Despite an overall trend downward in breast cancer mortality since 1990, the number of deaths from metastatic breast cancer (MBC) remains at 40,000 per year . MBC is the second most common cause of cancer deaths in women. Therefore, despite the increasing adoption of adjuvant/neoadjuvant chemotherapy for primary operable breast cancer, treatment of advanced disease remains important. Advances in the understanding of breast cancer biology have already translated into specific treatment strategies with remarkable benefit for selected patients. Results presented at the 26th Annual San Antonio Breast Cancer Symposium (SABCS) held December 3-6, 2003, help clarify the benefits of treatments already in use in the clinic, while offering promising glimpses into the imminent future of the treatment of MBC.
STATUS OF TAXANES
The taxanes, paclitaxel and Taxotere®, were rapidly adopted into the first-line treatment of MBC shortly after their introduction in the early 1990s. Numerous trials have established taxanes as the most active drugs for the treatment of MBC; however, clinicians have waited almost a decade to see results of a prospective head-to-head comparison of Taxotere® to paclitaxel in MBC. Finally, Jones, et. al presented the mature results of such a study in an oral session.1 In this trial, 449 patients with prior anthracycline and no prior taxane exposure were randomized to receive either Taxotere® at 100 mg/m2 over one hour every 3 weeks or paclitaxel 175 mg/m2 over three hours every 3 weeks. Baseline characteristics were well balanced: half of the patients were estrogen receptor positive and approximately 40% had more than three sites of disease. Results were analyzed by both intention to treat (ITT, N=449) and evaluable patients (N=394). Results are shown in table 1.
ITT = Intention to treat group; Eval = Evaluable group; MDR = Median duration of response; TTP = Time to progression; OS = Overall survival
Hematologic toxicity was greater for Taxotere® with 15% of patients experiencing febrile neutropenia, compared with 2% in the paclitaxel arm. However, growth factor support was not permitted as primary prophylaxis. Non-hematologic grade 3/4 toxicity was slightly higher for Taxotere® at 45% versus 35% for the paclitaxel group. There were no significant perceived quality of life (QOL) differences between arms as documented by the FACT-Breast scale. Both groups showed an upward trend in QOL during the treatment period, presumably reflecting improved disease control. The results of this trial establish Taxotere® as the superior taxane in MBC when used in an every-three-week dosing schedule.
Moving beyond first generation taxanes was the subject of a presentation at an added late-breaking session. A phase III trial compared ABI-007, a new formulation consisting of nanoparticle albumin-bound (nab) paclitaxel to standard cremaphor solvent paclitaxel in MBC.2 The (nab) paclitaxel does not require a solvent and is given over 30 minutes without a premed. Potential benefits include increased tumor penetration noted in preclinical models. In this trial, MBC patients were randomized to ABI-007 at 260 mg/m2 versus paclitaxel 175 mg/m2 over three hours with decadron and antihistamine premedication every 3 weeks. The primary endpoint was objective response rate. Half the patients had received 1-2 prior regimens for metastatic disease. Both groups received more than 97% of planned dose and over 5 cycles per patient on average. Only 2% of ABI-007 patients required IV steroids, compared to 95% of paclitaxel patients. Responses were graded by the investigator as well as an independent blinded radiology review. Response rates are shown in table 2.
OR = Overall Response, CR + PR
Toxicity analysis showed less grade 4 neutropenia for ABI-007, but more grade 3 sensory neuropathy (10% vs. 2%) compared to paclitaxel. Neuropathy was diminished after holding the drug for a median of 22 days. These promising results suggest that manufacturing changes for this class of drug may increase the therapeutic ratio while adding to patient convenience.
The use of trastuzumab (Herceptin®) as the backbone of treatment for patients with overexpression of the HER2 gene and amplification of the HER2 protein product has transformed the approach to the subgroup of patients expressing this phenotype. Indeed, from a group of patients with the worst prognosis and greatest resistance to chemotherapy, HER2-positive patients receiving Herceptin® and chemotherapy have the highest response rate and survival. It appears that the use of targeted therapy against this relevant biologic receptor has substantially altered the natural history of the disease.
Several studies presented at SABCS 2003 expanded on this theme. A randomized phase II trial compared Taxotere® alone vs. Taxotere® plus Herceptin® in 188 previously treated MBC patients.3 The response rate was 61% in the Taxotere®-Herceptin® arm, compared to 36% in the Taxotere® only arm (p=0.001). Time to progression was higher for Taxotere®-Herceptin® with a median of 10.6 months versus 6.1 months (p=0.0001). Overall, survival was superior for Taxotere®-Herceptin® to Taxotere® (p= 0.0002), despite 44% of patients crossing over to receive Herceptin® in the Taxotere®-only arm. This study, therefore, confirms the major findings of the pivotal trial of chemotherapy plus Herceptin® and strengthens the argument that Herceptin® should be used up front in MBC with chemotherapy for optimal results based on the increased survival time now documented in two trials.
Other drugs combined with Herceptin® are also extremely active in HER2-positive MBC. A multinational, multicenter trial of Navelbine® plus Herceptin® showed a 61% response rate as first-line treatment, with 79% of patients achieving clinical benefit from the combination.4 Thirty-six percent of patients on study were progression-free at the one-year follow-up point. There were no grade 4 nonhematologic toxicities and a low incidence of cardiac dysfunction. Similarly, preliminary analysis of a randomized trial of weekly paclitaxel versus paclitaxel and Herceptin® in HER2-positive untreated MBC showed an improved response rate of 83.4% for paclitaxel plus Herceptin®, compared to 62.6% for paclitaxel alone in IHC 3-positive patients.5
Triplet therapy with Herceptin®, paclitaxel and Paraplatin® was previously shown last year at San Antonio to be a superior strategy with increased time to progression (TTP), response rate (RR) and trend towards improved survival (Robert, SABCS 2002). Attempts to improve the therapeutic ratio was the subject of a study performed by the North Central Cancer Treatment Group and reported this year.6Patients were randomized to every 3 weekly Paraplatin® plus paclitaxel with weekly Herceptin® versus paclitaxel and Paraplatin® weekly with weekly Herceptin®. Response rates were similar in both arms, 65% in the every-3-week group versus 71% for the weekly treatment schedule, but there was less hematologic and nonhematologic toxicity with the weekly treatment. This included, in particular, much less grade 3 neurosensory findings (2% vs. 17%). Better tolerability of weekly therapy with high response rate and median duration of response (12.5 + months) favors weekly treatment with paclitaxel, Paraplatin® and Herceptin® for HER2-positive patients.
COMBINATION CHEMOTHERAPY FOR MBC
While controversy still rages over whether it is preferable to treat MBC with sequential single agents or combination therapy, there is a preponderance of evidence supporting increased response rates with the combination strategy. Hence, many studies have investigated various combinations to improve speed and extent of response, which should translate into prompt control of symptoms secondary to MBC.
In a preliminary report of a phase III trial of Ellence® and Taxotere® compared to Ellence® and cyclophosphamide (EC) in patients with a heavy tumor burden, there was a trend towards a higher overall response rate in favor of the Taxotere® regimen (53%) versus EC (44%).7 The final results, including the endpoints of duration of response and progression free and overall survival, will be forthcoming. A meta-analysis of anthracyclines plus taxanes as first line treatment in MBC showed a higher response rate in 7 out of 7 reported trials for the combination and a trend towards longer TTP.8 Infection and death were not more common with anthracycline and taxane combinations.
Finally, a randomized phase II trial of weekly paclitaxel (P) versus weekly paclitaxel plus Paraplatin® (PC)9for first-line treatment showed a trend for improved response rate for PC, compared to P (42.5% vs. 35%) and improved TTP (7.7 months for PC vs. 5.0 months for P, p= 0.054) without increased toxicity except for grade 3/4 neutropenia (38% vs. 14%). These trials confirm the benefit of anthracycline plus taxane combinations or Paraplatin® plus taxane combinations in delivering improved response rates. More importantly, these response rates are achieved without a high price to pay on the symptom side, making combination chemotherapy more attractive in controlling disease and tumor symptoms. Of course, individual patient factors should guide the decision-making as to the most appropriate treatment in first-line MBC.
Many new agents with activity targeted against specific cellular pathways are in phase I and II evaluation. Several new agents were presented at SABCS 2003. The final results of a phase II trial using single-agent CCI-779, a novel mTOR inhibitor, in MBC previously failing anthracycline and/or taxanes were presented.10Clinical benefit was noted in 37% of patients including 10% partial responses. Median duration of response was 5.4 months and responses were seen in HER2-positive as well as HER2-negative patients.
BMS-247550 is a semisynthetic version of epothilone B, a new class of tubulin toxins with activity in taxane-resistant cell lines. This agent was tested along with Xeloda® in a phase I study.11 Activity in paclitaxel and anthracycline-resistant MBC was seen with a 28% response rate and 60% clinical benefit rate. This promising combination is scheduled to be evaluated in a phase III trial.
A new small molecule, GW577016, is an orally active inhibitor of the tyrosine kinase activity of both EGFR and ERB2 (HER2). Burris, et. al presented phase I data including 20 patients with heavily pretreated MBC.12Three partial responses in paclitaxel and Herceptin®-resistant patients were noted. Grade 1 and 2 rash, nausea, vomiting and diarrhea were the most common side effects. In another study evaluating GW577016 in combination with paclitaxel, activity was also seen in taxane-resistant breast cancer.13 Development of drugs designed to inhibit specific pathways of proliferation in breast cancer cells, whether used alone or in conjunction with additional chemotherapy agents, is an exciting area of exploration.
The San Antonio Breast Cancer Symposium remains the premier yearly event where physicians involved in the care of breast cancer patients are exposed to the entire state-of-the-art therapy, ranging from the latest basic science discovery through phase I-IV treatments. As in previous years, studies focusing on the treatment of MBC have shown progress in defining the best drugs to use in specific groups of breast cancer patients and importantly, defining where single drugs or combinations of drugs can be used together with maximal benefit and minimal toxicity. These kinds of investigation allow us to provide women with MBC a better chance at prolonged life, as well as prolonged quality of life, by controlling the symptoms from their cancer without adding a large number of side effects from their therapy. Finally, the near future looks bright indeed, as some of the exciting new agents developed out of an improved understanding of the biology of breast cancer move into late-stage trials and eventual FDA approval.
Jones S, Erban J, Overmoyer B, et al. Randomized trial comparing docetaxel and paclitaxel in patients with metastatic breast cancer. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 10.
O’Shaughnessy J, Tjulandin S, Davidson N, et al. ABI-007 (ABRAXANE™), A Nanoparticle Albumin-bound (nab) Paclitaxel Demonstrates Superior Efficacy vs Taxol in MBC: A Phase III Trial. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract #44.
Extra JM, Cognetti F, Chan S et al. First-line trastuzumab (Herceptin® plus docetaxel versus docetaxel alone in women with HER2-positive metastatic breast cancer (MBC): results from a randomized phase II trial (M77001). Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 217.
Chan A, Untch M, Petruzelka L, et al. Navelbine and Herceptin combination as first line therapy for HER2-overexpressing metastatic breast cancer is a highly active and safe regimen. Final results of a multinational trial. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 219.
John M, Kriebel-Schmitt R, Stauch M, et al. Weekly paclitaxel plus trastuzumab shows promising efficacy in advanced breast cancer. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 221.
Perez E, Rowland K, Suman V, et al. N98-32-52: efficacy and tolerability of two schedules of paclitaxel, carboplatin and trastuzumab in women with HER2 positive metastatic breast cancer: a North Central Cancer Treatment Group randomized phase II trial. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 216.
Blohmer J, Hauschild M, Hilfrich J, et al. Multicenter randomized phase III study evaluating epirubicin-cyclophosphamide versus epirubicin-docetaxel for first-line treatment of metastatic breast cancer: good tolerability and efficacy of epirubicin-docetaxel in heavily pretreated patients with high tumor load. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 530.
Petrella T, Trudeau M. Combination anthracycline and taxane chemotherapy in first line metastatic breast cancer: a meta-analysis. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 531.
Robert N, Loesch D, Lindquist D, et al. A randomized, phase Ii trial of weekly paclitaxel versus weekly paclitaxel + carboplatin for first-line metastatic breast cancer. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 534.
Chan S, Scheulen M, Johnston S, et al. Final results of a phase 2 study of single-agent CCI-779 in locally advanced or metastatic breast cancer failing prior anthracycline and/or taxane regimens. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 346.
Thomas E, Bunnell C, Vahdat L, et al. A phase I study of BMS-2147550 in combination with capecitabine in patients with metastatic breast cancer previously treated with a taxane and an anthracycline. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 350.
Burris H, Hurwitz H, Dees C, et al. EGF10004: a randomized, multicenter, phase Ib study of the safety, biologic activity and clinical efficacy of the dual kinase inhibitor GW572016. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 39.
Jones S, Burris H, Willcutt N, et al. A phase I dose escalation study of the dual kinase inhibitor GW572016 in combination with paclitaxel. Breast Cancer Res and Treat, 82: Special Issue: 26th Annual San Antonio Breast Cancer Symposium. 2003; Abstract 349.