Lee Schwartzberg, MD, Director, The West Clinic, Memphis, Tennesse
Hope S. Rugo, MD, Director, Breast Oncology Clinical Trials Program, University of California, San Francisco
Georgiana Ellis, MD, Associate Professor, Medical Oncology Division, University of Washington School of Medicine, Seattle, Washington
Lori J. Goldstein, MD, Director, Breast Evaluation Center and Leader, Breast Cancer Research Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
The Evolving Role of Targeted Therapies
Newer Targeted Agents
Trastuzumab and Anthracyclines
Re-Treatment with Trastuzumab
Trastuzumab in CNS Metastasis
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The 2007 annual San Antonio Breast Cancer Symposium (SABCS) re-iterated the fact that individualizing treatment options is now the way in which to manage and treat breast cancer. Advances in targeted therapies, hormone therapies and even novel chemotherapy agents and regimens seek to identify subsets of patients based on cancer biology to determine who would benefit most from specific therapies.
Analyses from established trials, as well as phase I and II data including novel therapies were presented at this year’s meeting, provided promising foresight into the future direction of the treatment of metastatic breast cancer.
The Evolving Role of Targeted Therapies
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As treatment for metastatic breast cancer continues to progress, targeted therapies continue to take a front seat in the evolution of treatment of this disease. Trastuzumab, lapatinib and bevacizumab have demonstrated proof-of-principle that targeted therapies are indeed effective for metastatic breast cancer and the idea of individualizing therapies has become a reality in clinical practice.
Moving forward, however, identification of subgroups of patients who will ultimately derive the greatest benefit from these therapies, providing optimal combination regimens inclusive of these agents or their use as single agents, and consensus on defined endpoints that translate into overall benefit remain to be refined, with ever-more research continuing in these areas. Furthermore, several targeted agents continue to move along the continuum of the pipeline of up-and-coming therapies, with the hope of further improving outcomes coupled with low toxicities for patients with this disease.
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Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that is targeted against the human vascular endothelial growth factor (VEGF). As demonstrated in preclinical models, the effects of bevacizumab include, but are not limited to, regression of existing microvascular density, normalization of surviving vascular to improve the capacity of existing vasculature in more effective chemotherapy delivery, and inhibition of neovascularization.
Bevacizumab is indicated for first-or second-line therapy, in combination with 5-fluorouracil-based chemotherapy for the treatment of metastatic colon or rectal carcinoma, and for first-line therapy, in combination with carboplatin and paclitaxel for the treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer and continues to evaluated in several different types of cancer.
Probably the most well-known trial evaluating bevacizumab in the treatment of metastatic breast cancer is the E2100 trial, conducted by researchers affiliated with the Eastern Cooperative Oncology Group (ECOG). Patients in the E2100 trial were randomized to weekly paclitaxel, with or without bevacizumab administered every two weeks as initial therapy for metastatic disease. Patients with HER2-positive cancers had to have received prior therapy with trastuzumab, or were ineligible for therapy with trastuzumab. The primary endpoint was progression-free survival (PFS).
Results from this trial were first presented at the 2005 annual American society of clinical Oncology (ASCO) meeting.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn1 "_ednref1") Overall, patients on the bevacizumab arm demonstrated a near doubling of PFS compared to those treated with paclitaxel alone; results which were well-received and created hope for the use of bevacizumab in metastatic breast cancer at that time. Since then, a very recent analysis of E2100 was published in the New England Journal of Medicine demonstrating again a significant improvement in progression-free survival in the bevacizumab arm, but no real difference in overall survival between the two arms.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn2 "_ednref2") Coinciding with this publication, the United States Food and Drug Administration (FDA’s) Oncology Drug Advisory Committee (ODAC) voted against the recommendation of approval for bevacizumab for patients with metastatic breast cancer, as overall survival, although not the primary endpoint, was not significantly improved with the addition of bevacizumab.
However, there were several other presentations evaluating bevacizumab for the treatment of various stages of breast cancer presented at the 2007 SABCS. Dr. Hervitz and researchers affiliated with the University of California-Los Angeles (UCLA), conducted a phase II trial combining docetaxel with bevacizumab as first-line therapy for HER-2 negative metastatic breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn3 "_ednref3") This was a single-arm study that included 67 patients who were eligible for analysis.
- The overall response rate was 49%
- Median time to progression was 9.3 months
- The most common grade 3 or 4 toxicity was leucopenia and neutropenia
- Fatigue was also a common adverse event
These results demonstrate a remarkably high response rate, with good tolerability, as fatigue is also a common complaint among patients treated with docetaxel. Overall, this appears to be a promising regimen, with phase III data eagerly awaited.
There remains concern about the use of anthracyclines in combination with other therapies, as bevacizumab plus anthracyclines alerted healthcare providers to the potential increase in cardiotoxicity when the combination is used. This prompted affiliates of the Eastern Cooperative Oncology Group (ECOG) to conduct a phase II study evaluating the safety of adding bevacizumab to dose-dense chemotherapy including anthracyclines in node-positive breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn4 "_ednref4") The trial was a nonrandomized trial in which patients were treated in one of two arms: Arm A (n=104) included dose-dense doxorubicin/cyclophosphamide followed by paclitaxel and bevacizumab (10 mg/kg) every 2 weeks for 26 weeks. This was initiated concurrently with the dose-dense regimen. Arm B (n=122) included dose-dense doxorubicin/cyclophosphamide followed by paclitaxel and bevacizumab (10 mg/kg) every 2 weeks for 26 weeks, initiated concurrently with paclitaxel. Radiation therapy and hormone therapy were administered concurrently with bevacizumab when indicated. Overall, preliminary data suggests that bevacizumab can safely be added to anthracycline-containing regimens.
- There was no incidence of grade IV cardiotoxicity
- Median LVEF function was 60 in Arm A and 55 in Arm B at end of therapy
- Myelosuppression was common; however, febrile neutropenia was rare
- Cardiac monitoring is ongoing to assess potential long-term cardiac function
McArthur, H et al also conducted a trial to evaluate cardiotoxicity with the addition of bevacizumab to a dose-dense anthracycline-containing regimen plus nab-paclitaxel.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn5 "_ednref5") The results presented were preliminary, and included 80 patients with early breast cancer who had not received prior therapy with anthracyclines. Patients were treated with the following: 4 cycles of dose-dense AC 60/600 mg/m2 every 2 weeks starting at week 0, followed by nab-paclitaxel 260 mg/m2 every 2 weeks for 4 cycles; 8 cycles of bevacizumab 10 mg/kg every 2 weeks starting at week 0 followed by 12 cycles of bevacizumab 15 mg/kg every 3 weeks. Pegfilgrastim was administered on day 2 of each chemotherapy cycle. Radiation and hormone therapy were also administered, as indicated.
- No patients have developed symptomatic congestive heart failure to date
- Median LVEF at baseline was 68% and 63% at month 9
- 1.2% of patients experienced grade 4 hypertension, which was the only grade 4 event
- Patient monitoring is ongoing
The preliminary safety data from these trials demonstrate that bevacizumab appears to be safe when added to dose-dense anthracycline chemotherapy with taxanes for node-positive breast cancer patients, allowing for additional safe and effective potential treatment strategies for these patients.
Newer Targeted Agents
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There are several newer targeted agents that are progressing through different phases of clinical trials which are delivering promising results for the treatment of metastatic breast cancer.
Bosutinib (SKI-606) is an oral agent that is a competitive inhibitor of the Src and Able tyrosine kinases. Src is a protein that is a non-receptor tyrosine kinase that has many activities within cells and is increasingly recognized as an important component of MBC, particularly with regard to increasing breast cancer cells’ ability to migrate and invade and possibly have metastatic potential. Levels of Src kinase activity are often increased in a variety of cancers. Mutations within the Abl tyrosine kinase are well known to be implicated in the pathogenesis of several types of cancers, as well. Bosutinib has already demonstrated safety in phase I studies, and is now being evaluated in phase II studies. Researchers from several institutions in Europe, the Ukraine, China, and the United States recently conducted a phase II trial evaluating bosutinib in the treatment of advanced breast cancer among 73 women whose cancer had progressed following several lines of prior therapy. Nineteen percent of patients had triple-negative breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn6 "_ednref6")
- 6% of patients achieved responses
- Median progression-free survival was 14 weeks
- The most common adverse events were diarrhea, nausea, vomiting and fatigue
Bosutinib appears active in patients who have received extensive prior therapy, including those with triple-negative disease, which remains difficult to treat. It appears that its role may be best utilized in preventing disease progression, which parallels its mechanism of action, rather than obtaining measurable response. Agents such as bosutinib may provide these heavily pre-treated patients with meaningful improvements in survival. As well, bosutinib was generally well tolerated, representing another potential targeted agent that appears effective alone in patients with limited treatment options, and may demonstrate further effectiveness when used in combination with another agent, or if used earlier in the course of disease. Evaluation of these patients is continuing.
Another targeted agent, HKI-272, targets all 4 members of the HER (erbB) pathway. HKI-272 is an oral, small-molecule tyrosine kinase inhibitor that is an irreversible pan erB trosine kinase inhibitor. Preliminary phase II results were presented from a trial that included 102 HER2-positive patients who were treated with HKI-272; the majority of whom had received prior anti-HER2 therapy.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn7 "_ednref7")
- 10% of patients achieved a partial response
- A subset of patients who had not received prior anti0HER2 therapy had a median progression-free survival of 33 weeks
- Patients who had received prior trastuzumab had a median progression-free survival was 16 weeks and experienced a 30% partial response rate
HKI-272 appears to be another promising targeted agent in the treatment of HER2-positive breast cancer. Further exploration of HKI-272 is ongoing and eagerly awaited.
Sunitunib is a small molecule that is an inhibitor of multiple receptor tyrosine kinases, some of which are responsible for aspects of angiogenesis. Sunitinib is currently indicated for the treatment of gastrointestinal stromal tumors (GIST) following disease progression or intolerance to imatinib mesylate, and indicated for the treatment of advanced renal cell carcinoma (RCC). Sunitinib is another targeted agent that continues to be evaluated in various types and stages of cancer. Sunitinib has demonstrated single-agent activity in previously-treated metastatic breast cancer patients.
A phase I study was conducted by Kzoloff MF, et al. to evaluate sunitinib plus paclitaxel as initial therapy for advanced breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn8 "_ednref8") This study included 20 patients, 17 of whom had measurable disease and 7 of whom were chemotherapy-naïve. Treatment included sunitinib 25 mg/day with dose escalations to 37.5 mg/day or reductions to 12.5 mg/day, plus paclitaxel 90 mg/m2/wk.
- Discontinuations of therapy occurred in 8 patients due to disease progression, and 2 patients due to non-treatment related illness
- Grade 3 toxicities included fatigue, diarrhea, hand-foot syndrome and neuropathy
- Three partial and 2 complete responses were achieved
- Stable disease for at least 6 months was achieved in 3 patients
Of interest will be results from a phase III trial currently underway that will compare sutent and paclitaxel to bevacizumab and paclitaxel.
Researchers from France also conducted a phase I trial to evaluate the sequential administration of docetaxel and sunitinib in the treatment of advanced breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn9 "_ednref9") This exploratory evaluation included patients with unresectable recurrent, or metastatic breast cancer. The primary objective was the PK profile of sutent and taxotere (37.5 mg/d for 2 wks starting on Day 2 of a 3-wk cycle), with secondary endpoints being safety and preliminary responses. Patients were initially treated with the combination of sunitinib (75 mg/m2 on Day 1) and docetaxel (37.5 mg/d for 2 wks starting on Day 2 of a 3-wk cycle). If patients achieved responses or disease stabilization while on combination therapy, they continued with single-agent sunitinib until disease progression.
- Preliminary PK data demonstrated that no drug-drug interactions occur between docetaxel and sunitinib
- Most toxicities were mild to moderate in severity, with neutropenia being the most commonly observed adverse event
- Twelve of 13 patients enrolled in March 2007 continue on therapy
- One patient has discontinued; however, this was not due to progressive disease
- Seven of 12 patients are being treated with single-agent sunitinib following the completion of 6 cycle of sunitinib and docetaxel
- 8 patients achieved partial response and 4 stable disease as best response according to RECIST criteria
These results add further evidence that the combination of targeted therapies such as sunitinib to standard chemotherapy provides effective and safe treatment alternatives for metastatic breast cancer.
Continuing with the theme of combining targeted agents with standard chemotherapy agents, researchers from the Dana-Farber Cancer Institute, the University of Texas M.D. Anderson Cancer Center, and the National Cancer Institute recently conducted a phase II clinical trial evaluating the investigative agent AZD2171 in refractory breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn10 "_ednref10") AZD2171 is a small molecule tyrosine kinase inhibitor of the VEGF 1 and 2 receptors. This trial included 26 women with stage IV breast cancer who had evidence of progression on their most recent therapy. AZD2171 was given 45 mg daily (oral) until disease progression
- 10% of patients had a partial response for greater than 6 months
- 38% achieved disease stabilization
- Median PFS was 12 weeks
- Treatment-related toxicities included diarrhea, fatigue, hypertension, elevated TSH and esophagitis/upper oropharyngeal irritation; most of these adverse evens were mild to moderate in severity
The researchers stated that “AZD2171 has modest clinical activity as monotherapy in refractory breast cancer.” However, the hope is that “biomarker analyses may help identify correlates of activity in breast cancer patients”, continuing the individualizing of therapy for these patients. The 10% response rate mirrors that of other several other targeted agents used as monotherapy in metastatic breast cancer.
Research has clearly demonstrated that receptors and pathways are extremely complex, and do not necessarily tend to produce singular downstream effects. Rather, interconnection at innumerable points along pathways exist, with activity from one affecting several downstream targets, pathways, and subsequent products. As such, newer up-and-coming agents are trending towards combining mechanisms of action that include several targets, versus the comparatively “older” targeted agents that tend to focus on one target or specific pathway. The newer agents have been designed to target several destinations on many interrelated pathways simultaneously, so that more angles of a pathway involved in carcinogenesis and/or metastasis are blocked.
Vandetanib is an agent that is both a VEGFR and EGFR inhibitor. Vandetanib was evaluated in combination with docetaxel as second-line therapy for advanced breast cancer in a double-blind placebo controlled, randomized Phase II trial comparing vandetanib/docetaxel to docetaxel/placebo.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn11 "_ednref11") The primary endpoint, which was the demonstration of an efficacy benefit for vandetanib over placebo when added to docetaxel, was not met in this trial. Researchers speculate that although vandetanib did not meet its endpoint in this trial, results may be attributed to interaction with docetaxel or that vandetanib may provide greater efficacy in the earlier stages of breast cancer. Further study will reveal the answer to these questions.
AMG706 (motesanib) [diphosphate] is a small molecule tyrosine kinase inhibitor of VEGF that targets VEGFR 1, 2 and 3, as well as platelet-derived growth factor (PDGF). A phase I study evaluating safety and pharmacokinetic efficacy was recently conducted to evaluate motesanib in combination with either paclitaxel or docetaxel in patients with metastatic breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn12 "_ednref12") Since patients with metastatic breast cancer may often receive single-agent therapy to produce responses while maintaining quality of life, targeted agents that are able to provide meaningful benefit either as single agents or in combination with well-tolerated chemotherapy may provide a great addition to the therapeutic armamentarium. At present, the maximum tolerated dose of motesanib has not yet been reached; however, there was no pharmacokinetic interaction between motesanib and the taxanes studied. Furthermore, preliminary objective responses were demonstrated in a variety of doses of motesanib in combination with both taxanes. A large, randomized phase II clinical trial evaluating motesanib and paclitaxel is ongoing, and results are eagerly awaited as this novel agent appears well tolerated and active in combination with chemotherapy in the metastatic setting.
It also appears that the addition of Erbitux® (cetuximab) may
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HER2-positive disease and treatment with trastuzumab remained one of the most discussed topics this year at SABCS. Trastuzumab has helped to launch the idea of treating according to the biology of cancer in addition to standard variables, versus the historical staging alone. Although trastuzumab has been in the clinic for approximately a decade since their pivotal trial, much information continues to be sought and evaluated regarding its use. This information has opened the door for thought and progression on overall cancer biology and more individualized treatment approaches for cancer. Patients with HER2-positive disease have derived great benefit from trastuzumab, and it continues to remain standard of care for patients with HER2-positive breast cancer.
Questions surrounding the optimal use of trastuzumab remain, such as the optimal duration of use, overall clinical effects on patients with brain metastasis, efficacy and tolerability when used in combination with other agents including other targeted drugs, potential issues regarding cardiotoxicity, and efficacy among patients who have progressed while on therapy including trastuzumab.
Trastuzumab and Anthracyclines
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To further address the question regarding combination therapy, a phase II trial was conducted a trial to evaluate the combination of a third-generation vinca alklaloid, vinflunine with trastuzumab in patients with HER2-positive metastatic breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn13 "_ednref13") Two different treatment schedules and doses of vinflunine were evaluated in combination with trastuzumab. Approximately two-thirds of patients demonstrated responses, and all doses were well tolerated. This high response rate is encouraging and underscores the fact that trastuzumab is easily combined with several other agents.
Of concern, however, remains the potential cardiotoxicity with trastuzumab in combination with anthracyclines. Researchers from Germany recently conducted a prospective trial in which trastuzumab, epirubicin and cyclophosphamide were delivered simultaneously as initial therapy to 60 patients with HER2-positive breast cancer. Epirubicin was substituted for doxorubicin as it is associated with less cardiotoxicity.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn14 "_ednref14")
- There was no significant cardiac dysfunction as measured by LEVF or clinical heart failure
- There were no cardiac-related deaths
- Time to progression was comparable to that of other combination chemotherapy regimens in combination with trastuzumab
These results provide hope that perhaps trastuzumab may be safely used in combination with anthracyclines, even when delivered simultaneously. The switch of doxorubicin to epirubicin may provide the necessary reduction in the risk of cardiotoxicity; however, further study is necessary to confirm these findings.
Re-Treatment with Trastuzumab
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There is no clear answer as to the efficacy of re-treatment with trastuzumab following first-line progression in HER2-positive patients, with conflicting results to date. However, it does appear that some patients may gain benefit from re-treatment with trastuzumab following disease progression.
An interim analysis of the Trastuzumab Beyond Progression (TBP), German Breast Group (GBC) 26/Breast International Group (BIG) 3-05 study was performed that evaluated trastuzumab in in combination with capecitabine as re-treatment for patients with HER2-positive metastatic breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn15 "_ednref15") This was a prospective, randomized, phase III trial that included patients who progressed on first-line trastuzumab-based therapy; 71% of patients had received prior therapy with trastuzumab and a taxane. Following progression, patients were randomized to further treatment with trastuzumab and capecitabine, or capecitabine only. There are preliminary results with final study results anticipated in early 2008. There were 78 patients in each arm of the study and median follow-up is nearly one year.
- Median progression free survival was 8.5 months in the trastuzumab arm, compared with only 5.6 months in the capecitabine only arm (HR=0.71)
- Median overall survival was approximately 20 months in both groups
- There were 26 deaths in the trastuzumab arm, none of which were deemed treatment-related, and 31 deaths in the capecitabine-only arm
- Only one patient in the trastuzumab arm had decrease in LVEF < 40
- The only severe toxicity that was noted to occur at a greater rate in the trastuzumab arm was hand-foot syndrome
Montemurro, et al. from Italy conducted a retrospective evaluation from clinical records of 407 HER2-positive patients with advanced breast cancer who had been treated at Italian medical institutions. Of these patients, 245 had been treated with an initial trastuzumab-based regimen and progressed while on therapy;112 continued receiving trastuzumab-based therapy, while 133 patients discontinued therapy with trastuzumab.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn16 "_ednref16")
- Post-progression median survival was 20.8 months for patients continuing trastuzumab-based therapy, compared with 24.2 months for those not continuing on trastuzumab-based therapy (p=0.09)
- Median time to second progression was between 7.5 and 7.8 months for those discontinuing and continuing trastuzumab-based therapy, respectively (p=0.09)
In contrast to this, however, researchers from Germany conducted a retrospective analysis of the patterns of clinical routine use of trastuzumab in Germany from 2001-2006. The analysis included 910 patients who had records in 142 German medical centers. Not surprisingly, the data indicated that trastuzumab is often used for off-label indications. Interestingly, patients who were treated with trastuzumab following initial progression experienced a significantly improved median overall survival compared to those who did not receive trastuzumab following disease progression.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn17 "_ednref17")
The question of re-treatment with trastuzumab continues to be evaluated, and subgroup analyses to identify potential groups of patients who may benefit from additional trastuzumab-based therapies is of interest. Accrual into prospective trials attempting to evaluate re-treatment with trastuzumab has been slow following the approval of lapatinib. With the approval of lapatinib, the issue of re-treatment with lapatinib does not seem as critical as these patients now have an additional treatment option. Nonetheless, if continued responses with re-treatment with trastuzumab can provide meaningful clinical benefit for some patients who have experienced disease progression, this will allow for extended therapeutic options for these patients, and ultimately the potential for improved outcomes.
Trastuzumab in CNS Metastasis
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Of great concern in the trastuzumab-era is the prevalence of the development of brain metastasis among HER2-positive breast cancer patients who remain stable on trastuzumab, and the inability of trastuzumab to pass through the blood-brain barrier. It appears that lapatinib may provide a positive effect among these patients; however, questions surrounding trastuzumab and the best way in which to incorporate it into therapy for patients with brain metastasis continues.
A retrospective analysis was conducted to evaluate outcomes regarding the timing of trastuzumab (whether it was used before or after the diagnosis of brain metastasis) in patients with HER2-positive metastatic breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn18 "_ednref18") This analysis included 56 patients who presented with and underwent treatment for symptomatic brain metastasis between 2001 and 2006. Patients also received trastuzumab, either alone or in combination with chemotherapy, and had been receiving trastuzumab prior to diagnosis of brain metastasis, or had initiated trastuzumab therapy following diagnosis of brain metastasis.
- Overall survival was significantly improved among patients who were treated with trastuzumab following the diagnosis of brain metastasis compared with those who were treated with trastuzumab prior to the diagnosis of brain metastasis (p=0.006)
- However, this benefit appeared to be confined to patients with hormone receptor (HR)-negative tumors, as those with HER-positive tumors did not experience a survival difference dependent upon when they received trastuzumab
- On multivariate analysis, the only other factor that was independently associated with improved survival was a disease-free interval from stage IV or recurrent disease to the diagnosis of brain metastasis of at least one year
Although these results may not affect clinical practice at present, they add to information regarding the activity of HER2-positive disease and its targeted therapies.
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Lapatinib is an oral small molecule tyrosine kinase dual HER-family inhibitor, inhibiting both HER1 and HER2. It is approved for use in combination with capecitabine for the treatment of advanced or metastatic HER2-positive breast cancer among patients who have received prior therapy including an anthracycline, a taxane and trastuzumab.
Researchers from the Dana-Farber Institute and Europe recently updated results from the EGF105084 trial, in which patients who experienced progressive CNS disease while on single-agent lapatinib were given the option of continuing therapy with lapatinib plus capecitabine.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn19 "_ednref19") Preliminary results are available from the initial 40 patients who continued on combination therapy. Of these patients, 28% had received prior therapy with capecitabine.
- 20% of patients experienced at least a 50% volume reduction in CNS disease
- 40% of patients had a 20% or greater volume reduction of CNS disease
Further updates regarding tolerability and results from the remaining patients are expected; however, these results indicate that the combination of lapatinib and capecitabine provide significant responses in HER2-positive breast cancer patients with brain metastasis. These results provide encouragement that an option for treatment of brain metastasis may be available for HER2-positive breast cancer, an issue that has remained a hurdle in the treatment of this disease.
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Despite treatment approaches such as targeted and hormone therapy for breast cancer, chemotherapy remains an important component for the treatment of most breast cancers. Often, targeted agents and/or hormone agents are still combined with chemotherapy to provide optimal results, while chemotherapy as a single agent or in combination with other agents is the cornerstone of therapy for HER2-negative, HR-negative patients. In addition to advances in research that have occurred for targeted and hormone therapies, advancements continue for chemotherapy as well, with a focus on maintaining or improving outcomes while minimizing toxicities.
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Patients who are ER-/PR-/HER2-, or triple negative, have a subset of breast cancer that remains difficult to treat. Ixabepilone appears to preferentially provide responses to triple-negative patients, and may provide an additional treatment strategy for these patients.
Ixabepilone is a “first-in-class” chemotherapy agent that was recently approved as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients refractory or resistant to anthracyclines, taxanes, and capecitabine, or in combination with capecitabine for the treatment of advanced breast cancer resistant to anthracyclines and taxanes, or resistant to taxanes and contraindicated for anthracyclines. Ixabepilone is an epitholone-B analog, which are microtubule toxins.
An analysis of the pivotal trial that resulted in the approval of ixabepilone, in which ixabepilone plus capecitabine was compared to capecitabine only in anthracycline and taxane-resistant breast cancer, was undertaken in an attempt to identify subgroups of patients who may benefit most from this these agents.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn20 "_ednref20")
- Patients with triple-negative breast cancer had a 3-fold higher response rate to ixabepilone plus capecitabine
- Responses were achieved in 27% of patients with triple-negative breast cancer treated with ixabepilone plus capecitabine, compared with 9% of these patients treated with capecitabine only
- In the original trial, overall responses were achieved in 35% of patients treated with ixabeiplone/capecitabine compared with 14% of patients treated with capecitabine alone
These results suggest that ixabepilone provides preferential activity in triple-negative breast cancer, while capecitabine as a single agent has very modest activity in this group of patients. These results are encouraging as this patient population is difficult to treat.
Researchers affiliated with the Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial to evaluate the combination trastuzumab plus weekly ixabepilone and carboplatin among 59 patients with HER2-positive breast cancer.(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_edn21 "_ednref21") The primary objective of the study was to demonstrate superiority over paclitaxel/carboplatin/trastuzumab. The overall response rate was 44%, which is similar to that seen with taxane-based regimens. Disease stabilization for at least 6 months was achieved in nearly 23% of patients, The primary objective was not met, and appears to hint that ixabeiplone may not offer an advantage over taxanes in the HER2-positive group of patients. Again, these results seem to reinforce the idea that ixabepilone may be an important strategy for patients with triple-negative breast cancer.
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The key takeaway from the 2007 SABCS was that the way in which breast cancer is treated has substantially moved toward individualizing therapy, and that although progress has been made, research continues into the identification of subgroups that can best be managed by specific therapies. Moving forward, newer targeted agents, hormone agents, and chemotherapy agents will continue to evolve to provide optimal survival and quality of life, while refinement of classifying groups of patients largely based on biology of their tumor will continue. Furthermore, supportive care, with agents such as denosumab, will also continue to enhance patient’s lives while they are being treated for cancer, or while they are living as cancer survivors.
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(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref1 "_edn1") Miller K, et al. E2100: A phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Proceedings from the 2005 annual meeting of the American Society of Clinical Oncology (ASCO). Presented May 16, 2005 at “late-breaking” session. May 2005.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref2 "_edn2") Miller K, Wang M, Gralow J, et al. Paclitaxel plus Bevacizumab versus paclitaxel alone for metastatic breast cancer. New England Journal of Medicine. 2007; 357:2666-2676.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref3 "_edn3") Hurvitz SA, Kabbinavar FF, Allen HJ, et al. A phase II trial of docetaxel with bevacizumab as first line therapy for Her2/neu negative metastatic breast carcinoma. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4062.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref4 "_edn4") Miller KD, O’Neill A, Perez EA, Seidman AD, Sledge GW. Phase II feasibility trial incorporating bevacizumab into dose dense doxorubicin and cyclophosphamide followed by paclitaxel in patients with lymph node positive breast cancer: a trial of the Eastern Cooperative Oncology Group (E2104). Program and abstracts of the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007; San Antonio, Texas. Abstract 3063.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref5 "_edn5") McArthur HL, Rugo H, Paulson M, et al. Cardiac safety of adjuvant bevacizumab plus dose-dense doxorubicin/cyclophosphamide followed by nanoparticle albumin-bound paclitaxel in patients with early stage breast cancer. Program and abstracts of the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007 San Antonio, Texas. Abstract 3065.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref6 "_edn6") Campone M, Bondarenko I, Brincat S, et al. Preliminary results of a phase 2 study of bosutinib (SKI-606), a dual Src/Abl kinase inhibitor, in patients with advanced breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6062.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref7 "_edn7") Burstein H, Awada A, Badwe R, et al. HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: preliminary phase 2 results in patients with advanced breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6061.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref8 "_edn8") Kozloff MF, Chuang E, Roy J, et al. A phase I study of sunitinib plus paclitaxel for first-line treatment of advanced breast cancer: preliminary results. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6078.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref9 "_edn9") Gianni L, Cardoso F, Mariani G, et al. Exploratory evaluation of a sequential administration of docetaxel and sunitinib in women with Advanced Breast Cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6079.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref10 "_edn10") Mayer EL, Hamel S, Savoie J, et al. AZD2171 for refractory breast cancer: a phase 2 trial. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6080.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref11 "_edn11") Boer K, Lang I, Llombart-Cussac A, et al. Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo controlled, randomized phase II study. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6081.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref12 "_edn12") Coxon A, Bush T, Belmontes B, et al. Anti-tumor activity of motesanib diphosphate alone and in combination with docetaxel or tamoxifen in xenograft models of human breast carcinoma. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 1102.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref13 "_edn13")Paridaens R, Wildiers H, Dalenc F, et al. Vinflunine in combination with trastuzumab: an active combination in the treatment of HER2 positive metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 1082.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref14 "_edn14") Untch M, Tjulandin S, Jonat W, et al. Evaluation of first-line trastuzumab in combination with epirubicin/cyclophosphamide for patients with HER2-positive metastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4058.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref15 "_edn15") Von Minckwitz G, Vogel P, Schmidt M, et al. Trastuzumab treatment beyond progression in patients with HER-2 positive metastatic breast cancer. Program and abstracts of the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007; San Antonio, Texas. Abstract 4056.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref16 "_edn16") Montemurro F, Viale G, Donadio M, et al. Retrospective evaluation of clinical outcomes in HER2-positive advanced breast cancer patients progressing on trastuzumab-based therapy in the pre-lapatinib era. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4057.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref17 "_edn17") Jackisch C, Eustermann H, Schoenegg W, et al. Clinical use of trastuzumab (Herceptin) in metastatic breast cancer (MBC) in Germany from 2001 to 2006. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 4059.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref18 "_edn18") Nam BH, Kim SY, Han HS, Lee KS, Ro J. Survival gain by trastuzumab therapy after the onset of intracranial metastasis in metastatic breast cancer. Program and abstracts of the 30th Annual San Antonio Breast Cancer Symposium; December 13-16, 2007; San Antonio, Texas. Abstract 4061.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref19 "_edn19") Lin NU, Paul D, Dieras V, et al. Lapatinib and capecitabine for the treatment of brain metastases in patients with HER2+ breast cancer an updated analysis from EGF105084. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6076.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref20 "_edn20") Rugo H, Thomas E, Lee R, et al Combination therapy with the novel epothilone B analog, ixabepilone, plus capecitabine has efficacy in ER/PR/HER2-negative breast cancer resistant to anthracyclines and taxanes. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6069.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref21 "_edn21") Moulder S, Wang M, Gradishar W, et al. A phase II trial of trastuzumab, weekly ixabepilone (BMS-247550) and carboplatin (TIC) in patients with HER2/neu-positive (HER2+) metastatic breast cancer (MBC): a trial coordinated by the Eastern Cooperative Oncology Group (E2103). Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract 6070.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref22 "_edn22") McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. New EnglandJournal of Medicine. 2006;354:821-831.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref23 "_edn23") Lipton A, Steiger GG, Gigueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastasis. *Journal of Clinical Oncology.*2007;25:4431-4437.
(http://news.cancerconnect.com/updates-in-the-management-of-metastatic-breast-cancer-san-antonio-breast-cancer-symposium-sabcs-2007/#_ednref24 "_edn24") Ellis G, Bone HG, Chlebowski R, et al. A phase 3 study of the effect of denosumab therapy on bone mineral density in women receiving aromatase inhibitors for non metatastatic breast cancer. Presented at the 30th Annual San Antonio Breast Cancer Symposium. San Antonio, TX, December 13-16, 2007. Abstract #47.