Therapies for Breast Cancer: Practice-Changing Developments

Color-enhancement show magnetic resonance image (MRI) of individual breast.

Source: Dr. Steven Harmes. Baylor University Medical Center, Dallas Texas, The Web site of the National Cancer Institute (http://www.cancer.gov).

Adjuvant Bisphosphonates

Neoadjuvant and adjuvant therapies, administered before and after primary anticancer therapy, respectively, have been shown in numerous clinical trials to reduce recurrence and improve survival in patients with breast cancer. Here, we review the most significant recent developments in these experimental therapies for patients with breast cancer.Bisphosphonates are inhibitors of osteoclast-mediated bone resorption that were originally indicated for the treatment of osteoporosis and are now often used in patients with breast cancer to reduce the risk of skeletal complications resulting from cancer treatment-induced bone loss.

Studies have suggested that the use of bisphosphonates in the adjuvant setting could provide more than just supportive care, and in fact may exert anticancer activity. Conflicting data emerged from initial studies, but more recent trials have demonstrated a significant survival benefit in certain subgroups of patients. Results from the AZURE and ABCSG trials suggested that the anticancer activity of bisphosphonates may depend on a low estrogen environment, because efficacy in these trials was limited to postmenopausal women and to younger women who were pushed into artificial menopause by ovarian function suppression.^1,2

Data presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2013 appear to confirm this hypothesis. Results from a meta-analysis of adjuvant bisphosphonate treatment among more than 17,000 participants in randomized, phase III trials found a 17% reduction in the risk of mortality and a 39% reduction in the risk of bone metastases in postmenopausal patients.³

Adjuvant bisphosphonate therapy may also prove safe and effective after neoadjuvant therapy, according to the NATAN trial, also discussed at SABCS. Use of adjuvant zoledronic acid in 654 patients with breast cancer and with residual tumor following neoadjuvant chemotherapy led to a 17% improvement in disease-free survival (DFS) among a subset of patients aged 55 years or older.⁴Although this did not reach clinical significance, it is consistent with findings from other trials.

The PRIME-2 Study: Omission of Radiation Therapy for Elderly Patients

The importance of these findings and their potential impact on guidelines for breast cancer therapy were highlighted in a plenary lecture at SABCS by Michael Gnant, MD, professor of surgery at the Medical University of Vienna, Austria. Commenting on these studies, Gnant said, “The NATAN study overall is a ‘negative’ study, but this does not mean much since a suboptimal bisphosphonate was used in a suboptimal setting. More importantly, it supports the overall trend of the bisphosphonate meta-analysis that these agents are effective in postmenopausal women (or those young patients who are rendered postmenopausal by ovarian function suppression therapy), but not effective in the presence of a high-estrogen environment.” He said he believes that adjuvant zoledronic acid/clodronate therapy will be recommended as a standard of care in contemporary guidelines.The question of the use of adjuvant radiotherapy (RT) among older patients with breast cancer has been controversial. Despite guidelines from the National Comprehensive Cancer Network, which allow adjuvant RT to be omitted for patients aged ≥70 years, RT remains standard of care in this population. In 2004, a study demonstrated no difference in overall survival (OS) with RT in women aged ≥70 years with stage I estrogen receptor-positive breast cancer.⁵However, a survey performed in 2012 found that the study had not changed subsequent practice.⁶

In the PRIME-2 trial, presented at SABCS, the role of RT was examined in 1326 lumpectomy candidates aged ≥65 years. The 5-year tumor recurrence rate among patients who did not receive RT was less than 4%. Furthermore, there was no decrease in the rate of regional recurrence or distant metastases, or increase in OS, among patients who received RT. Also, the absolute reduction in recurrence was very small.⁷

C. Kent Osborne, MD

Platinum for TNBC?

“Sometimes it takes more data before doctors change their routine. This was a well-done study with convincing data and I think will lead to changes in practice for a subset of patients with the most common subtype of breast cancer,” said C. Kent Osborne, MD, professor of Medicine and Molecular and Cellular Biology and director of the Breast and Baylor Cancer Centers at Baylor College of Medicine in Houston, Texas.Numerous clinical trials are evaluating novel combinations of chemotherapy in the adjuvant and neoadjuvant settings. One prominent example is the use of platinum-based chemotherapy in patients with triple-negative breast cancer (TNBC). Platinum-based agents typically do not feature prominently in breast cancer treatment. However, it was hypothesized that patients with TNBC could be sensitive to DNA-damaging platinum-based chemotherapy because of deficiencies in BRCA-associated DNA repair mechanisms in these tumors.

Results from the recent GeparSixto trial demonstrated that addition of carboplatin to a combination of paclitaxel and pegylated liposomal doxorubicin in the neoadjuvant setting significantly increased pathologic complete response (pCR) rates (37.2% vs 46.7%). A subgroup analysis indicated that this increase was driven by the effect of carboplatin in the TNBC subgroup, with no significant improvement observed in patients with HER2-positive breast cancer.⁸A similar improvement in pCR rates was also reported in the phase 2 CALGB 40603 trial, evaluating the addition of carboplatin to neoadjuvant paclitaxel in patients with TNBC (33.7% vs 47.8%).

A corresponding increase in toxicity was observed with the addition of carboplatin in both studies, which has important implications for guiding practice. Biomarker analyses are underway, with the aim of identifying patients with TNBC who would derive the most benefit. Preliminary data suggest that immunologic biomarkers may be helpful in this regard; lymphocyte-predominant breast cancer as a tumor subgroup and also increased tumor-associated lymphocytes were significant predictors of response.⁹

The addition of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab was also assessed in both trials and led to increased pCR rates, an effect that was additive when carboplatin and bevacizumab were combined in the CALGB 40603 study. However, 20% of patients discontinued therapy because of significant toxicity associated with bevacizumab.¹⁰Discussing the CALGB study, lead author William Sikov, MD, medical oncologist at Brown University, Providence, Rhode Island said, ”This is consistent with the findings from the GeparSixto trial, but while patients in that trial received a nonstandard chemotherapy regimen and bevacizumab, 40603 showed the benefit of the addition of carboplatin to standard chemotherapy, with or without bevacizumab.”

Bevacizumab Shows No Benefit in HER2+ Disease

Sikov continued, ”The big question is whether the increase in pCRs will translate into improvements in recurrence-free and OS; while we will follow the enrolled patients for these endpoints, the study is not large enough to expect to see significant differences.“ Sikov said he believes that it is reasonable for physicians to consider the addition of carboplatin to neoadjuvant chemotherapy in patients with stage II-III TNBC, provided they are aware of the potential for increased toxicity.The effects of bevacizumab were the subject of another study presented at SABCS, the phase III BETH trial, which evaluated chemotherapy in combination with trastuzumab and bevacizumab in the adjuvant setting in patients with early-stage, HER2-positive, node-positive, or high-risk node-negative breast cancer. Because tumors overexpressing HER2 also overexpress VEGF and have increased angiogenic potential, the question of whether or not angiogenic inhibitors might provide added benefit to breast cancer treatment regimens has been heavily explored. However, the BETH trial also demonstrated disappointing results for bevacizumab in this setting, following the negative results of the BEATRICE trial reported at last year’s SABCS in which the addition of bevacizumab to chemotherapy in the treatment of early TNBC following surgery did not improve disease-free survival.¹¹

PIK3CAMutations as Predictors of Response

In the BETH study, the combination of docetaxel, carboplatin, and trastuzumab was found to be highly effective, with an invasive DFS rate of 92% at 38 months of follow-up. However, addition of bevacizumab to this regimen did not improve outcomes. Follow-up continues in this study to determine if bevacizumab has any longer-term effects, and a detailed biomarker analysis is also ongoing.¹²Research has focused on identifying biomarkers that predict response to adjuvant and neoadjuvant therapies, as a means of identifying patients who will benefit most from these treatments. Data that emerged from SABCS highlighted the importance of phosphatidy inositol-3 kinase (PIK3CA) mutations in guiding response to neoadjuvant therapy in patients with HER2-positive breast cancer. Among participants in the GeparQuinto and GeparSixto trials, in which patients received neoadjuvant therapies—including chemotherapy and targeted agents—PIK3CAmutations were associated with a much lower rate of pCR. The lowest pCR rates were observed in patients with HER2-positive, hormone receptor-positive,PIK3CA-mutated tumors.¹³

Sibylle Loibl, MD, PhD, associate professor at the University of Frankfurt, Germany, and lead author of the study, predicted thatPIK3CAmutation analysis for HER2-positive breast cancer will probably become routine.

”We and others found that the patients with HER2-positive tumors harboring the mutation do not respond to a HER2- targeted therapy, and they do not benefit at all from a double HER2 blockade. The group of mutation carriers is small; only 20% of tumors with HER2 overexpression harbor the mutation. Therefore, testing will probably be most important if double HER2 blockade in primary breast cancer becomes standard of care,” Loibl stated.

References

1. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in postmenopausal breast cancer.N Engl J Med. 2009;360(7):679-691.
2. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid.N Engl J Med. 2011;365(15):1396-1405.
3. Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: a meta-analysis of individual patient data from randomized trials. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S4-07.
4. von Minckwitz G, Rezai M, Eidtmann H, et al. Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer-the phase III NATAN study. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S5-05.
5. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer.N Engl J Med. 2004;351:971-977.
6. Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the Medicare population.J Clin Oncol. 2012;30:1601-1607.
7. Kunkler IH, Williams LW, Jack W, et al. The PRIME II trial: Wide local excision and adjuvant hormonal therapy ± postoperative whole breast irradiation in women ≥ 65 years with early breast cancer managed by breast conservation. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S2-01.
8. von Minckwitz G, Schneeweiss A, Salat C, et al. A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triplenegative and HER2-positivie early breast cancer (GeparSixto).J Clin Oncol. 2013;31(suppl; abstr 1004).
9. Denkert C, Loibl S, Salat C, et al. Increased tumor-associated lymphocytes predict benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S1-06.
10. Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S5-01.
11. Cameron D, Brown J, Dent R, et al. Primary results of BEATRICE, a randomized phase III trial evaluating adjuvant bevacizumab-containing therapy in triplenegative breast cancer. Presented at the 2012 San Antonio Breast Cancer Symposium; December 4-8, 2012. Abstract S6-5.
12. Slamon DJ, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013. Abstract S1-03.
13. Loibl S, Denkert C, Schneeweis A, et al. PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone receptorpositive breast cancer-prospective analysis of 737 participants of the Gepar- Sixto and GeparQuinto studies. Presented at the 2013 San Antonio Breast Cancer Symposium; December 10—14, 2013. Abstract S4-06.