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With thousands of clinical trials in play, many oncology specialists are reluctant to embrace findings from newly-released studies that would change the way they practice medicine. Laura Esserman, MD, MBA, a professor of surgery and radiology at the University of California, San Francisco, recommends that clinicians form a framework for evaluating the results of clinical trials as a method of deciding how they will react.

"This is a very thorny issue and it's very hotly debated," Esserman said during a presentation at the Miami Breast Cancer Conference Saturday.

She said there are a variety of reasons that clinicians hesitate to change their practices because of a study, including skepticism about the results and the burden that adopting new technology may represent.

Esserman, who also is director of the Carol Franc Buck Breast Cancer Center, suggested clinicians consider these questions about a given trial:

		What is the cost of adopting a new approach?

		What is the cost in terms of lost opportunity of not adopting an approach?

She has developed a model of evaluating new approaches that takes into account the quality-adjusted life years and the incremental cost effectiveness.

"The likelihood that the trial results will change practice can be estimated and modeled, and provide practitioners and patients with a more rational basis for making a decision about the early adoption of results” said Esserman.

PER® Miami Breast Cancer Conference

With thousands of clinical trials in play, many oncology specialists are reluctant to embrace findings from newly-released studies

Framework for Evaluating Trial Results Detailed

Should genomic profiles be used routinely to determine which breast cancer patients receive adjuvant chemotherapy?

That question was the subject of a lively debate at the Miami Breast Cancer Conference Friday, where the challenge of translating scientific advances into clinical practice was among the dominant themes.

In the “Pro” Corner: The Power of the Gene Assay

The Oncotype DX® test, with its 21-gene recurrence score (RS) assay, has proved its value as a prognostic tool and should be used regularly to evaluate treatment options for breast cancer patients, argued Norman Wolmark, MD.

Wolmark, professor and chairman of the Department of Human Oncology at Allegheny General Hospital in Pittsburgh, Pennsylvania, said the test is an accurate and practical method of quantifying the likelihood of recurrence in early-stage, node-negative, estrogen receptor-positive breast cancer, and of predicting which patients will benefit from chemotherapy.

He said >120,000 patients have undergone the test since it was introduced 7 years ago.

The professor, who also chairs the National Surgical Adjuvant Breast and Bowel Project, said the assay delivers results superior to those derived from the standard algorithm, which considers tumor grade and size and the age of the patient. He also noted that it has made other evaluative methods such as immunohistochemistry “an anachronism.”

Notably, Wolmark said, the RS method has shed light on which patients will benefit from chemotherapy. "It appears the entire benefit of chemotherapy is restricted to the one-third of patients [defined as] high risk," he said, although he noted more study is needed for patients who fall between the high- and low-risk categories.

As a result of the test’s accuracy, Wolmark said, some nations have mandated the test be administered to all appropriate patients. He cited one estimate that predicts $100 million in savings for the US healthcare system as patients avoid futile treatments.

"It’s remarkable to me that pathologists have not really embraced this assay," Wolmark said. "This is prime time. We have certainly crossed the threshold."

In the "Con" Corner: Skepticism About Value to Individuals

The predictive conclusions of genomic signature testing represent another way of looking at established trends and generally are not helpful to individuals facing treatment decisions, contended J. Michael Dixon,MD, clinical director of the Breakthrough Research Unit at the Edinburgh Breast Unit in the United Kingdom. He said they should not be made part of the routine practice for all patients.

"In reality, what comes out is what you expect,” said Dixon, who also is a professor of surgery and a consulting surgeon. "They measure what we already know."

Dixon said there are 2 commonly used genomic profiles, MammaPrint® and Oncotype DX, and that both have disadvantages: MammaPrint uses only frozen tissue and does not account for the HER2 gene, while Oncotype DX may not add to information available through routine immunohistochemistry.

He said both tests measure proliferation, which can predict the benefits of chemotherapy. Current methods, however, also measure proliferation, Dixon said. In addition, he said, the results are meaningful for groups but not individuals. "It gives us a percentage, but actually, the individual patient isn’t interested."

Dixon also said, "The concern about all of the tests is that the confidence intervals for predicting outcome for an individual patient are wide. What patients want is much greater certainty about their individual outcome and how treatment can influence that outcome."

"Molecular markers are on the right track but they’re stuck on the goal line and they’ve not yet scored," he told the conference audience.

Should genomic profiles be used routinely to determine which breast cancer patients receive adjuvant chemotherapy

Genomic Profiles as Routine Care Are a Hot Topic

Personalized treatment in oncology is a popular concept these days, but the goal remains elusive when it comes to tailoring adjuvant chemotherapy to achieve maximal therapeutic benefit, according to William F. Symmans, MD, a professor of pathology at the MD Anderson Cancer Center in Houston, Texas.

“We’ve made marginal progress toward personalization of adjuvant chemotherapy,” Symmans said during a presentation at the Miami Breast Cancer Conference.

Such therapies hold the promise that clinicians can identify which treatments are futile, toxic, and expensive for a particular patient, thereby giving doctors the tools to assess the relative difference and absolute benefit between the treatment options.

Symmans said the best advance in targeted oncology in the breast cancer arena was the addition of trastuzumab (Herceptin) to chemotherapy for HER2-positive disease. However, he said, the chemotherapy component should be tailored to patients based on whether they would benefit from a regimen that includes an anthracycline.

“To date, there has been no clear indication from biomarker studies to guide this decision,” he said.

In addition, Symmans noted that there are no predictive tests to help guide decisions on whether the benefits of concurrent administration of trastuzumab and an anthracycline outweigh the risks of cardiotoxicity. As a result, Symmans noted, patient selection for this therapy remains “based on risk assessment from clinicopathologic factors.”

Other clinical situations where biomarker tests would be useful include whether topoisomerase 2 is a selective biomarker for anthracycline sensitivity, which could guide treatment decisions in HER2-negative breast cancers, and whether the basal-like subset of triple-negative breast cancer patients would benefit from platinum-containing chemotherapy.

“Unfortunately, this field struggles with determining the best clinical trial approaches to develop accurate and specific predictors to select among adjuvant chemotherapy regimens,” Symmans said.

Symmans believes that prospective randomized neoadjuvant trials of standardized chemotherapy regimens “hold the greatest promise for such approaches to discriminate between different regimens.”

Personalized treatment in oncology is a popular concept these days, but the goal remains elusive

Personalized Treatment With Adjuvant Chemotherapy Shows Marginal Progress

It is time to rethink the way oncologists in the United States are treating ductal carcinoma in situ (DCIS), particularly in light of recent research suggesting that certain breast cancer rates may be on the rise, says Laura Esserman, MD, MBA, a professor of surgery and radiology at the University of California, San Francisco.

“We all are concerned that we are treating too much DCIS but no one knows how to get off the wheel and do something different,” Esserman said during a presentation at the Miami Breast Cancer Conference on Thursday.

Esserman, who also is director of the Carol Franc Buck Breast Cancer Center and Translational Informatics at UCLA, said that detection of DCIS has increased 500% since mammograms were introduced, and that surgeons in this country alone have removed >60,000 cases of DCIS per year for >10 years.

Yet, she said, the factors that cause DCIS to develop into invasive cancer remain unclear. DCIS, she noted, is heterogeneous, with variation in grade, receptor positivity, frequency of mutations, degree of necrosis, tumor density, and disease extent.

“Have we identified the right precursor lesion?” she asked. “If we want screening to be good, we have to be more thoughtful about what we’re trying to detect.”

Most experts agree that the decline in the incidence of breast cancer rates in 2003 stems from women abandoning hormone replacement therapy after research linked its use to cancer. Nevertheless, Esserman said, even a large drop in invasive cancer does not prove most DCIS is a precursor of invasive cancer.

Esserman said there are 2 important facts of risk: 1) the risk that an invasive cancer will appear in the same region; and 2) the timing of the risk.

“For high-grade lesions, the timing of risk is likely to be within the first 5 years,” she said in her presentation abstract. She said the approach in those cases should be “to study the biology and employ window trials to start screening potential risk-reducing agents.”

However, Esserman suggested lesions with a 20% to 35% risk of progression should be classified as high risk and not as cancer, and should be followed as such. She suggested low-grade DCIS be called “atypia” and that intermediate DCIS be referred to as “ductal intraepithelial neoplasia.”

“If we continue on the same clinical path, we cannot hope to have any type of change,” Esserman said.

It is time to rethink the way oncologists in the United States are treating ductal carcinoma in situ

A Call for Change in Treating DCIS

The addition of sorafenib to capecitabine as a first-line therapy for patients with advanced breast cancer resulted in a 42% reduction in the risk of disease progression or death among participants in a phase IIB trial, according to research reported at the Miami Breast Cancer Conference. 

In one of the top posters presented at the conference, researchers said that the results warranted a phase III trial for sorafenib, an antiangiogenic and antiproliferative multikinase inhibitor. In fact, a phase 3 trial was launched in February.

Lead investigator Patricia Gómez, MD, an attending physician and senior clinical investigator at the Hospital Vall d’Hebron, Barcelona, Spain, said the research team wanted to examine how the addition of a targeted therapeutic agent would impact conventional therapy. She said they chose sorafenib because of its antiangiogenic qualities and because patients can take it orally.

Until now, sorafenib (Nexavar), which was approved by the FDA in 2005, has been used only for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. However, the SOLTI-0701 multinational, double-blind study enrolled 229 patients with advanced HER2-negative breast cancer previously treated with ≤1 prior chemotherapy regimens. Patients were randomized virtually 1:1 to sorafenib with capecitabine or placebo with capecitabine. Progression-free survival (PFS) was the primary endpoint of the study.

As first-line therapy, PFS for patients in the sorafenib arm was 7.6 months, compared with 4.1 months for those in the placebo group. Gómez said that was the most significant finding of the study.

As second-line therapy, sorafenib made a measurable but not statistically significant difference, improving median PFS to 5.7 months compared with 4.1 months for the placebo group.

In overall survival (OS), a secondary endpoint, the median OS for the sorafenib arm was 22.9 months, compared with 20.9 months for the placebo arm.

Gómez said the most significant adverse effect in the sorafenib arm was hand-foot skin reaction, with 44% of patients reporting grade 3 symptoms. She felt those symptoms could be managed.

The study is 1 of 4 phase IIB trials studying the combination of sorafenib with other therapies as part of the TIES (Trials to Investigate the Effects of Sorafenib) breast cancer program.

The addition of sorafenib to capecitabine as a first-line therapy for patients with advanced breast cancer

Phase II Sorafenib Study Yields Positive Results

Daniel A. Osman, MD, Founder and Course Director of the Miami Breast Cancer Conference Discusses Methods for Detecting Malignant Conditions in Breast Cancer

Dr. Osman on Detecting Malignant Breast Cancer

The climate for medical malpractice litigation in breast cancer treatment seems to be worsening, with “designer lawsuits” linked to imaging and genetic tests among the emerging trends, according to Patrick I. Borgen, MD chairman of the Department of Surgery and director of the Brooklyn Breast Cancer Program at Maimonides Medical Center in Brooklyn, New York.

“Failure to diagnose breast cancer accounts for about 40% of all medical malpractice suits filed,” said Borgen, a widely published author and editor.

He said allegations of a delay in diagnosis of breast cancer is the number 1 basis for medical malpractice lawsuits and the second most expensive generator of liability claims against physicians. 

Borgen identified these allegations as emerging areas of litigation:

		Failure to identify genetic risk factors

		Failure to use available technology to determine ideal treatment

		Breast cancer caused by hormone replacement therapy

He also said plaintiffs are showing an increased interest in genomic profiling in cases where complications arose after unnecessary chemotherapy.

“What’s driving this today more than anything else is unrealistically high expectations,” Borgen said.

Often, these expectations are fueled by simplistic media reports that fail to convey the complexities of breast cancer or the limitations of clinical studies, Borgen said. For instance, he cited research showing that 57% of women over 40 years old believe getting a mammogram reduces their risk of breast cancer.

Borgen said oncologists could take steps to prevent malpractice suits, such as controlling their practices, maintaining documentation, and managing a patient’s anger at her condition. He also suggested that physicians could be more selective about the patients they treat.

Above all, he said, oncologists must manage expectations about treatment outcomes—their own expectations and those of their patients.

The climate for medical malpractice litigation in breast cancer treatment seems to be worsening

Malpractice Claims Target Breast Cancer Specialists

Breast pain is among the most common reasons that women seek medical attention from a breast specialist. According to speakers at the Miami Breast Cancer Conference, an appropriate diagnosis is of utmost concern even though the condition most frequently proves to be benign.

The reasons for breast pain can be attributed to hormonal cycles or to diet and lifestyle patterns. Benign breast conditions were the focus at a mini-symposium Wednesday as 2 speakers presented both an American and European perspective on diagnosis and treatment.

An American Perspective: Watch Out for Bursitis

Women who experience breast pain often fear they have cancer, so alleviating their cause of distress is essential, according to V. Suzanne Klimberg, MD, a professor of surgery and pathology and director of the Breast Cancer Program at the Winthrop P. Rockefeller Cancer Institute in Little Rock, Arkansas.

Klimberg noted that 7% of breast cancer patients present with breast pain only, heightening the importance of diagnosing pain.

“When a patient complains of breast pain, important first steps are determining the relationship between her symptoms and her menstrual cycle, and whether the pain radiates from her arm or bears similarities to bursitis, Klimberg explained.

“There are a variety of factors that could play a role in breast pain,” Klimberg said. These include dietary factors such as caffeine use, consuming high-fat meals, or eating chocolate, cheese, or drinking wine. Stress can also exacerbate the pain, she said.

As a result, reassurance works well for half of the patients with mild breast pain. For dietary issues, nutritional changes often help.

Klimberg finds the most frequent cause of difficult-to-treat breast pain is bursitis. “Breast pain associated with bursitis is important to diagnose because it is the most often missed and the easiest to treat with physical therapy or trigger point injections,” she said.  She uses long- and short-acting pain medication.

A European Perspective: Repetitive Strain Has an Impact

R. Douglas Macmillan, MBChB, MD, FRCS, found that the strain of typing all day at a computer keyboard or toting around a young child frequently causes breast pain, which, in severe cases, is treatable with steroid injections.

Macmillan, an oncoplastic surgeon and clinical lead at the Nottingham Breast Institute, United Kingdom, said that breast pain can be divided into 2 broad categories:

		Hormonal pain usually linked to the patient’s menstrual cycle and to hormone replacement therapy in postmenopausal women

		Chest wall pain that can be diagnosed more precisely into 2 repetitive strain syndromes by determining which ribs are affected

For hormonal pain, “the mainstay of management is reassurance with expectation of spontaneous resolution,” with severe cases requiring low-dose, short-term, intermittent tamoxifen.

When it comes to chest wall pain, the answer often lies in the patient’s daily activities. Macmillan analyzed rib complaints of 138 women and found that pain was localized to 1 rib in 66% of the patients and to 2 ribs in 21%.

In the serratus syndrome, 2 or 3 adjacent ribs of the upper 8 ribs where the serratus arises are most commonly affected; these patients likely work regularly at a computer although other activities that involve using the same arm position for long periods of time (ie, hairdressing or repetitive lifting) might also cause this type of pain.

In the pectoralis syndrome, pain in ribs 3 to 5 at the origin of the pectoralis minor typically is caused when a patient carries a young child on the affected side or regularly performs similar lifting tasks.

To manage the pain, Macmillan first recommends that patients avoid the activity causing the problem. For patients with resistant, more severe pain localized to 2 or 3 ribs, a direct steroid injection such as depomedrone 80 mg was shown to be effective for 85% of patients in 1 small study. Other treatments can include a Botox injection, acupuncture, or local anesthetic patches.

Breast pain is among the most common reasons that women seek medical attention from a breast specialist.

Diet and Lifestyle Are Factors in Breast Pain

Daniel A. Osman, M.D. Founder and Course Director of the Miami Breast Cancer Conference on Breast Cancer Changes in the Past 10 Years

Dr. Osman on Breast Cancer Changes in the Past 10 Years

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