The following articles are all taken from the MBCC Daily News...
Exploring New Genomic Targets in Metastatic Disease
By Anna Azvolinsky, PhD
Fabrice André, MD, PhD, has focused his research on translational oncology and the development of novel targeted agents for the treatment of breast cancer through his research as an associate professor and director of INSERM Unit U981 at the Institut Gustave-Roussy in Villejuif, France.
He is one of the principal investigators of a prospective clinical trial, SAFIR01, in France that is combining genomic sequencing and tumor biopsy data for better treatment decision making in women with metastatic disease.
André will discuss the need to individualize treatment for patients based on their tumor biology in his presentation, “Use of Genomic Approaches to Select Patients for Targeted Therapy,” scheduled for Friday at 8:15 AM. In this interview, André addresses several targets being explored in clinical research.
Currently, patients with HER2-positive breast cancer are treated with adjuvant trastuzumab-based therapy, and those with estrogen receptor (ER)-positive disease are treated with hormonal adjuvant therapies. For other types of breast cancer, what are the selective targeted therapies that appear promising and how far away are they from widespread use?
André: The four targeted therapies that deserve interest are mammalian target of rapamycin (mTOR) inhibitors, the phosphatidylinositol 3-kinase inhibitors (PI3K), cyclin-dependent kinase (CDK) inhibitors, particularly CDK4, and fibroblast growth factor receptor 1 (FGFR1).
Are there any trials that have been completed or are ongoing that you would highlight?
André: CDK4 inhibitors were highly effective in a phase II trial reported at the San Antonio Breast Cancer Symposium in 2012 [Abstract S1-6]. The CDK4/6 inhibitor, PD 0332991, in combination with letrozole, showed a significant improvement in progression-free survival, an 18.6 month difference, compared with letrozole alone. The study was in postmenopausal women with ER-positive, HER2-negative advanced breast cancer.
The mTOR inhibitor everolimus is a first-in-class drug approved for women with advanced ER-positive breast cancer based on the BOLERO-II trial. What kind of impact has this targeted therapy had on treating these patients?
André: Everolimus is improving outcomes for these ER-positive patients. But on top of that, these results open other avenues. Now we can further develop trials and drugs to fine-tune this first-in-class result.
There are at least two trials, in the US and in France, that are addressing the utility of everolimus in the adjuvant setting. Can you discuss the designs of these trials?
André: Yes, one trial by SWOG (Southwest Oncology Group), one of the five cooperative groups that are part of the National Cancer Institute’s network of clinical trials, compares endocrine therapy to endocrine therapy plus everolimus 10 mg per day for one year, right after chemotherapy (ClinicalTrials.gov Identifier: NCT01674140). The French trial will compare endocrine therapy with or without everolimus for two years in patients who are free of disease after three years of endocrine therapy. The French trial will recruit patients with more than three positive nodes after neoadjuvant therapy. In the US trial, the patients need to be at high risk for recurrence, with one to three positive nodes, or else have four or more positive nodes independent of their recurrence score.
Aromatase inhibitors are widely used as treatment for postmenopausal women who have hormone receptor positive-disease, but not all patients respond and even those who do will still inevitably stop responding. Are we any closer to understanding the mechanisms of either primary resistance or acquired resistance to aromatase inhibitors?
André: The mechanisms of resistance to aromatase inhibitors are multiple and may involve kinase activation either at baseline or after treatment exposure. A trial in France that is starting soon will perform biopsies and also high-throughput genomic analyses in patients who present resistance to aromatase inhibitors.
What has been the progress in identifying molecular markers, either alone or in conjunction with biological features, which render a patient unresponsive to chemotherapy? What are the main challenges of understanding the pathways of inherent or acquired chemotherapy resistance?
André: Chemotherapy is more complex than endocrine therapy, since it can have many mechanisms of action. We are still struggling to find molecular mechanisms of chemoresistance. Nevertheless, it seems that immune activation could play a role in the sensitivity to chemotherapy.
There have been many attempts to characterize triple-negative breast cancer and identify novel subtypes. What have been the main challenges in identifying these subtypes?
André: Triple-negative breast cancers account for around 15% of all breast cancers. So, the number of samples we can obtain from triple-negative patients is lower than that for ER-positive subtypes, so the research moves slower. Triple-negative breast cancer is a highly unstable disease at the genomic level. This means that a patient’s disease can look different over time due to genomic instability. Nevertheless, several papers have recently succeeded in proposing homogenous subclasses of triple-negative breast cancers. This new research suggests that triple-negative breast cancers include tumors with mutations in DNA repair, with immune activation, and activation in the Src tyroskine kinase and in the PI3K pathway.
What is a current, interesting target or class of targets for triple-negative breast cancer?
André: The most promising target is certainly the Chk1 protein in this field.
The Overdiagnosis and Overtreatment of DCIS
By Ben Leach
According to the American Cancer Society, more than 60,000 cases of ductal carcinoma in situ (DCIS)—a noninvasive form of breast cancer in the lining of the milk ducts—are diagnosed and removed each year in the United States. However, despite treatment, a concomitant decrease in the incidence of invasive breast cancer has not been observed.
The logical conclusion, according to Laura J. Esserman, MD, MBA, director of the Carol Franc Buck Breast Care Center and co-leader of the Breast Oncology Program at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California, is that DCIS is being overdiagnosed and overtreated.
“I think it’s important because it’s not clear that DCIS is indeed the precursor of cancer,” Esserman said in an interview. “It’s simply a risk factor for invasive cancer, and we need to get our treatment of this entity in line with the way we treat other risk factors for breast cancer.”
Esserman will give her thoughts on some of the shifts that she feels are required to adequately treat DCIS in a presentation on Friday at 9:30 AM entitled, “Are We Overdiagnosing and Overtreating DCIS?”
One of the key shifts Esserman said is needed to treat DCIS appropriately is to recognize the difference between larger, potentially invasive lesions and smaller lesions that have a very low potential to become malignant.
“I think we need to distinguish that DCIS is not one entity just like breast cancer is not one entity,” Esserman said. “A lot of these small, low-grade lesions are clearly no different from atypia, and they should be treated as such.”
Screening studies that are used to identify these indolent lesions bring them to clinical attention, and therefore, lead to the potential for overdiagnosis. Esserman said that the Oncotype DX test for DCIS has consistently found that the risk of developing invasive cancer ranges from 2.5% to 10% at 5 years, and perhaps as high as 20% at 10 years.
“That [level of risk] is really not a whole lot different from someone walking around the street,” Esserman said. “In many cases, we’re treating non-disease. We treat mutation carriers who have an 85% risk of developing cancer quite differently. We don’t operate on them all. We offer prophylactic surgery as an option to some patients, but only when it’s appropriate.”
To lower the rate of overdiagnosis, Esserman said that oncologists should adopt strategies designed to minimize the detection of these inconsequential or minimal risk lesions. Even though the Oncotype DX DCIS test is relatively accurate, other methods may be required to determine if women who are diagnosed with DCIS are truly at risk for developing invasive disease.
Esserman said a better classification system would allow oncologists to change the terminology associated with DCIS, including removal of the term cancer for patients with low-risk lesions.
“It is not a cancer,” Esserman said. “It is a risk factor for developing invasive disease. That’s how it should be presented. People should be presented the risks and the actions for close surveillance, prevention, and treatment.”
Esserman said that the University of California campuses have collaborated on establishing a registry for DCIS to help determine what the best approach is to reclassifying DCIS. However, she said that it would take several such registries across the United States working collaboratively to enable groups like the American Society of Clinical Oncology and the National Comprehensive Cancer Network to recommend sweeping changes in how DCIS is classified.
“I think that Barry Kramer, MD, MPH, who is head of the Division of Cancer Prevention at the National Cancer Institute, considers this to be a top issue,” Esserman said. “He actually agrees that overdiagnosis and overtreatment is common and prevalent, and we actually are recommending a change in the classification of these lesions. We’ve called for efforts to change the threshold for biopsy and to use time to enable us to really learn to not make people feel that they need an intervention, but that they need to be watched closely so we can start to learn a lot more about it.”
While Esserman said these changes are necessary, she also said that many clinicians have embraced the idea that some lesions pose more of a risk than others, and that these patients should receive different treatment options for their disease. Rather than intervention, Esserman said prevention strategies should instead be emphasized to women who have these indolent lesions.
“We need to focus on improving treatments for the people who are at risk to die of their disease and reducing therapeutic interventions for people who don’t have risky disease and the treatments will make them worse than what they have,” Esserman said. “We need to restrict our interventions to people who have extensive high-grade DCIS, and to start offering different options to the rest.”
Piccart Discusses Translating Genomic Testing Into Practice
By Anita T. Shaffer
Although multigene signature tests are being widely used in the United States to help oncologists evaluate the need for adjuvant chemotherapy for certain patient populations, two large clinical trials are expected to define the impact that employing genomic tests in treatment decisions has on survival outcomes, according to Martine J. Piccart, MD, PhD.
Piccart, director of Medicine at the Jules Bordet Institute in Brussels, Belgium, discussed genomic testing and its translational value thus far during a presentation and subsequent interview Friday morning at MBCC.
As president of the European Society of Medical Oncology, Piccart recently cautioned that the era of personalized medicine has not truly arrived, and she echoed that theme in her remarks at the conference.
She said that although “we have witnessed the development of several quite good multigene prognostic signatures,” not much progress has been made in terms of predictive tools that help clinicians select the best chemotherapy.
“We’ve come to realize that identifying predictive markers is really a very complex endeavor,” Piccart said. “One of the reasons that we have probably failed up until now is that we have concentrated our efforts on the tumor and it’s becoming increasingly [apparent] that the macroenvironment plays a major role.”
In less than a decade, prognostic genomic testing has become widespread in the United States, but less so in Europe, Piccart noted. “Information generated from genomic tests has resulted in a change in decision making in approximately 25% to 30% of cases,” according to the IMPAKT 2012 Working Group, a cooperative translational research effort in Europe that Piccart helped develop.1
Last year, IMPAKT researchers evaluated six genomic tests for their analytical validity, clinical validity, and clinical utility.1
The researchers concluded that OncotypeDX, a 21-gene recurrence score, and MammaPrint, a 70-gene assay, have demonstrated analytical and clinical validity.
OncotypeDX has been incorporated into the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines; it is indicated for women with stage I/II, node-negative, estrogen receptor-positive invasive breast cancer who will be treated with hormone therapy and provides a score for the risk of local recurrence.
The IMPAKT group said there are not enough available data to arrive at a conclusion on the analytic and clinical validity of four other tests: CGI, a 97-gene assay; PAM50, a 50-gene assay; the Breast Cancer Index, a 2-gene ratio and molecular grade index; and EndoPredict, an 11-gene assay.
Piccart said EndoPredict has been gaining popularity in Europe. She said that EndoPredict incorporates information on Ki67, a nuclear antigen used to compare proliferation between tumor samples2, and on tumor burden to predict for long-term disease-free survival.
So far, the genomic tests have aided in treatment decisions, Piccart said. She said the tests are useful for luminal breast cancers, not for HER2-positive or triple-negative malignancies that would automatically be classified as high risk.
“These tests are already now quite useful in the clinic and have already led to a significant decrease in adjuvant chemotherapy prescription in the United States,” Piccart said in an interview.
“We are still waiting for the results of these very important trials, TAILORx and MINDACT, to be completely sure that these tests are clinically useful and improve the outcome of patients,” she said. “In this case, what we expect is a reduction in chemotherapy prescriptions without any worsening of survival.”
TAILORx, which involves about 11,000 women, is comparing the disease-free survival of women with previously resected axillary-node negative breast cancer with an Oncotype DX Recurrence Score of 11 to 25 treated with adjuvant combination chemotherapy and hormonal therapy versus adjuvant hormonal therapy alone.3
MINDACT, which involves 6600 women, compares the 70-gene signature with standard clinical-pathological criteria used to determine whether patients with breast cancer with 0 to 3 positive nodes should receive adjuvant chemotherapy.4
1. Azim HA, Michiels S, Zagouri F, et al. Utility of prognostic genomic tests in breast cancer practice: the IMPAKT 2012 Working Group Consensus Statement. Ann Oncol [published online ahead of print January 20, 2013]. 2013; 24(3):647-654. doi:10.1093/annonc/mds645.
2. Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group [published online ahead of print September 29, 2011]. 2011;103(22):1656-1664. doi:10.1093/jnci/djr393.
3. Hormone therapy with or without combination chemotherapy in treating women who have undergone surgery for node-negative breast cancer (The TAILORx Trial). Clinical Trials PDQ®. National Cancer Institute website. http://cancer.gov/clinicaltrials/search/view?cdrid=472066&version=healthprofessional. Updated December 3, 2012. Accessed March 8, 2013.
4. EORTC Trial 10041 (BIG 3-04)¾MINDACT. European Organisation for Research and Treatment of Cancer website. www.eortc.be/services/unit/mindact/MINDACT_websiteii.asp#Current. Updated October 14, 2009. Accessed March 8, 2013.
Oncology Enters Era of Genomics
Sledge Calls for Overhaul of Clinical Trials System
By Anita T. Shaffer
As the genomic era in oncology unfolds, the development of new therapeutics increasingly will involve targeting a range of mutations simultaneously, requiring a “next-generation clinical trials system” to match the advances that technology is delivering, according to George W. Sledge, Jr, MD.
Sledge told attendees at the 30th Annual Miami Breast Cancer Conference Saturday that last year marked a leap forward in understanding breast cancer as the results of many genomic analyses became available. The range of mutations uncovered in individual tumors will necessitate moving beyond battling cancer by identifying a particular molecular process, as has been the case in the targeted therapy era, to multiple driver mutations.
“We’re clearly entering a new age and that age is what I consider to be the genomic era,” said Sledge, who is chief of the Oncology Division at Stanford University School of Medicine in California and a past president of the American Society of Clinical Oncology. “This is an era of great promise. We’re at the point where we’ll be able to tell an individual what’s driving their cancer but it’s going to require a whole lot more of us.”
In developing new therapeutics, researchers will have to focus not only on qualitative mutations but also quantitative aberrations, Sledge said. “We don’t need a magic bullet, we need a magic shotgun,” he said. “We need something that can shoot pellets at a lot of different targets and do so more or less simultaneously.”
He said the current clinical trials system is poorly equipped to take advantage of advances in knowledge about cancer genomics and that many changes are needed. His ideas for overhauling the system include trials designed around multitargeting, greater collaboration among research entities, an information network for clinical trials, a redesigned informed consent process, and a “fundamentally different regulatory apparatus.”
“We have next-generation sequencing. We need a next-generation clinical trials
system, “ Sledge said.
Sledge noted that technological advances have delivered an explosion of information at an ever-decreasing cost. He said the sequencing of the first human genome took 13 years and cost approximately $3 billion; in the next several years, researchers likely will be able to sequence a genome in less than two weeks at a cost of about $1000. He said the price would drop further and that the challenge would be using the information generated.
“The evaluation of that gene chip that you order will be incredibly complicated and will require a significant amount of playing out over the next decade in terms of how we use it,” he said.
Sledge said genomics research has revealed that cancers can be described broadly as either “stupid” or “smart.”
Cancers that are stupid have a single dominant mutation and a small mutational load, meaning that monotherapy will be effective and that resistance to therapy will occur rarely and along the same pathway.
In contrast, smart cancers show multiple mutational drivers with a large mutational load, requiring multitargeted therapy to which resistance is common and occurs early in treatment.
Chronic myeloid leukemia, with bcr-abl as a target and a relatively small mutational load, is an example of a stupid cancer, Sledge said. Smart cancers with a greater mutational load include those where patients’ lifestyles play a role, such as lung cancer and melanoma.
Breast cancer falls in the middle of the mutational spectrum, with subtypes that reflect the genomic complexities of the malignancies, Sledge said. “This distinction between stupid cancers and smart cancers drives a lot of what we know about the prognosis of human cancers, and it increasingly will drive how we approach these cancers from a therapeutic standpoint,” he said.
For example, Sledge said, an analysis of triple-negative breast cancer found 32 somatic mutations,1 showing a “genomic chaos” that makes the malignancy a collection of orphan diseases. Attacking a tumor type with so many mutations becomes an oncology version of the Whack-a-Mole arcade game, he said.
“We’re dealing with this rapid emergence of compensatory mechanisms of resistance that have a deep genomic basis which we now for the very first time in human history can measure and increasingly will be able to measure by an individual basis,” Sledge said. “One has to think this will change how we think about the cancer and how we approach cancer from a therapeutic standpoint.”
1. Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395-399.
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