Developments in the Treatment of Metastatic Breast Cancer

Developments in the Treatment of Metastatic Breast Cancer

Developments in the Treatment of Metastatic Breast Cancer: A Report from the 29th Annual San Antonio Breast Cancer Symposium

Lee Schwartzberg, MD, FACP, The West Clinic

December 14-17, 2006San Antonio, TexasLee Schwartzberg, MD, FACP, The West Clinic

The San Antonio Breast Cancer Symposium of 2006 brought together over 8,000 people from all corners of the globe for the unifying purpose of sharing the current state-of-the-art on all aspects of breast cancer. As usual, this years symposium devoted time to significant advances in the entire spectrum of the disease including prevention, screening, prognostic factors, adjuvant chemotherapy, hormonal therapy and treatment of metastatic disease. The following report will discuss highlights of results presented on metastatic breast cancer.

Metastatic Breast Cancer

The challenge now for metastatic breast cancer treatment is manipulating the multiple agents available to provide the highest benefit and least number of side effects for the long term. One thrust is to develop less toxic and potentially more effective versions of older drugs.

An example of this concept is Abraxane® (nanoparticle albumin-bound nab-paclitaxel), a novel platform of drug delivery, which does not require a solvent to dissolve large organic agents like paclitaxel. Abraxane is already approved in metastatic breast cancer. Several studies continue to explore the possibilities of Abraxane, particularly in developing the best schedule and dosing of this agent. Prior trials have demonstrated that weekly Taxol® (paclitaxel) was superior to every-three-week Taxol, and every-three-weekTaxotere® (docetaxel) was superior to every-three-week Taxol but at the expense of greater toxicity.[[1]]( "_ednref1"),[[2]]( "_ednref2") In an interim analysis, investigators presented the results of a phase II 4-arm randomized trial of weekly Abraxane at 100 mg/m2 or 150 mg/m2 three out of four weeks, Abraxane 300 mg/m2 every three weeks or Taxotere 100 mg/m2 every three weeks.[[3]]( "_ednref3") Three hundred patients were accrued. About 40% of the sample had prior adjuvant chemotherapy. The response rates were higher for weekly Abraxane at 58-62% compared to the every 3 week dosing response rate, 33% or compared to the response rate for Taxotere, 36%.

Progression-free survival with one-third of potential events documented showed superiority for Abraxane at any dose and schedule compared to Taxotere. In terms of toxicity, neutropenia was more common in Taxotere-containing arms (p<0.001), while Abraxane 100 mg/m2 had less grade 3/4 neutropenia than Abraxane 150 mg/m2 or 300 mg/m2 every three weeks. Peripheral neuropathy was less common in Abraxane 100 mg/m2 compared to higher doses. Other common Taxotere toxicities such as fatigue, arthralgias and mucositis were more common with the Taxotere and high dose Taxol arms. If these results hold and are replicated in a phase III study, there will be an alternative that satisfies the dual criteria of simultaneously both more effective and less toxic.

Single agent Abraxane was given at 125 mg/m2 day 1,8,15 every 28 days was evaluated in first line MBC patients.[[4]]( "_ednref4") The response rate was high at 26/35 (74%). Seven of these patients were also receiving Herceptin® (trastuzumab) for HER2 positive tumors. Response rates were not reported by HER2 status. Studies combining Abraxane with a second agent were also reported. Interim results of a phase II study of weekly Abraxane 125 mg/m2 day 1, 8 combined with Xeloda® (capecitabine) for 14 days every 3 weeks in first line HER2- metastatic breast cancer was reported.[[5]]( "_ednref5") In 34 evaluable patients, out of a projected 50 patients on study, the response rate was 54%. Median time to progression has not been reached.

Abraxane has also been combined with Avastin® (bevacizumab) in a pilot trial of 27 patients with >3 prior chemotherapy regimens.[[6]]( "_ednref6") Sixteen of 27 patients have responded, including 3 achieving complete responses. This clinical result is supported by pre-clinical work demonstrating that Abraxane can induce VEGF in a cell line, which then protects against the drug effect. By adding Avastin, the anti-tumor effect in a preclinical model was synergistic with Abraxane.[[7]]( "_ednref7") In sum, weekly Abraxane is a conveniently scheduled drug, which either alone or combined with other agents yields high activity with manageable toxicity.

Vinca Alkaloids

Another drug class with major activity in MBC is the vinca alkaloids, with Navelbine® (vinorelbine) currently representing the agent of choice. Vinflunine is a novel next generation microtubule inhibitor with promising activity in breast cancer. At SABCS, results of a third line study utilizing vinflunine at 320 mg/m2 every 21 days after anthracyclines and taxanes was reported.[[8]]( "_ednref8") Independent radiologic review demonstrated that 7/56 patients (12.5%) had an objective response, disease control occurred in 43%, and a median duration of third line response lasted 6.9 months. Most common adverse events were hematologic with 22 patients exhibiting grade 4 neutropenia but only 2 experienced febrile neutropenia. Common non-hematologic toxicities were fatigue, myalgia, constipation, nausea and vomiting, and abdominal pain; severe toxicities were nonetheless uncommon.

Vinflunine was also tested combined with Xeloda in a phase I dose escalation and pharmacokinetic study.[[9]]( "_ednref9") The recommended dose to carry into phase II was vinflunine 280 mg/m2 on day 1 with Xeloda 825 mg/m2 BID days 1 14 every three weeks. Seven of 16 patients treated in the phase I study responded, and at the recommended dose there was one grade 4 neutropenia and no grade 3/4 non-hematologic toxicity. An alternative day 1, 8 schedule of vinflunine with Xeloda is now being tested. This drug shows good potential as a possible replacement for previous vincas in breast cancer, and further study is awaited.

HER2+ Metastatic Breast Cancer

The discovery that approximately 20% of breast cancers over express HER2 led to a paradiagm shift in the way we think about and treat metastatic breast cancer (MBC). With the availability of Herceptin, a monoclonal antibody which targets the HER2 receptor, and the remarkable clinical benefit discerned when this agent was added to chemotherapy treatment, the concept of targeting important growth pathways in cancer cells in conjunction with cytotoxic chemotherapeutic agents was confirmed.

Numerous studies at SABCS 2006 advance the clinical science of treating HER2+ breast cancer. Tykerb® (lapatinib), an oral small molecule EGFR/HER2 receptor antagonist, which targets the intracellular kinase domain of these molecules, has been tested with Xeloda vs. Xeloda alone in pretreated HER2+ MBC and recently reported.[[10]]( "_ednref10") Patients with prior anthracycline, taxane and Herceptin were eligible for this randomized trial. The overall TTP was almost double to 36.7 weeks from 19.1 weeks for patients who received Tykerb and Xeloda (p=0.00004).

A specified subgroup analysis of this trial presented at the meeting examined the circulating extracellular domains (ECD) of EGFR and HER2.[[11]]( "_ednref11") The circulating ECD fragment of HER2 is found in about 60% of patients with HER2+ MBC and is associated with a worse prognosis. In this study, high baseline levels of HER2+ ECD were associated with shorter PFS in the Xeloda group (p=0.026) and there was a trend towards shorter PFS in the Xeloda + Tykerb group (p=0.14). However, the benefit of Tykerb was seen in patients who had both high and low baseline HER2 ECD levels.

Undoubtedly, we will see further interesting results from this study. Now that there is another agent available against HER2+ disease, a host of questions arise: Should patients on Herceptin have ECD HER2 tested regularly in anticipation of switching to Tykerb if rising? Should Tykerb be used sequentially with Herceptin or is there value in current HER2 blockade? Do the effects seen with Xeloda translate to other cytotoxics? Is there value in ERb1 over expressions in the absence of HER2 over expression? Many of these questions will be answered by the current generation of clinical trials in progress.

The most common combination used in HER2+ breast cancer is Herceptin and a taxane. Wardley et al. examined the addition of Xeloda to Herceptin and Taxotere, building on the known time to progression and overall survival superiority of the Xeloda plus Taxotere doublet.[[12]]( "_ednref12") In an interim analysis of their randomized phase II study, 225 patients received full dose HT or lower dose Taxotere 75 mg/m2 + Xeloda 950 mg/m2 b.i.d. x 14 days and Herceptin every three weeks (HT+X). Response rates were comparable between the arms, 71% for HT + X vs. 73% for HT. There was a trend towards a longer PFS of 14.8 vs. 12.8 months, p=0.006 and longer TTP of 18.2 vs. 13.8 months with the triplet at a cost of significantly more nonhematologic toxicity, particularly hand-foot syndrome and diarrhea. Median overall survival has not yet been reached in either arm. The benefit of adding an additional drug to an active Herceptin-positive combination is not yet clear. The same degree of disease control could possibly have been obtained by switching to Xeloda at the first sign of progression, potentially with less overall toxicity. Such a hypothesis, however, will require a randomized trial of combined therapy vs. sequential, a difficult trial design to conduct successfully.

There is great interest in using combined biologicals in HER2+ MBC based on the preclinical data demonstrating the induction of VEGF expression in tumors that over express HER2. Building on a phase I study suggesting increasing effect of the combination of Herceptin and Avastin with no unique toxicities, Pegram and colleagues reported a phase II trial of 37 patients with HER2+ chemotherapy-naïve metastatic breast cancer patients.[[13]]( "_ednref13"),[[14]]( "_ednref14")

The response rate to Herceptin plus Avastin was 54%, including 1 CR and 13 PR. This response rate was much higher than expected from historical controls of Herceptin alone as a single agent. Seven patients had grade 3 hypotension, 1 patient had grade 4 LV dysfunction, while 7 had grade 1 and 5 had grade 2 adverse events. Adding chemotherapy to the combination would seem the next logical approach.

Hope for the Future

Two presentations derived from retrospective analyses of large databases give a glimpse of what can be expected in the future of breast cancer. Sir Richard Peto presented the first results of the Early Breast Cancer Trial 1st Collaborative Group latest five year analysis for 2005-2006.[[15]]( "_ednref15") The Oxford review, as it is known, now comprises over 660,000 patients enrolled in clinical trials since 1984 and provides a broad canvas meta-analysis of the effects of breast cancer treatment.

The group has demonstrated that the large decrease in breast cancer mortality that has occurred since 1990 in women under the age of 70 is due to the accumulated effect of multiple small to moderate improvements in treatment. Trends emerging from the most recent analysis include the benefit of adding radiation therapy to adjuvant chemotherapy for all lymph node positive patients and the benefit of anthracycline-based chemotherapy vs. CMF. The 15-year recurrence rate difference for patients < 50 years of age who receive chemotherapy is about 12%, particularly prominent in ER negative patients. The authors predict that the overall deaths from breast cancer in 2010 will be one-half of what they were in 1990 in the United Kingdom and the United States.

Ravdin and colleagues presented exciting and encouraging data from the most recent analysis from the SEER database utilizing incidence data in invasive breast cancer through 2004.[[16]]( "_ednref16") There was a significant decrease in the number of breast cancer cases diagnosed in 2003 and 2004 compared to an essentially flat line incidence from 1998 to 2002. Virtually all of the decrease was in ER positive cases. Overall, there was a 7% decrease in age adjusted breast cancer incidence in 2003 relative to 2002 which translated into almost 14,000 less patients diagnosed. Subgroup analyses demonstrated that almost all of the reduction was accounted for women by > 50 years of age.

What factors underlie this marked decrease? The authors postulated two leading possibilities: (1) change in mammographic screening levels or (2) change in the use of hormonal therapy. There was virtually no change in mammographic screening in 2003. However, the publication of the Womens Health Initiative results in July 2002 led to a dramatic 50% reduction in hormonal therapy usage within 6 months with further decline in hormonal therapy usage by women through 2004. The prior use and reduction in use was mainly seen in women > 50 years of age. These trends support the concept that cessation of hormone replacement therapy may keep ER+ tumors from progressing from a pre-clinical state to a clinically apparent one. Obviously this potentially exciting result will require both more study and more time to assess if 2003 was merely an aberration or hopefully the beginning of a new era of reducing the burden of breast cancer.


[[1]]( "_edn1") Seidman A, Berry D, Cirrincione C, et al. CALGB 9840: phase III study of weekly (w) paclitaxel (p) via 1-hour (h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc Am Soc Clin Oncol 2004;22:512a.

[[2]]( "_edn2") Jones S, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005;23(24):5542-51.

[[3]]( "_edn3") Gradishar W, Krasnojon D, Cheporov S, et al. A randomized phase 2 study of weekly (w) or every-3-week (q3w) ABI-007 (ABX) versus every-3-week docetaxel (TXT) as first-line therapy in patients (pts) with metastatic breast cancer (MBC). Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 46.

[[4]]( "_edn4") Mirtsching B, Cosgriff T, Chidiac T, et al. Single agent abraxane given weekly (3/4) as first-line therapy for metastatic breast cancer (an international oncology network study, #1-04-012). Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 6073.

[[5]]( "_edn5") Schwartzberg L, Arena F, Mintzer D, et al. Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first line treatment of metastatic breast cancer (MBC): interim results. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1096.

[[6]]( "_edn6") Link J, Waisman J, Jacobs C. Bevacizumab (Avastin) and albumin bound paclitaxel (Abraxane) treatment in metastatic breast cancer. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1095.

[[7]]( "_edn7") Ran S, Biven C, Trieu V, Desai N. Synergistic effect of albumin-bound paclitaxel (Abraxane) and anti-VEGF-A antibody (avastin) on growth of orthotopic MDA-MB-231 breast tumors as well as lymphatic and pulmonary metastases. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 1094.

[[8]]( "_edn8") Fumoleau P, Cortes-Funes H, Chan S, Taleb A, et al. Phase II study of i.v. Vinflunine (VFL) as third-line treatment of metastatic breast carcinoma after failure of anthracycline-/taxane-based chemotherapy. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 6070.

[[9]]( "_edn9") Campone M, Fumoleau P, Roche H, Bonneterre J, et al. A dose-finding and pharmacokinetic study of I.V. vinflunine (VFL) in combination with capecitabine (CAPE) as second line treatment of metastatic breast cancer (MBC). Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 6069.

[[10]]( "_edn10") Geyer C, Forster J, Lindquist D, Chan S, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355(26):2733-43.

[[11]]( "_edn11") Cameron D, Stein S, Zaks, et al. Lapatinib plus capecitabine shows superior efficacy compared to capecitabine alone in patients with ErbB2 positive advanced or metastatic breast cancer initial biomarker data. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 2.

[[12]]( "_edn12") Wardley A, Anton-Torres A, Pivot X, et al. Trastuzumab plus docetaxel with or without capecitabine in patients with HER2-positive advanced/metastatic breast cancer: first efficacy results from the phase II MO16419 (CHAT) study. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 2063.

[[13]]( "_edn13") Pegram M, Yeon C, Ku N, et, el. Phase I combined biological therapy of breast cancer using two humanized monoclonal antibodies directed against Her2 proto-onco-genes and vascular endothelial growth factor (VEGF). Proceedings of the 27th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2004; Abstract 3039.

[[14]]( "_edn14") Pegram M, Chan D, Dichmann R, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 301.

[[15]]( "_edn15") EBCTCG Secretariat, on Behalf of EBCTCG, University of Oxford, Oxford, United Kingdom. Highlights from the early breast cancer trialists collaborative group (EBCTCG) 205-2006 worldwide overview. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 40.

[[16]]( "_edn16") Ravdin P, Cronin K, Howlander N, Chlebowski R, Berry D. A Sharp decrease in breast cancer incidence in the United States in 2003. Proceedings of the 29th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2006; Abstract 5.