An interview with Debu Tripathy, MD, summarizing noteworthy results from the 2012 ASCO Annual Meeting and SABCS, including clinical studies in local, adjuvant, and metastatic breast cancer therapies.
Debu Tripathy, MD
In 1998, the first targeted therapy for the treatment of breast cancer entered broad clinical practice when the FDA approved trastuzumab (Herceptin) for patients with metastatic tumors that overexpress the human epidermal growth factor receptor 2 (HER2) protein.
Yet although HER2 has become one of the best-known biomarkers in oncology, continuing exploration of the molecular nature of tumor biology has yielded fresh insights and some surprises about HER2 signaling in breast cancer.
The latest research into HER2 gene mutations was among the highlights that Debu Tripathy, MD, emphasized in his presentation on “ASCO and San Antonio Updates” as the 30th Annual Miami Breast Cancer Conference (MBCC) opened Thursday.
Tripathy’s review of key abstracts presented at the 2012 American Society of Clinical Oncology (ASCO) annual conference and the San Antonio Breast Cancer Symposium (SABCS) has become a staple of MBCC. Tripathy, coleader of the Women’s Cancers Program and a professor of Medicine at the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, is one of the program directors of MBCC.
In addition to HER2 research, Tripathy summarized noteworthy results from clinical studies in local, adjuvant, and metastatic disease therapies. His presentation covered 15 abstracts. In this interview, Tripathy discussed some of the most noteworthy studies.
Researchers from the Washington University School of Medicine in St. Louis, Missouri, used genome-sequencing data to more precisely identify the role of HER2 mutations in driving tumors. Some patients whose tumors are HER2- negative based on standard assays may harbor undetected HER2 gene mutations that are driving disease and may be sensitive to HER2-directed therapies, the researchers suggested in an abstract presented at SABCS1 and in an article in Cancer Discovery.2
Investigators compiled data from several genome sequencing projects to identify patients whose tumors exhibited HER2 somatic mutations but not HER2 gene amplification. They then used experimental techniques, including in vitro kinase assays and protein structure modeling, to characterize activating mutations and determine which anti-HER2 therapies might be effective.
Bose et al concluded that HER2 somatic mutations promote HER2 signaling activity, and that these mutations also can be anticancer targets. One drug that is being tested as a result of their research is neratinib, an oral dual HER1/HER2 inhibitor.
Based on these findings, Bose and colleagues also hypothesize that undetected HER2 mutations, as opposed to HER2 amplification, may be present in 1.5% to 2% of patients with breast cancer, which would translate to more than 4000 of the newly diagnosed patients annually in the United States.
Tripathy said the findings make diagnosing and treating HER2 breast cancers more complex, and that the implications for targeting driver mutations go beyond this particular gene.
“We have generally thought that the way HER2 drives breast cancer is when it is present in large amounts,” Tripathy said. “Now we’re also discovering that another way HER2 can activate cancer is when it is present in normal amounts but when the gene itself is mutated in such a way that turns it on. This is a fundamentally different way that a gene can cause cancer.”
Tripathy said one challenging aspect of the knowledge gained through genome sequencing and other novel methods is that many of the mutations being discovered are relatively uncommon.
Untreated breast cancer cells with HER2 mutations, top image. Cells shrink after treatment with neratinib, bottom.
“We find many mutations that are only present in 1%, 2%, or 3% of cancers, which means that if we try to design therapy that counteracts the effects of these mutations with new therapies that are really targeted to these mutations, we’re going to have to come up with a whole panel, a whole set of therapies,” Tripathy said.
“Moreover, we’re finding that any given cancer has not only one mutation in it but may contain several—up to 40—and that would suggest that we’re going to have to develop cocktails of drugs, and that we are going to have to create a customized one for each patient depending on the sequence of their tumor,” he said.
The findings of the HER2 research have been somewhat surprising, Tripathy added, yet reflect knowledge gained through technological advances. “Keep in mind that sequencing an entire gene has been very laborious up until the advent of next-generation sequencing a few years ago,” he said.
As far as translating such research into the clinic is concerned, Tripathy noted that the technology is moving ahead of what oncologists can offer their patients. “This is going to be a slow process, but I believe that ultimately it will incrementally lead to better and better outcomes and more focused therapy,” he said.A decade-long effort to identify the optimal administration of adjuvant radiotherapy following surgery for patients with early breast cancer has led researchers from the United Kingdom to endorse a regimen involving a lower total dose delivered in fewer, larger fractions (Fr).
The results from the two START trials confirm the use of 40 Gy delivered in 15 Fr as the standard of care for women requiring adjuvant radiotherapy, which has been incorporated into the National Institute for Health and Clinical Excellence guidelines since 2009, according to an abstract presented at SABCS.3
The START trials, which enrolled patients from 1999 to 2002, involved 4451 women with completely excised breast cancer (T1-3, NO-1, MO) who were randomized after primary surgery to radiotherapy regimens. In START A, patients received either 50 Gy in 25 Fr over 5 weeks versus 41.6 Gy or 39 Gy in 13 Fr over 5 weeks. In START B, patients received either 50 Gy in 25 Fr over 5 weeks versus 40 Gy in 15 Fr over 3 weeks. The primary endpoints were locoregional (LR) tumor relapse and late/normal tissue effects (Table).
In START A, the best results were obtained with the 41.6 Gy regimen. At a median follow-up of 9.3 years, the rate of LR relapse was 6.3% among that group (95% CI, 4.7-8.5), compared with 7.4% in the 50 Gy group and 8.8% after 39 Gy. In START B, the most favorable outcomes came from the 40-Gy dosage. At median follow-up of 9.9 years, the LR relapse rate was 4.3% after 40 Gy (95% CI, 3.2-5.9), compared with 5.5% after 50 Gy.
Tripathy said the START trials represent “a very elegant set of both biological and clinical experiments” in which researchers were able to identify “the optimal balance between minimizing tissue injury and maximizing the effect in terms of preventing a local recurrence, which, of course, is the main point of radiation.”
Since the trials have been under way for 10 years, the results are not news to British oncologists, but they are to Americans, Tripathy noted. “This has now become the standard in England, and so this was very provocative,” he said.
At the same time, however, Tripathy said researchers in Canada took a more conservative approach in limiting lower-dose radiotherapy to patients with negative lymph nodes for a series of studies that reached similar conclusions.
Clinical Trial Arms
Local-Regional Tumor Relapse Ratea (95% CI)
Late Normal Tissue Effectsb Rate (95% CI)
39 Gy in 13 Fr over 5 wk
41.6 Gy in 13 Fr over 5 wk
50 Gy in 25 Fr over 5 wk
40 Gy in 15 Fr over 3 wk
50 Gy in 25 Fr over 5 wk
bModerate/marked late effects of therapy in normal tissue, such as swelling, hardness, and changes in skin appearance.
CI indicates confidence interval; Fr, fractions; Gy, gray.
“In the United States, it’s still controversial as to whether you can hypofractionate,” Tripathy said. “I know that in our center, the radiation oncologist said, yes, you can do it but only in limited patients—those who are node-negative, those with smaller tumors, and perhaps older women because the local recurrence rates are a little bit lower. So they’re still being a little more cautious here than they are in the UK.”The question of whether patients with estrogen receptor (ER)-positive early breast cancer benefit from longer-term treatment with adjuvant tamoxifen was addressed in the ATLAS trial. The findings, presented at SABCS4, are perhaps the “most informative and immediately applicable” results among a group of clinical trials comparing treat-
ment regimens that came to fruition last year.
In the ATLAS trial, 6846 women with ER-positive disease who had been taking tamoxifen for approximately 5 years were randomized to an additional 5 years of the drug or to no more tamoxifen.
After about 8 years of follow-up, 1328 recurrences and 728 deaths after recurrence were reported. Treatment assignment had little or no effect on rates of recurrence or death in the period 5 to 9 years after diagnosis. However, in the second decade after diagnosis, women who continued on tamoxifen had a 25% lower recurrence rate and 29% lower breast cancer mortality rate compared with women who stopped after 5 years of tamoxifen.
The risk of dying due to breast cancer 5 to 14 years after diagnosis was 12.2% for continuing tamoxifen users versus 15% for those who had only 5 years of treatment, representing an absolute gain of 2.8%, favoring continuing treatment with tamoxifen for 10 years.
Tripathy said the ATLAS results validate what clinicians have intuitively believed. “It’s a very sort of common sense thing that maybe we should use more tamoxifen because we know that patients, especially patients with hormone receptor-positive breast cancers, can have recurrence many, many years after their five years of tamoxifen is up,” Tripathy said. “It makes sense that one would want to investigate whether more prolonged therapy helps.”
He said, however, that large clinical trials over long periods of time were needed to sort out these treatment questions. Now that mature results from the ATLAS trial are available, Tripathy believes the results will change practice, particularly since the benefits of 10-year tamoxifen outweigh the risks of serious adverse events. For instance, the cumulative risk of death from endometrial cancer between 5 and 14 years after diagnosis was 0.4% for the continuing tamoxifen users versus 0.2% for those who did not continue, researchers reported at SABCS.
Tripathy said the new standard for premenopausal women with higher-risk disease would be 10 years of tamoxifen. He said the matter would continue to be more nuanced for patients with small, node-negative tumors, particularly if they are having hot flashes and other side effects on tamoxifen. Studies investigating 5 versus 10 years of aromatase inhibitor therapy will be reporting results in the future.In the realm of new therapies for metastatic breast cancer, trastuzumab emtansine (T-DM1) has occupied center stage since primary results were reported at ASCO in June.5 On February 22, the FDA approved Genentech’s application for the use of T-DM1 for patients with HER2- positive metastatic disease who have previously received trastuzumab (Herceptin) and taxane chemotherapy. The trade name is Kadcyla, and the formulation is now referred to as ado-trastuzumab emtansine.
In the phase III EMILIA trial, 991 patients were randomized 1:1 to receive either T-DM1 or standard therapy with the doublet regimen of capecitabine and lapatinib.
After a median follow-up of about 20 months, patients who received T-DM1 had a 32% reduced mortality risk compared with patients who received lapatinib and capecitabine (hazard ratio [HR] = 0.68; P <.0006). Median overall survival was 30.9 months for patients who received T-DM1 compared with 25.1 months for patients who received lapatinib and capecitabine.
Tripathy said the data indicate that T-DM1, an antibodydrug conjugate, would replace lapatinib and capecitabine as the new standard of care for second-line therapy. “The interesting thing about T-DM1 is that not only is it effective in patients who had numerous HER2-targeted therapies and progressed, but it also is remarkably free of side effects,” he said.
He said the most notable adverse event likely is low platelet counts, but that has typically proved to be mild and manageable in clinical trials.
Clinical trials are under way to evaluate its use in a variety of first-line settings, including in combination regimens with pertuzumab or chemotherapy, and in early breast cancer, Tripathy said.
Best of ASCO and SABCS
Here is a list of abstracts that Debu Tripathy, MD, has chosen for discussion at MBCC. The abstracts were presented at the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting last June in Chicago and at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) in December.