Noteworthy Abstracts From the Breast Cancer Symposium Include Studies of Novel Therapies and of the Impact of Disease Subtypes on Outcomes


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Elizabeth Mittendorf, MD, PhD

Shalu Pahuja, MD

Vipin Das Villgran, MD, MMS

David Page, MD

More than 150 oral and poster presentations were featured at the 2014 Breast Cancer Symposium, held September 4–6 in San Francisco. The multidisciplinary meeting is sponsored by ASCO, the American Society of Breast Disease, American Society of Breast Surgeons, American Society for Radiation Oncology, National Consortium of Breast Centers, Inc, and Society of Surgical Oncology. Brief summaries of some of those studies are presented here.

Proof of Principle for Breast Cancer Vaccines

In the adjuvant setting, a novel HER2-derived peptide (GP2) vaccine reduced the rate of breast cancer recurrences (though nonsignificantly) and proved safe and well tolerated in a phase II study by investigators working in the vaccine arena. Elizabeth Mittendorf, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, presented the results.1

GP2 is one of a number of vaccines being developed in breast cancer, of which the HER2-derived E75 vaccine (nelipepimut-S) is furthest along in development, now in a phase III registration trial. This human leukocyte antigen (HLA)-A2/A3–restricted immunogenic peptide designed to stimulate CD8-positive T cells to recognize tumor cells with any level of HER2 expression (1+, 2+, or 3+ by immunohistochemistry).

The multicenter phase II randomized study included 180 women with HLA-A2+ node-positive or high-risk node-negative breast cancer with any level of HER2 expression. All patients had been rendered disease-free by standard-of-care therapy (including trastuzumab [Herceptin], where appropriate). The women were randomly assigned to receive GP2 plus granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine], an immunostimulant) or GM-CSF alone. They received 6 monthly intradermal inoculations during the primary vaccination series followed by five boosters administered every 6 months.

At a median follow-up of 34 months, in the intent-to-treat population, disease-free survival rates were 88.1% for the vaccinated group vs 81.0% for the control arm, a 37% reduction in risk (P = .428). In the per-treatment comparison, 93.5% of optimally vaccinated patients were disease-free, compared to 85.0% of controls—a 57% risk reduction (P = .168). This latter comparison excluded patients who had a disease recurrence during the vaccination series or who developed a second nonbreast malignancy.

Importantly, patients with the highest expression of HER2 who received the vaccine after completing trastzu­mab, 100% were disease-free, compared with 90% of the control arm. An in vivo antigen-specific immune response was attained with vaccination.

When questioned about the lack of statistical significance in these comparisons, Dr. Mittendorf noted that as a phase II trial, the study “accomplished what we wanted it to do” in that it established activity and safety and identified a patient population in which the vaccine can be further investigated. Most toxicities were grade 1 and occurred at the same rate as in the GM-CSF–alone arm.

While the current study evaluated the sequential use of trastuzumab and the vaccine, concurrent administration of the two, which may take advantage of trastuzumab’s immune-mediated mechanism of action, could be more effective in preventing recurrences, Dr. Mittendorf hypothesized. These studies are underway.

Veliparib in BRCA-Mutated Tumors

Veliparib showed antitumor activity comparable to that observed in other poly(ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA1 or BRCA2 mutations in a phase I dose escalation study presented by Shalu Pahuja, MD, of the University of Pittsburgh Cancer Institute.2

She and her colleagues evaluated single-agent veliparib, at a maximum dose of 500 mg twice daily, in 70 patients with BRCA-mutated tumors (breast and elsewhere) and 28 with wild-type tumors. They found activity to be greater among patients with mutated vs wild-type disease, with responses observed in 37% of all patients with BRCA-positive tumors at the optimal dose levels, and in 50% of patients with BRCA-positive breast cancer, compared to 0% of those with wild-type ovarian cancer and 19% of those with wild-type breast cancer.

The clinical benefit rates were similar for mutated ovarian cancer (34%) and breast cancer (36%). The only common grade 3 or 4 toxicity was lymphopenia (15%). The dose that will move forward in phase II trials is 400 mg twice daily.

Ongoing correlative studies from archival tissues and mandatory biopsy cohort includes BRCA promoter methylation, BRCA reversion mutation, and nonhomologous end-joining (NHEJ) pathway analysis and will provide early insights on potential predictors of response and resistance. Dr. Pahuja hypothesized that veliparib will combine well with chemotherapy. Phase III trials evaluating veliparib in combination with chemotherapy in BRCA-mutated and triple-negative breast cancer are underway.

Tumor-Infiltrating Lymphocytes and Response Rates

In a poster that earned a Merit Award at the meeting, high levels of tumor-infiltrating lymphocytes in pretreatment breast tumor biopsies, as well as low levels after neoadjuvant therapy, predicted for pathologic complete response, according to a meta-analysis from Chinese researchers.3

In the pooled analysis of 13 neoadjuvant studies involving 3,555 patients, higher number of tumor-infiltrating lymphocytes at baseline was correlated with a greater likelihood of a pathologic complete response, with an odds ratio (OR) of 3.82, reported Yan Mao, MD, of Shanghai Jiao Tong University School of Medicine in China.

Tumor-infiltrating lymphocytes especially predicted for higher rates in patients with triple-negative disease (OR = 5.03) and patients with HER2-positive tumors (OR = 5.54). No significant association was seen in those with hormone receptor–positive/HER2-negative disease (OR = 2.57).

Triple-Negative Breast Cancer and Renal Cell Cancers

In another poster that earned a Merit Award, Joyce Georges Habib, MD, and colleagues were the first to report a direct association between primary triple-negative breast cancer and secondary kidney cancer and an inverse association between triple-negative breast cancer and colorectal cancer.4

Dr. Habib, of Sammons Cancer Center, Texas Oncology, in Dallas, pointed out that most large databases predate HER2 testing, which precludes the ability to look for associations by breast cancer subtype. The current study was able to do so.

Their retrospective database analysis of US Oncology Network practices identified 105,795 patients with breast cancer, 2,237 (2.1%) of whom were diagnosed with at least one secondary nonbreast malignancy at a mean time of 2.6 years after breast cancer diagnosis. They were most commonly non–small cell lung (n = 346), colorectal (n = 250), uterine (n = 192), ovarian (n = 130), thyroid (n = 106), and renal cell cancers (n = 73).

On multivariate analysis, triple-negative breast cancer was predictive of secondary kidney cancer (OR = 2.00; P = .019) but was a negative predictor for secondary colorectal cancer (OR = .47; P = .009), age ≤ 55 (OR = .27; P < .0001), and body mass index ≤ 30 (OR = .64; P = .019).

The association between triple-negative breast cancer and kidney cancer is greater than the association seen with smoking on the univariate analysis. “Triple-negative breast cancer was a strong independent risk factor for kidney cancer,” she indicated. The negative associations between age, lower body mass index, and secondary colorectal cancer have been reported in the past, but this is the first study describing a negative association between primary triple-negative cancer and secondary colorectal cancer.

“The short follow-up makes it unlikely that the secondary cancer associations were caused by the antecedent breast cancer treatments,” Dr. Habib said. “The results may potentially be attributed to genetic, environmental, or lifestyle factors.”

Tumor Subtypes and Radiotherapy to the Brain

Breast cancer subtype is a significant prognostic factor for survival for patients who receive whole-brain radiation therapy for brain metastases, but not for those who receive only stereotactic radiosurgery, according to a study from the University of Pittsburgh Medical Center in Pennsylvania.5

Breast cancer subtypes have an important prognostic role in metastatic disease, but whether they also have a prognostic role in patients receiving radiotherapy for brain metastases has not been known. This single-center study investigated the association between breast cancer subtype and overall survival among 193 breast cancer patients with brain metastases treated between 1997 and 2013. Of them, 131 received whole-brain radiotherapy (with or without stereotactic radiosurgery) and 62 received only stereotactic radiosurgery. Overall survival was defined as the time from diagnosis of brain metastases to death or last follow-up.

In keeping with what was expected, the stereotactic radiosurgery group generally had better survival, since patients who receive this form of radiotherapy tend to have less burden of disease. However, patients with HER2-positive/hormone receptor–negative breast cancer had substantially better outcomes when treated with whole-brain radiotherapy than with stereotactic radiosurgery. Median overall survival was 30 months vs 11 months, respectively, reported Vipin Das Villgran, MD, MMS,
along with joint first author Aju Mathew, MD, and colleagues.

Additionally, with whole-brain radiotherapy, median overall survival was significantly different among the subtypes (P = .0003), whereas for the stereotactic radiosurgery–only group, these differences reflected a nonsignificant trend (P = .07, Table 1, page 30).

Dr. Villgran suggested that the greater benefit seen with whole-brain radiotherapy in the HER2-positive/hormone receptor–negative patients may be the result of the radiation rendering the blood-brain barrier more permeable to trastuzumab.

Ipilimumab/Cryoablation and Immune Response

In light of the association of tumor-infiltrating lymphocytes with favorable prognosis in early-stage breast cancer, novel immunotherapies are being evaluated for the potential to augment antitumor immunity and prevent recurrence. In a poster earning a Merit Award, favorable immunologic effects of cryoimmunotherapy were reported from a pilot study of early-stage breast cancer patients. In this multidisciplinary study led by principal investigator, Heather McArthur, MD, patients received preoperative ipilimumab (Yervoy) and/or cryoablation.

 The data came from 18 patients, 13 of whom had hormone receptor–positive disease, two with HER2-positive disease, and three with triple-negative disease. The therapies were well tolerated, with evidence of enhanced immune activation following cryoimmunotherapy, as measured by the T-cell activation marker, inducible costimulator.6

At the Breast Cancer Symposium, David Page, MD, of Memorial Sloan Kettering Cancer Center, New York, reported that the majority of patients treated with combination therapy experienced sustained increases in plasma interferon gamma (a cytokine attributed to antitumor T-cell activity), vs only two patients treated with ipilimumab alone and no patients receiving cryoablation alone.7 These potentially beneficial immune effects were observed in both hormone receptor–positive and hormone receptor–negative subtypes, as well as in tumors with low or high baseline density of tumor-infiltrating lymphocytes, suggesting that cryoimmunotherapy should be further investigated across all subtypes of early-stage breast cancer, and in patients with both high and low baseline tumor-infiltrating lymphocyte counts. ■

Disclosure: Drs. Mittendorf, Pahuja, Habib, Villgran, and Page reported no potential conflicts of interest.

References

1. Schneble EJ, Perez SA, Murray JL, et al: Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients. Breast Cancer Symposium. Abstract 134. Presented September 5, 2014.

2. Pahuja S, Beumer JH, Appleman LJ, et al: Outcome of BRCA 1/2 – mutated and triple-negative, BRCA wild-type breast cancer patients in a phase I study of single-agent veliparib. Breast Cancer Symposium. Abstract 135. Presented September 5, 2014.

3. Yan M, Qing Q, Yuzi Z, et al: Tumor infiltrating lymphocytes to predict response to neoadjuvant chemotherapy in breast cancer. Breast Cancer Symposium. Abstract 138. Presented September 5, 2014.

4. Habib JG, Espirito JL, Harrell RK, et al: Secondary nonbreast malignancies after primary breast cancer. Breast Cancer Symposium. Abstract 112. Presented September 4, 2014.

5. Villgran VD, Mathew A, Rosenzweig MQ, et al: Effect of tumor subtype on overall survival in brain metastatic breast cancer patients treated with cranial irradiation. Breast Cancer Symposium. Abstract 74. Presented September 4, 2014.

6. Diab A, McArthur HL, Barnett S, et al: A pilot study of preoperative, single-dose ipilimumab and/or cryoablation in women with early-stage resectable breast cancer. ASCO Annual Meeting. Abstract 1098. Presented June 2, 2014.

7. Page DP, Yuan J, Ginsberg A, et al: Tumor and systemic immune responses to preoperative cryoablation plus immune therapy with ipilimumab in early-stage breast cancer. Breast Cancer Symposium. Abstract 64. Presented September 4, 2014.



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