increased expression of 

 was associated with late recurrence, while increased expression of 

“Some of the genes that were identified were expected and reassuring, while others were unexpected and novel,” Liu said.

The study was a collaboration with researchers from Georgetown, the University of Edinburgh in Scotland, and Virginia Polytechnic Institute. High-quality, frozen tumor samples were obtained at time of diagnosis from women with Stage I-III HR+ breast cancer before being treated with tamoxifen (but not chemotherapy) at the University of Edinburgh, Scotland. All women were followed for more than 10 years for recurrence and metastatic disease. The tissue samples were linked to data on treatment and clinical outcomes.

RNA was extracted from the tumor samples and arrayed on gene chips, and scientists at Virginia Polytechnic Institute examined the gene expression patterns using a novel computational procedure; these researchers created a statistical model of the signaling patterns. A sophisticated sampling method identified estrogen receptor network topology represented by the genes and their predicted interconnections. The results were validated using an established dataset from a study by Loi et al. Liu and colleagues were able to identify gene expression patterns among the tumor samples that correlated strongly with the development of distant metastatic disease.

She said that the study focused on the development of distant recurrences and that they are still analyzing the data to identify gene expression patterns for women who did not have a recurrence.

Women with HR+ breast cancer are often treated with tamoxifen, which can prevent or delay recurrence. However, some tamoxifen-treated women will recur more than 10 years after their original diagnosis. Until this study, the molecular basis for early versus late recurrence was unknown, she explained. Her group plans to study gene expression patterns for recurrence in patients treated with aromatase inhibitors.

“The ability to predict patterns of recurrence will lead to more appropriate recommendations for adjuvant therapy. It might also identify those women who would benefit most from studies using investigational agents that enhance the effects of hormonal therapy, such as tamoxifen or aromatase inhibitors,” Liu suggested.

The next step is to validate the predictive model for the timing of recurrence on treatment with tamoxifen so that physicians and patients can make more informed decisions about treatments and whether or not  patients should participate in clinical trials. “We will also investigate combinations of molecular targets with the ultimate goal of delaying or preventing the development of metastatic breast cancer,” Liu said.

It may be possible to predict which women with HR+ invasive breast cancer will experience recurrence by using a series of gene expression profiles.

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