A number of presentations at last week's San Antonio Breast Cancer Symposium focused on personalized approaches to treating breast cancer.
The following studies represent some of the highlights from SABCS.
Roche Presents Data on Pertuzumab in HER2-Positive Metastatic Breast Cancer
In the Clinical Evaluation of Pertuzumab and Trastuzumab trial, or CLEOPATRA, researchers led by Jose Baselga of Harvard Medical School randomized more than 800 previously untreated, HER2-positive metastatic breast cancer patients to receive either pertuzumab combined with Herceptin and chemotherapy or just the Herceptin/chemo regimen.
Genentech, which markets Herceptin (trastuzumab), is also developing the HER2 dimerization inhibitor pertuzumab. The compound prevents the HER2 receptor from joining with other HER receptors, such as EGFR/HER1, HER3, and HER4, thereby stopping cancer growth by blocking cell signaling in HER2-positive cancer.
The primary endpoint of the study was progression-free survival evaluated by an independent review panel. Additionally, the study investigators assessed progression-free survival, overall survival, overall response rate, and safety. Researchers in the study also correlated biomarkers with clinical response to the treatment regimens.
Results from the study, funded by Roche, were published last week in the New England Journal of Medicine and presented at SABCS. In the NEJM article, Baselga et al. reported that patients treated with the pertuzumab/Herceptin/chemotherapy combination treatment experienced median progression-free survival of 18.5 months compared to 12.4 months for those on the Herceptin/chemo arm.
An assessment by an independent review committee found that patients treated with the pertuzumab combination regimen had statistically significant improvements in progression-free survival.
At interim analysis, which was conducted after following patients for approximately 19 months, researchers saw a trend that suggested that patients treated with the pertuzumab regimen may live longer than those not receiving the investigational drug. However, the survival analysis had not yet reached statistical significance at the time of the interim analysis.
"The survival data are not yet mature, since the interim analysis of overall survival was performed after 165 events had occurred (43 percent of the prespecified total number of events for the final analysis)," Baselga and colleagues wrote in the NEJM paper. "Although there is a strong trend toward prolonged survival with pertuzumab plus trastuzumab plus docetaxel, the result is exploratory," they wrote. Survival data from the final analysis is slated to be reported in 2013.
Around 80 percent of patients treated with the pertuzumab/Herceptin/chemotherapy combo responded to treatment, while 69 percent responded to the Hercpetin/chemo regimen. Patients who received pertuzumab experienced more than 2 percent higher rates of neutropenia, febrile neutropenia, and diarrhea than patients in the Hercpetin/chemo arm. "The combination of pertuzumab, Herceptin and chemotherapy was not associated with a higher incidence of cardiac adverse events or left ventricular dysfunction compared with Herceptin and chemotherapy," Roche said.
Roche subsidiary Genentech has previously said that based on the success of CLEOPATRA, it is planning to file for regulatory approval from the US Food and Drug Administration for pertuzumab in combination with Herceptin and docetaxel as a new treatment for HER2-positive metastatic breast cancer. Last week, Dako said it will collaborate with Genentech to gain approval from the FDA for its HercepTest and HER2 FISH pharmDx as companion diagnostics for pertuzumab. Genentech plans to submit the regulatory application for pertuzumab before year end.
Genentech already markets Herceptin for the treatment of HER2-positive metastatic breast cancer and HER2-positive stomach cancer. Baselga et al. explain in the NEJM paper that "targeting HER2-positive tumors with two anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a more comprehensive blockade of HER2 and highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest extent possible."
Genentech is also studying pertuzumab in early-stage breast cancer.
Genomic Health Reports Positive Prognostic Validation Data for Oncotype DX DCIS Test
Researchers from Genomic Health and the Eastern Cooperative Oncology Group analyzed more than 300 ductal carcinoma in situ specimens with the Oncotype DX DCIS test. The aim of the prospective validation trial was to gauge how accurately the DCIS recurrence score could assess the likelihood that patients' cancer would recur in the same breast over a decade.
In the study, breast cancer patients who received a low DCIS score had a 12 percent chance of an invasive form of breast cancer or of DCIS recurring in the same breast. This low-risk group had around a 5 percent chance of developing invasive breast cancer. Patients who had a high DCIS score had a 27 percent chance of local recurrence; half of these patients would likely develop a new invasive breast cancer.
"The DCIS score also demonstrated consistent association with local recurrence across subgroups regardless of lesion size, grade, surgical margins, or menopausal status," Genomic Health said in a statement.
According to Genomic Health, these data suggest that approximately 75 percent of patients who receive a low DCIS score may be able to forego radiation therapy. Currently, industry observers estimate that around 85 percent of DCIS patients receive radiation treatment.
"The treatment of DCIS has been highly variable in the absence of having reliable methods to select patients for treatment with surgery alone without radiation," said Steven Shak, chief medical officer of Genomic Health. "By revealing the underlying biology of DCIS, we can now help quantify the likelihood of local recurrence, which is key to devising an individualized treatment plan."
Although the investment community was optimistic about these results, some cautioned that the ECOG validation study wasn't designed to gauge whether the DCIS score can predict which patients would benefit from radiation treatment.
"It is important to note that the ECOG validation study was designed to demonstrate the test's ability to stratify DCIS breast cancer patients based on a recurrence risk score, rather than demonstrate an ideal treatment (radiation) pathway," wrote Jon Wood of Jefferies & Company in a note to investors. Wood pointed out that a study that can definitively conclude that the DCIS score can be used to guide treatment would need to enroll a patient group treated with surgery alone and compare their outcomes with another cohort treated with both surgery and radiation.
Wood added that "the absence of a direct treatment (radiation) benefit claim may impede more rapid adoption."
Shak disagreed with this assessment, however, and said that the current DCIS validation study provides "critical clinical information which can benefit patients."
He noted that DCIS requires different treatment strategies than invasive breast cancer. "The addition of therapies like tamoxifen or radiation therapy in DCIS … has not been shown to provide any survival advantage," Shak told PGx Reporter. "So, for a DCIS diagnosis that is pre-invasive or non-invasive breast cancer, the ECOG investigators are confident that these results mean that … the DCIS score [is] a new tool that can benefit patients today."
According to Genomic Health, the DCIS test runs on the same RT-PCR-based platform as its other Oncotype Dx tests but employs a DCIS-specific algorithm to analyze patient samples for the expression of multiple genes and provide a recurrence score. In this study, patient samples were garnered from the ECOG5194 study of breast-conserving surgery.
Genomic Health estimates that around 45,000 patients are diagnosed with DCIS every year in the US. DCIS is a form of cancer where the disease starts in the milk ducts within the breast.
The standard treatment in such cases is breast-conserving surgery. However, between 20 percent and 25 percent of patients treated with surgery alone experience local recurrence of DCIS or a new invasive breast cancer within 10 years. Although radiation therapy has been shown in studies to reduce the risk of recurrent breast cancers, such treatment does not prolong patients' lives.
Genomic Health said that it will launch the Oncotype DX DCIS test on Dec. 28.
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Phase III Trial Evaluating Avastin, Herceptin, Docetaxel in First-Line HER2-Positive Breast Cancer Suggests Need for Biomarkers
Researchers from Roche and various institutions conducted a Phase III study, called AVEREL, in which they randomized HER2-positive breast cancer patients with locally recurrent or metastatic disease to receive either an Avastin/Herceptin/docetaxel regimen or just Hercpetin plus docetaxel. The study, however, reached different conclusions about the effect of adding Avastin to Herceptin and docetaxel in HER2-positive breast cancer patients when the results were assessed by investigators and an independent review committee.
In AVEREL, researchers led by Luca Gianni of San Raffaele Hospital in Milan enrolled more than 400 patients with HER2-positive locally recurrent or metastatic breast cancer from 60 centers over a period of three years. Patients' HER2 status was established by immunohistochemistry, fluorescence in situ hybridization, or chromogenic in situ hybridization.
Roche markets both Avastin (bevacizumab) and Herceptin (trastuzumab). According to the investigators involved in AVEREL, earlier phase studies have suggested that HER2-positive breast cancer patients might benefit from combination treatment with an anti-angiogenic drug, Herceptin, and a taxane. This is the first Phase III study, however, combining Herceptin and Avastin.
The primary endpoint in AVEREL was progression-free survival; overall survival and safety were among several secondary outcome measures. At 26 months median follow up, investigators found that when Avastin was added to Herceptin and docetaxel, patients experienced an 18 percent reduction in risk of progression or death compared to those who received just Herceptin and docetaxel. However, an independent review committee found that adding Avastin resulted in a 28 percent reduction in risk for progression or death.
Investigators reported a 2.8-month increase in progression-free survival when Avastin was added, while the independent review committee reported an increase of 2.9 months.
According to the abstract, researchers observed no new safety signals in the Avastin/Herceptin/docetaxel arm. Grade 3 or grade 4 adverse events, such as congestive heart failure, febrile neutropenia, and hypertension were common in the Avastin-containing arm. Grade 5 adverse events occurred in 1.4 percent of the patients treated with the Avastin regimen compared to 1.9 percent of patients in the comparator arm.
"The addition of [Avastin] to Herceptin plus docetaxel improved PFS without reaching statistical significance, according to investigator assessment," the researchers concluded. However, the independent review committee found the improvement to be statistically significant.
"Evaluation of biomarkers is ongoing to try to identify those patients who may benefit from first-line [Avastin]-containing therapy for HER2-positive [locally recurrent or metastatic breast cancer]."
The FDA recently revoked Avastin accelerated approval as a treatment for metastatic breast cancer (PGx Reporter 11/30/2011). In the months leading up to the removal of the breast cancer indication, Genentech had proposed that the FDA keep Avastin on the market while it conducts another validation study, in which the company would use a molecular diagnostic to try to pick out best responders to the drug.
In AVEREL, "in a way, we confirmed that combining an anti-angiogenic and [other treatment] is a good idea. But now, we have to search the subset of women who have the characteristics associated with benefit from addition of an anti-angiogenic. The key element is looking for a restricted indication that might have a longer-lasting effect than we can observe in AVEREL," Gianni said in a statement, adding that "biomarkers will be important in helping determine the best role for [Avastin] in treating HER2-positive cases."
Agendia's MammaPrint, BluePrint Characterize Patient Response to Chemotherapy in I-SPY 1 Trial
Researchers led by Stefan Glück of the University of Miami analyzed breast cancer patient samples in the multi-center I-SPY 1 Trial using Agendia's 70-gene microarray-based breast cancer recurrence test MammaPrint and its 80-gene breast cancer subtyping test BluePrint. They aimed to gauge whether these two tests could predict which breast cancer patients would experience a survival advantage with neo-adjuvant chemotherapy and those who wouldn't benefit from such treatment.
The study investigators compared molecular classifications for samples from 149 patients and followed patients for nearly four years.
According to a poster presented at SABCS, using MammaPrint, researchers classified 9 percent, or 13, patients as low risk. This subset was then tested with BluePrint, which classifies patients into basal-type, luminal-type, and HER2-type breast cancer. It identified one patient as HER2-type and 12 as luminal-type. While these patients had "excellent" survival rates, none of them experienced a pathologic complete response after neo-adjuvant therapy, Glück et al. wrote in the abstract.
"These findings support the need to investigate whether low-risk, luminal-type patients could be managed with endocrine therapy alone," the investigators wrote.
MammaPrint assessed the remaining 136 patients as high risk. In this population, BluePrint found 43 percent to be high risk luminal-type (luminal B) with a pathologic complete response rate of 13 percent. Thirty-eight percent of patients were basal-type with a pathologic complete response rate of 34 percent. Finally, 11 percent were HER2-type and had a pathologic complete response rate of 53 percent.
Researchers reported three-year disease-free survival rates for patients with basal-type tumors at 66 percent; 78 percent for HER2-type; 87 percent for 70-gene high risk/luminal-type; and 100 percent for 70-gene low risk/luminal-type.
"Combining BluePrint with MammaPrint risk-classification can detect specific groups of patients who are at high risk of recurrence and suggests who would have a higher likelihood to benefit from chemotherapy," Glück et al. concluded.
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Molecular Signaling Distinguishes Early ER-Positive Breast Cancer Recurrence in Patients Receiving Adjuvant Tamoxifen
Researchers led by Minetta Liu of Georgetown University tested their hypothesis that patients who experience early recurrence of estrogen receptor-positive breast cancer while being treated with tamoxifen harbor different molecular changes in their tumors than those who experience later recurrence.
In the study, researchers extracted RNA from tumor samples of patients from a cohort in Edinburgh who had stage I-III breast cancer before starting treatment with tamoxifen, and who were followed for 10 years to gauge recurrence.
Minetta and colleagues chose samples comprising greater than 50 percent malignant epithelium and arrayed these on Affymetrix U133 Plus 2.0 GeneChips. The researchers then developed a computational method to identify transcriptome differences in the samples and associate them with early or late recurrence. In the study, early recurrence was when the disease returned in under three years and late recurrence was when the patient relapsed after 10 years.
"Substantial overlap of the network features and topology was seen between datasets," Minetta et al. wrote in the abstract presented at SABCS. "Specifically, increased relative expression of ESR1, ESR2, EGFR, BCL2, and AR was seen in late versus early recurrent tumors, and increased expression of CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1 was seen in early versus late recurrent tumors."
This data, Minetta and colleagues believe, "provide clear evidence that robust molecular differences exist between ER-positive breast cancers that recur early versus much later despite adjuvant tamoxifen" treatment.
They added that further exploration of these molecular differences could enable "reliable prediction of early treatment failure, and guide use of novel therapeutics specifically directed at preventing early versus late recurrences on endocrine therapy."