Research Roundup from San Antonio: New Data on Triple-negative, HER2-positive, Local, and Advanced Breast Cancer 


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The 2012 San Antonio Breast Cancer Symposium featured more than 2,500 abstracts and lectures, including timely research in the field and discussions for scientists and clinicians alike. In addition to nearly two dozen in-depth reports from the meeting, The ASCO Post brings readers the following news briefs.

Bevacizumab in Triple-negative Breast Cancer

Bevacizumab (Avastin) did not improve outcomes when added to chemotherapy in patients with early breast cancer who have the triple-negative subtype, the results of the randomized phase III BEATRICE study showed.1

Overall, the outcomes were better than expected, but “in terms of improvement in outcomes, giving 1 year of bevacizumab isn’t the answer,” said David Cameron, MD, Professor of Oncology at Edinburgh University in Scotland.

C. Kent Osborne, MD, Director of both the Breast Center and Cancer Center at Baylor College of Medicine, Houston, who moderated the press conference where the results were first presented, added, “It’s getting to the point where it’s going to be difficult to know the role of bevacizumab, if any, in breast cancer.”

BEATRICE included 2,591 women with triple-negative invasive early breast cancer starting adjuvant chemotherapy with a taxane, anthracycline, or both. Patients were randomly assigned to four to eight cycles of chemotherapy, alone or with the addition of bevacizumab. Treatment was continued for 1 year.

Invasive disease–free survival was achieved by 83.7% in the bevacizumab arm compared with 82.7% for chemotherapy alone, for a 13% nonsignificant reduction in risk.

While the overall survival analysis was premature, a similar trajectory was observed. The bevacizumab arm had a 16% nonsignificant reduction in mortality. Bevacizumab was associated with more cardiovascular toxicity, but most cases were reversible after discontinuation.

Intraoperative Radiotherapy vs External-beam Radiotherapy

Low-dose intraoperative radiation therapy proved comparable to whole-breast irradiation (ie, external-beam radiotherapy) for preventing breast cancer recurrence in an updated analysis of the randomized noninferiority TARGIT-A trial.2

After a median follow-up of 29 months, the 34 cases of ipsilateral breast recurrence were observed slightly but significantly more often in the targeted intraoperative radiotherapy group. Nonetheless, the absolute difference of 2.01% fell within the prespecified boundary for noninferiority of targeted intraoperative radiotherapy (2.5%), reported Jayant Vaidya, MD, FRCS, PhD, Reader and Consultant Surgeon at the University College London.

The study population consists of 3,451 women aged 45 and older with unifocal early invasive breast cancer (preferably < 3.5 cm). The updated results showed a hazard ratio for recurrence of 2.05 for targeted intraoperative radiotherapy vs external-beam radiotherapy (P = .042). In addition to the recurrences, 88 deaths have occurred in the two treatment groups, but in this case there was a trend toward 30% fewer deaths overall with targeted intraoperative radiotherapy (P = .099) and a 53% reduction in non–breast cancer mortality (P = .009) vs external-beam radiotherapy.

Dr. Vaidya maintained that focusing radiation therapy on the primary tumor site, where most recurrences are observed, is a logical strategy, giving rise to the targeted intraoperative radiotherapy protocol. After surgical excision, patients receive about a 20Gy dose directly to the wound bed. Patients with high-risk features (~15%) receive supplemental external-beam radiation therapy in this “risk-adapted” approach.

Prespecified stratification by hormone receptor as a surrogate for radiation sensitivity status showed that the difference in recurrence rate owed primarily to increased locoregional recurrence in patients with progesterone receptor–negative tumors and delayed delivery of targeted intraoperative radiotherapy (necessitating reopening of the wound cavity). An analysis limited to the 1,625 progesterone receptor–positive women who received targeted intraoperative radiotherapy concurrent with lumpectomy produced a between-group difference for local recurrence of 0.18% and a reduction in overall mortality of 3.1% (P = .08) vs external-beam radiotherapy.

Dr. Vaidya emphasized the need for careful patient selection in applying targeted intraoperative radiotherapy in clinical practice. “Patients should fulfill the eligibility criteria for the TARGIT-A trial,” he said. “The preferred treatment option is concurrent [targeted intraoperative radiotherapy at the time of surgery] in progesterone receptor–positive patients. Add external-beam radiotherapy if adverse prognostic factors are present.”

Cognitive Impairment May Precede Chemotherapy Treatment

A small study by Bernadine E. Cimprich, PhD, RN, FAAN, Emerita Professor, and colleagues at the University of Michigan3 found that some common neurocognitive problems associated with chemotherapy in the treatment of breast cancer, such as poor performance on verbal working memory tasks (ie, “chemobrain”), are often present before treatment begins and may be the result of fatigue and anxiety.

The research involved testing the neurocognitive responses of 65 patients with stages 0 through IIA breast cancer and 32 age-matched healthy subjects using functional magnetic resonance imaging (MRI). The functional MRI was performed 24 to 34 days after surgery and before either adjuvant anthracycline-based combination chemotherapy (n = 28) or radiotherapy (n = 37) for localized breast cancer. The participants were asked to perform a verbal working memory task during functional MRI scanning and provide self-reported levels of fatigue both 1 month prior to treatment and 1 month following therapy.

The findings showed that the chemotherapy group had significantly greater severity of fatigue (P < .05) and performed less accurately on the verbal working memory task both 1 month pre- and 1 month post-treatment, compared with participants in the other two groups. The radiotherapy-treated patients had an intermediate cognitive function score between that of the chemotherapy and control groups.

The researchers concluded that pretreatment neurocognitive compromise and fatigue are contributors to the cognitive impact often attributed solely to chemotherapy. Moreover, they noted that early therapeutic interventions that target fatigue may improve cognitive function and reduce the distress of “chemobrain” during adjuvant treatment.

According to press conference moderator C. Kent Osborne, MD, of Baylor College of Medicine, Houston, worry and stress of a breast cancer diagnosis, as well as anticipatory anxiety before chemotherapy, can affect cognitive function. This problem needs attention because cognitive effects can worsen over time, he added.

Duration of Trastuzumab in HER2-positive Early Breast Cancer

Two years of trastuzumab (Herceptin) is not better than the standard 1 year of trastuzumab therapy for HER2-positive breast cancer, according to 8-year follow-up of the HERA trial reported by Martine Piccart, MD, President of the European Society for Medical Oncology and Chair of the Breast International Group, Institut Jules Bordet, Brussels, Belgium.4

HERA accrued 5,102 women with early HER2-positive breast cancer who were treated with neoadjuvant or adjuvant therapy according to the investigators’ choice and then randomly assigned to 1 or 2 years of trastuzumab following chemotherapy.

At 8 years, no difference in disease-free survival was observed between the two arms and both were significantly better than observation. No difference in the cumulative incidence of severe cardiac endpoints was observed between the two arms.

“We were concerned that there would be a progressively smaller effect of 1 year of treatment with trastuzumab over time. Now with 8 years of follow-up, there is no further attenuation of benefit as was seen at 1 year, and a very robust effect with 1 year of trastuzumab,” she said. “One year of trastuzumab should remain the standard of care.”

Higher Doses of Fulvestrant in Metastatic Breast Cancer

Fulvestrant (Faslodex) at 500 mg achieved superior survival vs the 250-mg dose in postmenopausal women with estrogen receptor–positive metastatic breast cancer in an update of the randomized CONFIRM trial.5 The higher dose did not increase toxicity.

The standard of care in this setting has been fulvestrant at 250 mg. “Our results indicate that this should be modified to 500 mg,” said lead author Angelo Di Leo, MD, PhD, Head of the Department of Medical Oncology at the Hospital of Prato, Istituto Toscano Tumoria, Prato, Italy.

The multinational phase III CONFIRM trial randomly assigned 736 women to 250 mg of fulvestrant vs 500 mg. An analysis performed after 75% of the women died showed that the 500-mg dose achieved a clinically relevant 4.1-month difference in median overall survival compared with 250 mg: 26.4 months and 22.3 months, respectively. The relative risk reduction in death was 19% for those taking the higher dose of fulvestrant.

Serious adverse events were reported in 8.9% of the 500 mg-dose group and 6.7% of those on the lower dose.

EndoPredict Identifies Women at Risk for Distant Metastases

The EndoPredict score identifies women with estrogen receptor (ER)-positive /HER2-negative breast cancer at risk for late distant metastases, according to Peter Dubsky, MD, Associate Professor of Surgery at the Medical University of Vienna in Austria.6

Other predictive tests, including Oncotype DX and MammaPrint, have been trained and validated to predict recurrence within the first 5 years, Dr. Dubsky explained. The good news about the EndoPredict score is that it predicts late metastases. “Risk of recurrence persists for estrogen receptor–positive breast cancer, even beyond 15 years of follow-up. This is in sharp contrast to estrogen receptor–negative breast cancer. Thus, a multigene assay that assesses not only a short-term, but also long-term, prognosis meets an unmet medical need” he noted.

Unlike other multigene tests that are based largely on genes with a role in tumor proliferation, the EndoPredict score also factors in genes involved in estrogen receptor regulation and genes with a role in tumor differentiation. These biologic motifs are contained in the eight genes of the test; three reference genes are also included. Furthermore, data derived from tumor size and nodal status factor into the final test result.

Among 1,702 women with estrogen receptor–positive/HER2-negative breast cancer, the EndoPredict score defined about two-thirds with an excellent prognosis; 98.2% with a low risk score were free of distant metastasis at 10 years. One-third of women with higher risk scores had a five times higher risk of late recurrence than the low-risk group, Dr. Dubsky explained.

Expanded studies are ongoing. EndoPredict is currently available for diagnostic use in Austria, Germany, and Switzerland.

Breast Cancer Index and Late Recurrences in ER-positive Patients

The polymerase chain reaction–based Breast Cancer Index (BCI) assay, performed on primary tumors in node-negative estrogen receptor–positive patients traditionally considered at good risk, identifies groups of patients with a high risk of recurrence, and performs independently of clinical characteristics, such as number of nodes, tumor grade, and age.7

“The residual risk of recurrence remains a substantial concern for estrogen receptor–positive patients with breast cancer. Current multigene signatures have significant prognostic performance in predicting early recurrences, ie, 0 to 5 years postdiagnosis. However, such signatures have limited performance in predicting the risk of late recurrence, ie, beyond 5 years,” said Dennis Sgroi, MD, Associate Professor of Pathology at Harvard Medical School, Boston.

The Breast Cancer Index consists of two independently developed biomarkers: the HOXB13:IL17BR gene expression ratio and the molecular grade index, a set of cell cycle–related genes. Investigators examined the prognostic performance of the Breast Cancer Index as compared to the 21-gene Recurrence Score and IHC4 test with regard to early and late recurrences.

The population included 665 patients from the translational arm of the Arimidex, Tamoxifen, Alone or in Combination trial (TransATAC), followed for a median of 10 years. Prognostic evaluation for early recurrences was done by censoring survival time to 5 years, and for late recurrences, by analyzing patients who had remained recurrence-free for at least 5 years.

The index distinguished three risk groups: BCI-low (58%), BCI-intermediate (25%), and BCI-high (17%). With BCI-low as a reference, the BCI-intermediate group had nearly a threefold risk for distant recurrence at 10 years and the BCI-high group had nearly a fivefold risk (P < .001). The BCI-high group also had more than an eightfold risk of early recurrence, with disease recurring in 18% within 5 years.

“As it relates to late recurrence, BCI demonstrated sustained significant prognostic performance in a multivariate analysis, while IHC4 and Oncotype DX Recurrence Score lost their prognostic ability,” Dr. Sgroi noted.

“At the point of diagnosis, BCI identified two groups: those at low risk of early recurrence who are adequately treated with endocrine therapy alone. And those at high risk of early recurrence who do not benefit adequately from simple endocrine therapy and who should be considered for additional therapy,” he said.“

“At the point of 5-year follow-up among patients who are disease-free, the BCI identified two groups as well: those at low risk of late recurrence who do not need subsequent therapy and those at significant risk of late recurrence who should be considered for additional or alternative systemic adjuvant therapy,” he concluded.

HER2 Status by Central Laboratory Testing

HER2 status is more reliably determined with novel central laboratory testing techniques than routine local HER2 testing such as immunohistochemistry and in situ hybridization, a multicenter retrospective biomarker study showed.8 The finding could have implications for patients with HER2-negative breast cancer as well, said ­Denise A. Yardley, MD, Senior Investigator, Breast Cancer Research Program, at Sarah Cannon Research Institute, Nashville, Tennessee.

Her team evaluated the HERmark assay, a novel method for quantitatively measuring HER2 total protein expression in breast cancer. They compared results obtained with the HERmark assay to those obtained by local (“real-world,” site-reported) HER2 testing and by central laboratory HER2 retesting of formalin-fixed, paraffin-embedded breast cancer tissues. They correlated the results with tumor histopathologic characteristics and overall survival in a cohort of 192 formalin-fixed, paraffin-embedded breast cancer samples from patients, 90% of whom had not received HER2-targeted therapy. Study sites were instructed to identify approximately 50% HER2-positive and 50% HER2-negative breast cancer cases.

High HER2 total protein expression levels (> 13.8) determined by the HERmark assay significantly correlated with poor overall survival (HR = 5.6; P < .001), whereas HER2-positive status determined by local testing only trended toward an overall survival association (HR = 1.78; P = .098). The observed discrepancy in survival based on different HER2 classification methods appeared to be due to the misclassification of HER2 status determined by local testing, Dr. Yardley said.

Interestingly, of the 24 triple-negative cases that were reported via the local testing, 4 were reclassified as HER2-positive by HERmark testing. Quantitative HER2 total protein expression determined via the HERmark assay may enrich the identification of both HER2-positive and HER2-negative breast cancers and thus may provide added clinical value to real-world local HER2 testing, she said.

Vitamin D Levels and Breast Cancer Outcome

Postmenopausal women with sufficient levels of vitamin D were much less likely to have breast cancer recur in their bones and in distant recurrence to any tissue when their standard chemotherapy was combined with zoledronic acid (Zometa), found researchers from the University of Sheffield in the United Kingdom.9 The finding was based on the analysis of stored blood samples taken from a subgroup of participants in the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial before they began treatment. The subgroup included 606 premenopausal women and 266 postmenopausal women.

The researchers looked at the baseline serum levels of two markers of bone turnover—beta C-terminal telopeptide type 1 collagen (βCTX) and N-terminal propeptide type 1 procollagen (P1NP)—and baseline measurements of 25-hydroxyvitamin D (25-OHD) as a marker of bone and general health.

Although neither of the two bone turnover markers predicted outcomes, the investigators found that 25-OHD levels > 30 ng/mL were significantly associated with lower risk for bone relapse (hazard ratio [HR] = 0.11, 95% confidence interval [CI] = 0.02–0.76, P = .0257). A similar trend was seen for any site of distant recurrence (HR = 0.56, 95% CI = 0.31–1.01, P = .0519). Only 10.3% of the women in the subgroup had vitamin D levels above this cutoff.

“We should be measuring vitamin D and replenishing it appropriately…. [But] whether vitamin D as an intervention will change outcome, I don’t know,” said lead researcher Robert Coleman, MD, Professor of Medical Oncology at the University of Sheffield, United Kingdom, at the San Antonio meeting.

Age and Likelihood of Complete Response to Neoadjuvant Chemotherapy

According to the results of a meta-analysis of 8,949 women with breast cancer by researchers from the German Breast Group,10 women aged 35 years or younger more often achieved a pathologic complete response with neoadjuvant chemotherapy than older women, especially in the subgroups of luminal and triple-negative tumors. The researchers determined that 23.6% of the subgroup of 704 younger women in the study were able to achieve a pathologic complete response following neoadjuvant chemotherapy, compared with 17.5% of the 4,167 women in the 35- to 50-year-old age range and 13.5% of the 4,078 older women (P < .001).

The subgroup of younger women included a greater proportion of triple-negative breast cancer cases and a smaller proportion of luminal A–type breast cancer cases, compared with the group of women over age 35 (26% vs 19% for triple-negative disease and 21% vs 27% for luminal A–type disease). The study results found no difference in disease-free survival according to age among patients who achieved a pathologic complete response. However, disease-free survival was significantly worse among younger women who did not achieve a pathologic complete response.

Tumor biology, especially in young women, also seemed to play a role in predicting pathologic complete response and disease-free survival. Researchers found that pathologic complete response was able to predict disease-free survival in luminal A patients only among the younger women. The worst disease-free survival rate among women with luminal A–type cancer was seen in those who were younger than 35 and did not achieve a pathologic complete response. The best disease-free survival rate in this group was found among women younger than 35 who did achieve a pathologic complete response.

“The most surprising finding was that young women with a luminal A–type tumor—hormone receptor–positive and HER2-negative—who achieved a pathologic complete response had a better survival rate than the patients with nonpathologic complete response. This is not true for other age groups, which indicates that breast cancer in the young—even with a luminal-type breast cancer—is chemosensitive,” Sibylle Loibl, MD, Associate Professor of Gynecology at the University of Frankfurt and lead author of the study, said at the San Antonio meeting. ■

Disclosure:Drs. Cameron, Osborne, Cimprich, Dubsky, Sjroi, Yardley, and Loibl reported no potential conflicts of interest. Dr. Vaidya received support for ISC meetings/conferences and honoraria from Carl Zeiss. Dr. Piccart is a consultant for and receives honoraria from Sanofi-Aventis, Amgen, Bayer, Roche-Genentech, PharmaMar, and AstraZeneca; and receives honoraria from Novartis. Dr. Di Leo received honoraria from AstraZeneca, Novartis, and Pfizer for participation in advisory boards and as a speaker at sponsored symposia. Dr. Coleman received research support and provided expert testimony for Novartis, and was on the speakers bureau for Amgen.

References

1. Cameron D, Brown J, Dent R, et al: Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triple-negative breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S6-5. Presented December 7, 2012.

2. Vaidya JS, Wenz F, Bulsara M, et al: Targeted intraoperative radiotherapy for early breast cancer: TARGIT-A trial—updated analysis of local recurrence and first analysis of survival. 2012 San Antonio Breast Cancer Symposium. Abstract S4-2. Presented December 6, 2012.

3. Cimprich B, Hayes DF, Askren MK, et al: Neurocognitive impact in adjuvant chemotherapy for breast cancer linked to fatigue: A prospective functional MRI study. 2012 San Antonio Breast Cancer Symposium. Abstract S6-3. Presented December 7, 2012.

4. Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al: HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow-up. 2012 San Antonio Breast Cancer Symposium. Abstract S5-2. Presented December 7, 2012.

5. DiLeo A, Jerusalem G, Petruzelka L, et al: Final analysis of overall survival for the phase III CONFIRM trial: Fulvestrant 500 mg versus 250 mg. 2012 San Antonio Breast Cancer Symposium. Abstract S1-4. Presented December 5, 2012.

6. Dubsky P, Brase JC, Fisch K, et al: The EndoPredict score identifies late distant metastases in ER+/HER2- breast cancer patients. 2012 San Antonio Breast Cancer Symposium. Abstract S4-3. Presented December 6, 2012.

7. Sgroi DC, Sestak I, Cuzick J, et al: Comparative performance of Brest Cancer Index vs. Oncotype Dx and IHC4 in the prediction of late recurrences in hormonal receptor-positive lymph node-negative breast cancer patients: A TransATAC study. 2012 San Antonio Breast Cancer Symposium. Abstract S1-9. Presented December 5, 2012.

8. Yardley D, Kaufman P, Adams J, et al: Quantitative measurement of HER2 expression in breast cancers: Comparison with “real world” HER2 testing in a multi-center Collaborative Biomarkers Study and correlation with clinicopathological features. 2012 San Antonio Breast Cancer Symposium. Abstract P2-05-06. Presented December 6, 2012.

9. Coleman RE, Rathbone EJ, Marshall HC, et al: Vitamin D, but not bone turnover markers, predict relapse in women with early breast cancer: An AZURE translational study. 2012 San Antonio Breast Cancer Symposium. Abstract S6-4. Presented December 7, 2012.

10. Loibl S, Jackisch C, Gade S, et al: Neoadjuvant chemotherapy in the very young, 35 years of age or younger. 2012 San Antonio Breast Cancer Symposium. Abstract S3-1. Presented December 6, 2012.



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