Researchers, clinicians, and other professionals from around the world convened in San Antonio, Texas, in December to present and discuss the latest breast cancer research. Among the findings presented were those from several studies conducted at The University of Texas MD Anderson Cancer Center involving the aggressive HER2-positive, inflammatory, and triple-negative subtypes. A few of these studies are highlighted below.
Lapatinib may be effective for trastuzumab-resistant HER2-positive metastatic breast cancer
Lapatinib has a clinically relevant benefit for patients with HER2-positive metastatic breast cancer previously treated with pertuzumab and ado-trastuzumab emtansine (T-DM1), according to findings from a retrospective study (Abstract P4-21-20). The study compared responses to lapatinib, which is approved in combination with capecitabine for trastuzumab-resistant HER2-positive metastatic breast cancer, in patients previously treated with pertuzumab and T-DM1 and patients who had received other trastuzumab-based regimens.
Looking at medical records in an MD Anderson database, researchers identified patients who had trastuzumab-resistant HER2-positive metastatic breast cancer and were treated with lapatinib. The target cohort included 29 patients who received lapatinib after pertuzumab and T-DM1, and the comparison cohort included 445 patients who received lapatinib after trastuzumab-based regimens that did not include pertuzumab and T-DM1.
In the target cohort, 58% of patients had a clinical benefit—defined as a complete response, partial response, or stable disease for at least 6 months—compared with 78% in the comparison cohort. The median overall survival was 23.9 months for patients in the target cohort and 25.8 months for those in the comparison cohort. The median time to progression was 4.9 months for the target cohort and 5.7 months in the comparison cohort. In both cohorts, patients with de novo disease had longer overall survival and time to progression than did those with recurrent disease.
“We found that over half the patients who were previously treated with pertuzumab and T-DM1 received a clinical benefit from lapatinib for more than 6 months and had no significant increase in toxicity,” said Luis Báez-Vallecillo, M.D., a fellow in the Division of Cancer Medicine and the report’s lead author. “Thus, there is a partial lack of cross-resistance among these HER2-targeted therapies.”
The differences in the clinical benefit rate, overall survival, and time to progression between cohorts could be attributed to the fact that patients in the target cohort had received more previous therapies than those in the comparison cohort. About 25% of patients in the target cohort had received three or more lines of therapy compared with only 10% in the comparison cohort.
The researchers plan to validate their findings in a larger cohort in a collaborative retrospective study at MD Anderson and four other institutions.
Dr. Báez-Vallecillo said, “Our data suggest that lapatinib can be used after trastuzumab, pertuzumab, and T-DM1 because patients showed a clinical benefit, and some may have a very long time to progression despite prior exposure to HER2-targeted therapies.”
Researchers propose new breast cancer staging system
A new breast cancer staging system that would incorporate clinical and biological factors is being recommended on the basis of recent findings (Abstract P6-09-35). The current American Joint Committee on Cancer staging system focuses on tumor size and disease spread and does not include other clinical and biological factors that affect the prognosis of breast cancer patients.
“Staging has historically been based on describing the anatomical extent of disease,” said Rashmi Murthy, M.D., an assistant professor in the Department of Breast Medical Oncology and lead researcher of the study. “However, in this era of personalized medicine, other factors should be incorporated into the staging system.”
Using an MD Anderson database, the researchers identified 21,691 patients with newly diagnosed stage I–III invasive breast cancer who received surgery as an initial treatment from 1997 to 2014. To determine factors associated with breast cancer–specific survival, the researchers retrospectively analyzed patients’ age at diagnosis; tumor pathological stage, grade, estrogen receptor status, progesterone receptor status, and HER2 status; adjuvant treatment history; and outcomes.
On multivariable Cox regression analysis, age, tumor grade, hormone receptor status, and HER2 status were associated with breast cancer–specific survival. On the basis of these findings, the researchers proposed that the current staging system be modified to include clinical and biological factors. Dr. Murthy said that such a system could provide more accurate prognostic information and reflect current standards of care.
Dr. Murthy and her colleagues plan to confirm their findings by analyzing patient data from a larger national database as well as an external validation set. “Hopefully, these analyses will add to the literature to help support including these other variables in the breast cancer staging system,” Dr. Murthy said.
Image-guided biopsy may predict which breast cancer patients do not need surgery
Image-guided biopsy can accurately identify which patients do not need surgery after neoadjuvant therapy, according to a recent clinical trial (Abstract P5-16-30). Currently, nearly 60% of patients who have early-stage triple-negative or HER2-positive breast cancer and receive neoadjuvant therapy experience a pathological complete response, a measure used to predict prognosis; but this response cannot be detected by imaging alone.
“The problem is that imaging can’t tell us with any accuracy that there’s no residual disease,” said Henry Kuerer, M.D., Ph.D., a professor in the Department of Breast Surgical Oncology and the study’s lead researcher. Thus, patients typically undergo surgery to remove the tumor even though surgery may not be necessary. Image-guided biopsy can accurately detect disease at diagnosis, but whether this technique could also detect disease after neoadjuvant therapy has not been studied until now.
To determine the predictive value of image-guided biopsy, Dr. Kuerer and his colleagues conducted an MD Anderson–only trial that enrolled 34 patients who had early-stage triple-negative or HER2-positive breast cancer—two subtypes for which neoadjuvant therapy is commonly used. The patients received standard neoadjuvant systemic therapy and underwent ultrasound- and/or mammography-guided vacuum-assisted core biopsy (VACB) and image-guided fine-needle aspiration (FNA) biopsy before surgery. For each individual biopsy technique and the two techniques combined, the researchers measured the accuracy, false-negative rate, and predictive value for determining whether residual disease was present after neoadjuvant systemic therapy.
VACB and FNA together had 100% accuracy, sensitivity, and specificity; a 0% false-negative rate; and 100% negative and positive predictive values for determining whether residual disease was present. These results suggest that image-guided biopsy can accurately identify which patients do not have residual disease and therefore do not need surgery.
“We believe surgery may be redundant for many patients—at least among patients with these two subtypes of breast cancer,” Dr. Kuerer said. However, he cautioned, “This is not at all standard practice. It is just the beginning of these studies.”
Dr. Kuerer recently opened a phase II trial (No. 2016-0046) to determine the safety of forgoing surgery for patients with stage I or II HER2-positive or triple-negative breast cancer who experience a complete pathological response to neoadjuvant therapy.
Biomarker assay may detect breast cancer, distinguish inflammatory breast cancer
Using a protein biomarker assay to analyze plasma samples, researchers distinguished between patients with breast cancer and healthy participants and between patients with inflammatory breast cancer (IBC) and those with non-IBC disease (Abstract P1-02-07). The main objective of the study was to develop a non-invasive clinical tool to identify cancer.
For IBC, several large-scale, multi-institutional studies have been conducted for gene expression profiling but not protein expression. “Studies have shown that gene expression does not translate into anything meaningful because the ultimate product of the functional unit is a protein,” said Gitanjali Jayachandran, Ph.D., a senior research scientist in the laboratory of James Reuben, Ph.D., a professor in the Department of Hematopathology. “So we need to pay attention to the protein.”
Previous multi-protein biomarker panels lacked the necessary specificity, sensitivity, scalability, and dynamic range to distinguish cancer. But recently, Olink Proteomics developed a proximity extension assay with several biomarker panels that measure 92 proteins simultaneously. This technology overcomes the inherent shortcomings of traditional protein quantification methods and requires only 1 μL of a biological sample.
The researchers obtained plasma samples from 25 patients with IBC, non-IBC, metastatic breast cancer, and non-metastatic breast cancer and samples from seven healthy participants. The samples were then analyzed using the 92-protein biomarker assay.
The analysis revealed several plasma protein signatures that could distinguish between all the sample types. Dr. Jayachandran, the study’s lead researcher, said, “At this point, we don’t know enough to say if this panel can be used as a diagnostic tool, but we are hopeful.” Evan Cohen, Ph.D., a postdoctoral fellow in Dr. Reuben’s lab, is working to confirm these findings in a larger cohort that includes additional breast cancer subtypes. So far, Dr. Jayachandran said, “The preliminary results are very encouraging.”
Tucatinib plus capecitabine and trastuzumab shows efficacy against HER2-positive disease
The HER2 inhibitor tucatinib, in combination with capecitabine and trastuzumab, has a clinical benefit in patients with HER2-positive metastatic breast cancer, according to the preliminary results of an ongoing clinical trial (Abstract P4-21-01).
The multicenter phase IB dose-escalation trial enrolled patients with HER2-positive metastatic disease who had previously been treated with one or more lines of trastuzumab, a taxane, and T-DM1. The patients received tucatinib (also called ONT-380) as monotherapy, with trastuzumab, with capecitabine, or with capecitabine and trastuzumab. Updated preliminary results for the tucatinib, capecitabine, and trastuzumab combination were presented at the symposium by Dr. Murthy, a co–principal investigator on the trial.
Patients treated with tucatinib, capecitabine, and trastuzumab had a median progression-free survival of 7.8 months, a clinical benefit rate of 74%, an overall response rate of 61%, and a median response duration of 10 months. Most toxic effects were grade 1 effects; grade 3 effects included palmar-plantar erythrodysesthesia, diarrhea, fatigue, and reversible increases in liver enzyme levels.
Stacy Moulder, M.D., an associate professor in the Department of Breast Medical Oncology and a co–principal investigator on the trial, said the preliminary results are encouraging, especially the toxicity profile. “Although other oral drugs have been used to block HER2, most cause substantial diarrhea or skin rash because they also block EGFR/HER1,” Dr. Moulder said. “Tucatinib is a specific HER2 inhibitor with much less toxicity than that reported for other drugs in its class.”
Also promising were the results for a subset of patients with central nervous system (CNS) metastases. Subset analyses showed that patients with CNS metastases and those without CNS metastases had similar durations of response and stable disease.
“CNS metastases affect up to 50% of patients with HER2-positive metastatic breast cancer and represent an area of unmet clinical need,” Dr. Murthy said. “The updated data show that the combination of tucatinib, capecitabine, and trastuzumab can safely produce durable responses in patients with and without CNS metastases who have received multiple lines of prior treatment.”
On the basis of these results, a randomized controlled phase II trial of tucatinib or placebo plus capecitabine and trastuzumab (HER2CLIMB, No. 2016-0054) is now under way at MD Anderson and other centers. The new trial is open to patients with HER2-positive metastatic or locally advanced breast cancer, including those with brain metastases.
For more information, the studies described in this article are only a small sample of the research from MD Anderson and other institutions presented at the 2016 San Antonio Breast Cancer Symposium. More information about the conference, including abstracts and poster presentations, is available at www.sabcs.org.
OncoLog, February 2017, Volume 62, Issue 2