Highlighting Advances in Breast Cancer

New research and Emerging Trends from the San Antonio Breast Cancer Symposium

The 30th Annual Charles A. Coltman, Jr. San Antonio Breast Cancer Symposium (SABCS) was held December 13—16, 2007, at the Henry B. Gonzalez Convention Center, San Antonio, Texas. The scientific program consisted of invited lectures and mini-symposia by experts in clinical and basic research, selected slide and poster presentations chosen from the submitted abstracts, and case discussions.

The SABCS is a division of the Cancer Therapy & Research Center (CTRC) at the University of Texas Health Science Center at San Antonio. The CTRC is an independent, nonprofit institution directed by a volunteer Board of Governors committed to providing the highest quality cancer treatment, research, and education. Its objective is to provide state-of-the-art information on the experimental biology, etiology, prevention, diagnosis, and therapy of breast cancer and premalignant breast disease to an international audience of academic and private physicians and researchers.

This symposium is directed primarily toward academic and private physicians and researchers involved in breast cancer in medical, surgical, gynecologic, and radiation oncology, as well as other appropriate health care professionals. The majority of participants are physicians and researchers, with a smaller representation of affiliated health care professionals.

CTRC-AACR San Antonio Breast Cancer Symposium

At this most recent SABCS, the CTRC and the American Association for Cancer Research (AACR) announced a collaboration for future symposia, the result of which will be renamed the beginning in 2008. As stated in the announcement, “Complementing the clinical strengths of the highly regarded annual San Antonio Breast Cancer Symposium, the AACR’s scientific prestige in basic, translational, and clinical cancer research will create a unique and comprehensive scientific meeting that will advance breast cancer research for the benefit of patients.”

Patient Characteristics and Time Course of CNS Metastases In Patients with HER2-Positive Metastatic Breast Cancer: Results of a Prospective, Observational Study of More Than 1,000 Patients

Clinically apparent central nervous system (CNS) metastases are reported to occur in 6% to 16% of women with metastatic breast cancer. The true incidence is not known, as autopsy series have revealed CNS metastases in 18% to 34% of patients with metastatic breast cancer. The development of brain metastases has been associated with young age, HER2-positive status, estrogen receptor—negative status, and basal phenotype.

Patients with HER2-positive metastatic breast cancer are much more likely to develop CNS metastases than those with HER2-negative metastatic breast cancer, with estimates of the incidence ranging from 23% to 48% based on retrospective reviews of trastuzumab trials and single institution experiences. Predictors of CNS metastasis are not well characterized.

Denise A. Yardley, MD, from the Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, Tennessee, presented the results of an analysis of RegistHER data performed to characterize the incidence and predictors of CNS metastases among patients with HER2-positive metastatic breast cancer.

RegistHER is an observational cohort of 1,030 women with HER2-positive metastatic breast cancer treated in community and academic settings. Patients were enrolled in the RegistHER study between January 2003 and February 2006. This analysis was restricted to patients with metastatic breast cancer diagnosed on or before July 1, 2005 (N = 772). The median follow-up from diagnosis of metastatic breast cancer was 20 months at the time of data cutoff (December 30, 2006).

A total of 173 patients (22.4%) developed CNS metastases, of whom 35 (4.5%) had CNS metastases at the time of diagnosis, and 138 (17.9%) developed CNS metastases as a later site of disease progression. Patients who developed CNS metastases were younger (<50 yr of age, 46% vs. 39%), had disease that was hormone receptor— negative (52% vs. 40%) and had a greater disease burden (>2 metastatic sites at initial diagnosis, 60% vs. 52%), compared with patients without CNS metastases.

Among patients who later developed CNS metastases, the CNS was the only site of disease progression in 50 (36.2%) and was a first site of progression in conjunction with other sites in 14 (10.1%). Median time to CNS progression among patients without CNS disease at baseline was 12.1 months.

The brain is the first metastatic target of the HER2-positive cells in about 50% of patients, rather than a late occurrence, said Dr. Yardley. On the other hand, treatment with trastuzumab appears to extend survival in women with brain metastases, even though the drug does not cross the blood-brain barrier.

Gemcitabine/Docetaxel Versus Capecitabine/ Docetaxel in Patients With Anthracycline-Pretreated Metastatic Breast Cancer: New Phase III Data Demonstrate Similar Efficacy and Suggest Better Tolerability for Gemcitabine/Docetaxel

Gemcitabine, capecitabine, and docetaxel are highly active agents in anthracycline-pretreated metastatic breast cancer. A comparison of gemcitabine plus docetaxel (GD) and capecitabine plus docetaxel (CD) would provide valuable information for the clinician to help guide treatment decisions.

Stephen Chan, MD, MRCP, FRCR, Head of the department of clinical oncology at Nottingham City Hospital, Nottingham, United Kingdom, presented survival results of a phase III study comparing GD and CD in anthracycline-pretreated patients with metastatic breast cancer. Patients with histologically confirmed metastatic breast cancer who relapsed after an anthracycline- based regimen (either in neoadjuvant or first-line metastatic disease) were randomized to GD (G 1000 mg/m² d1,8; D 75 mg/m² d1) or CD (C 2500 mg/m² d1-14; D 75 mg/m² d1) q21 days. Neoadjuvant pretreatment with taxanes was allowed if completed more than six months before entry. In a previous analysis², GD demonstrated similar efficacy to CD, but with a better non-hematologic toxicity profile.

Between October 2002 and March 2004, 305 patients were randomized. The treatment arms were well balanced. Median age was 55 years; 86% of enrollees had visceral disease; 81% had two or more metastatic sites; 67% were estrogen receptor/progesterone receptor—positive; 17% were HER2 over-expressed; 17% received prior taxane treatment; and 34% received prior chemotherapy for metastatic disease.

P

P

P

P

P

In the current analysis (median follow-up, 19.2 mo), median overall survival (OS) was 19.3 months in the GD group, compared with 21.5 months in the CD group ( = 0.983). Grade 3/4 hematologic toxicity was similar in both arms, except for grade 3/4 thrombocytopenia (11% in the GD arm vs. 3% in the CD arm; = 0.014). Nonhematologic toxicities were low in both arms, but significantly different grade 3/4 toxicities were more pronounced in the CD arm. These included diarrhea (8% in the GD arm vs. 18% in the CD arm; = 0.0088), mucositis (4% in the GD arm vs. 15% in the CD arm; = 0.0008), and hand-foot syndrome (0% in the GD arm vs. 26% in the CD arm; < 0.0001). Thirteen percent of patients discontinued therapy because of an adverse event in the GD arm, compared with 30% of those in the CD arm. Dr. Chan stated, “These data suggest that the two regimens are comparable in OS; however, a more favorable toxicity profile on the GD arm may be a determining factor in selecting a better treatment option.”

Quality of Life in Patients With Node-Positive and Those With Node-Negative, HER2-Positive Early Breast Cancer Treated with Docetaxel- and Trastuzumab (Herceptin)-Based Regimens

In a poster session, Heather-Jane Au, MD, MPH, Department of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada, presented the results of the Breast Cancer International Research Group (BCIRG) Study 006, which assessed quality of life in patients with node-positive and those with node-negative, HER2-positive early breast cancer treated with docetaxel- and trastuzumab-based regimens.

BCIRG 006 was a large-scale (N = 3,222), randomized, controlled trial comparing adjuvant doxorubicin plus cyclophosphamide (AC) for four cycles, followed by either docetaxel for four cycles (AC-T) or one of two trastuzumab-containing regimens—AC followed by T with trastuzumab for one year (ACTH) or T with carboplatin for six cycles with trastuzumab for one year (TCH) in patients with node-positive or high-risk, node-negative, HER2- positive early breast cancer.

P

The European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaires C-30 and BR-23 were administered at baseline; mid-chemotherapy; end of chemotherapy; and at six, 12, and 24 months after chemotherapy. The primary endpoint for quality of life compared Physical Function, Global Health Status, Systemic Therapy Side Effects, and Future Perspective mean changes from baseline to mid-chemotherapy, end of chemotherapy, and 12 months post-chemotherapy using a two-sample t-test. Owing to the three-arm comparisons, < 0.017 was considered statistically significant.

P

P

P

P

P

P

P

P

P

P

Physical Function change scores were —7.2 for TCH, –5.2 for AC-TH, and –5.9 for AC-T at mid-chemotherapy ( = 0.0081 TCH vs. AC-TH); —8.9, –8.9, and –10.1, respectively, at end of chemotherapy ( > 0.017); and —0.5, –1.7, and –1.5, respectively, at 12 months post-chemotherapy ( > 0.017). Global Health Status change scores were —6.8 for TCH, –5.4 for AC-TH, and –7.2 for AC-T at mid-chemotherapy ( > 0.017); —6.7, –8.4, and –8.6, respectively, at end of chemotherapy ( > 0.017); and 3.6, 2.8, and 4.1, respectively, at 12 months post-chemotherapy ( > 0.017). Systemic Therapy Side Effects change scores were 25.4 for TCH, 25.0 for AC-TH, and 26.7 for AC-T at mid-chemotherapy ( > 0.017); 20.2, 25.1, and 28.8, respectively, at end of chemotherapy ( < 0.0001 for TCH vs. AC-TH and TCH vs. AC-T; = 0.0007 for AC-TH vs. AC-T); and 3.6, 5.1, and 4.2, respectively, at 12 months post-chemotherapy ( > 0.017). Future Perspective change scores were similar between arms, improving at each time point: 3.0 to 4.9, 3.3 to 5.8, and 10.7 to 14.8 at mid-chemotherapy, end of chemotherapy, and 12 months post-chemotherapy, respectively.

The Systemic Therapy Side Effects change scores were significantly better for TCH patients compared with AC-TH and AC-T patients at the end of chemotherapy and by response analysis, supporting the conclusion that this regimen was better tolerated. Physical Function was slightly worse at mid-chemotherapy for TCH patients compared with those just starting their taxane on AC-TH, but otherwise was similar between arms. Dr. Au stated that all arms had recovery of the deterioration in Physical Function, Global Perspective, and Systemic Therapy Side Effects quality-of-life scales by one year.

New Data Support the Pharmacokinetic Profile, Tolerability, and Preliminary Antitumor Activity of Sequential Administration of Sunitinib (Sutent) and Docetaxel (Taxotere) in Patients With Advanced Breast Cancer

Sunitinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), the cytokine receptor KIT, the receptor tyrosine kinase—encoding proto-oncogene RET, and the receptor tyrosine kinase FLT3. Sutent is currently approved for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate. In mouse xenograft models of breast cancer, sunitinib has been shown to enhance the antitumor activity of docetaxel.

In a poster session moderated by Luca Gianni, MD, Head of the Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, results of a phase I study evaluating the pharmacokinetic profile, tolerability, and preliminary antitumor activity of sequential administration of sunitinib and docetaxel in patients with advanced breast cancer were presented.

Patients with unresectable, locally recurrent, or metastatic breast cancer who relapsed after anthracycline-based chemotherapy in the adjuvant setting were eligible for the study. The primary objective was to study the pharmacokinetic profile of sunitinib and docetaxel. Secondary endpoints were the safety and the preliminary activity of the combination. Patients received intravenous docetaxel 75 mg/m² on day 1 and oral sunitinib 37.5 mg/day for two weeks starting on day 2 of a three-week cycle. After discontinuation of docetaxel, responsive patients (those achieving partial response or stable disease) could continue sunitinib as a single agent until progression of disease.

Twenty-two patients received 75 mg of intravenous docetaxel three times a week in addition to sunitinib 37.5 mg/day, administered in a dosing schedule of two weeks on treatment, followed by one week off. Dosing of docetaxel was reduced to 60 mg in six patients and delayed in 10 patients, while dosing of sunitinib was reduced to 25 mg/day in three patients, and escalated to 50 mg/day in one patient. Dosing of sunitinib was interrupted in 13 patients. After discontinuation of docetaxel, patients who responded to treatment continued on sunitinib as a single-agent until the disease progressed.

Of 18 evaluable patients, 13 (72%) have experienced an objective response to date, all of which were partial responses, as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Nine of these patients—several of whom had visceral disease&mdash; experienced decreases in tumor size after two cycles of therapy.

In this exploratory study, the combination of sunitinib and docetaxel demonstrated preliminary activity with no pharmacokinetic drug—drug interaction. Treatment with the combination was generally well tolerated, with most adverse events proving mild or moderate in severity. The most commonly reported severe adverse event was transient neutropenia (grade 4); however, the investigators concluded that sunitinib can be given among patients with grade 3–4 neutropenia, with no need for dose interruption. Grade-3 adverse events were few and included one case each of fatigue, diarrhea, stomatitis, and hand– foot syndrome. Eleven patients discontinued treatment for reasons including lack of efficacy (5 pts), adverse events (2 pts), and non–treatment- related discontinuations (4 pts).

Dr. Gianni summarized the results by stating, “Previous studies have shown sunitinib malate to be well tolerated in combination with standard of care chemotherapy regimens—including paclitaxel and capecitabine&mdash;in patients with advanced breast cancer. Based on these and other evolving data, this compound is continuing to be evaluated both as a single agent and in combination with other agents to treat metastatic breast cancer.”

A phase III study of sunitinib plus docetaxel compared with docetaxel alone in the first-line treatment of advanced breast cancer is currently underway. The results of this trial are eagerly anticipated.

Two-Year, Phase III Study Looks at Denosumab in Preventing Bone Loss Caused by Aromatase Inhibitors

The aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor—positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, aromatase inhibitors are associated with significantly more osteoporotic fractures and greater bone mineral loss. Furthermore, adjuvant therapy with aromatase inhibitors is well established in postmenopausal women with hormone receptor– positive breast cancer, but may be complicated by accelerated bone loss and increased risk of fracture. Strategies for the identification and management of treatment-induced bone loss are currently being defined.

A late-breaking presentation moderated by Georgiana K. Ellis, MD, Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington, highlighted the results of a phase III, randomized, double-blind, placebo-controlled study evaluating the effect of denosumab therapy on bone mineral density (BMD) in women receiving aromatase inhibitors for non-metastatic breast cancer. Denosumab is a fully human antireceptor activator of nuclear factor κB (RANK) antibody. It is also known as RANK ligand (RANKL), and is an essential mediator of osteoclast formation, function, and survival that is expressed on osteoblasts and stromal cells. RANKL is a member of the tumor necrosis factor (TNF) ligand family, which is essential for this process. RANKL attaches to RANK, a receptor on the cell surface of osteoclasts and osteoclast precursors, to stimulate proliferation and differentiation of cells to form the osteoclast phenotype and inhibit apoptosis. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. Since denosumab is highly specific, the chance of systemic effects in other parts of the body is low, so patients do not need routine laboratory monitoring.

To test the effectiveness of denosumab in preventing bone loss caused by aromatase inhibitors, a clinical trial recruited 252 patients who had been treated for early-stage breast cancer and for whom treatment with anastrozole, an aromatase inhibitor, was planned. Eligible patients were 18 years of age or older with histologically confirmed, HR , nonmetastatic breast cancer. Enrollees were stratified by duration of AI therapy (≤6 vs. >6 mos) and received placebo (N = 125) or denosumab 60 mg (N = 127) subcutaneously every six months for four doses. All patients were instructed to take daily doses of calcium and vitamin D.

At enrollment, all patients had evidence of bone loss, but no one had osteoporosis or T scores less than —2.5 at the lumbar spine, total hip, and femoral neck. The primary endpoint was percentage change from baseline to Month 12 in lumbar-spine BMD, based on dual-energy x-ray absorptiometry measurement.

P

P

P

P

The study lasted for two years. At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab and placebo groups ( < 0.0001 at both time points). These increases were not influenced by duration of AI therapy. Increases in BMD were also observed consistently at the total hip and total body, and at predominantly cortical sites at the femoral neck and distal third of the radius, at 12 and 24 months ( < 0.0001). Greater proportions of the denosumab-treated patients than those who received placebo had preservation of lumbar spine BMD (>0% change from baseline) at 12 (97% vs. 36%; < 0.0001) and 24 months (95% vs. 34%; < 0.0001).

Overall, by the end of the first year, the bone density of the women receiving denosumab had increased by nearly 5%, while the women who did not receive denosumab had bone density decreases of almost 1%. By the end of the second year, the difference was even greater: In the women receiving denosumab, bone density had increased by almost 6%, while the bone density of the women who did not receive denosumab decreased by nearly 2%. Side effects of denosumab were similar to those reported in the control group.

The investigators concluded that in women with nonmetastatic breast cancer who had low bone mass and were receiving adjuvant AI therapy, twice-yearly administration of denosumab consistently increased BMD over 24 months at trabecular and cortical bone sites, with overall adverse event rates similar to placebo.

Based on these results, denosumab appears to be a safe and effective treatment for preventing bone loss in women taking AIs, offering an attractive alternative to existing therapies, such as oral or intravenous bisphosphonates.

Docetaxel-Based Chemotherapy Significantly Improves Overall Survival Compared With Standard Anthracycline-Based Chemotherapy in Early-Stage Breast Cancer

In an oral presentation given by Steve E. Jones, MD, Medical Director of US Oncology Research, Inc., Houston, Texas, seven-year results of US Oncology Adjuvant Trial 9735 were reported. The new data update the five-year data reported previously.¹ This trial compares docetaxel (Taxotere)/ cyclophosphamide (TC) with standard chemotherapy doxorubicin/cyclophosphamide (AC) in women with node-negative (~50%) and node-positive early breast cancer. Dr. Jones was the principal investigator of the study.

Patients were eligible if they had Stage I—III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and Dec-ember 1999, 1,016 patients were assigned to four cycles of either standard-dose AC (60/600/mg/ m²) (N = 510), or TC (75/600mg/m²) (N = 506), by intravenous infusion every three weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor—positive disease, were given after completion of chemotherapy.

P

P

In the updated analysis, overall survival (OS) at seven years was statistically greater among women treated with TC compared with those treated with AC (87% vs. 82%). The 31% reduction in the risk of death was statistically significant ( = 0.032). At seven years, disease-free survival (DFS) was also statistically greater among women treated with TC than among those treated with AC (81% vs. 75%). The 26% reduction in the risk of cancer recurrence among women treated with TC was statistically significant ( = 0.033). The DFS benefit seen in elderly patients (≥65 yr; 31% risk reduction of recurrence) is consistent with that in the overall patient population.

The TC regimen was well-tolerated, even in older women, without excessive toxicity. The investigators of the study concluded that TC was associated with improved DFS, as well as improved OS compared with standard AC. As Dr. Jones stated, “the investigational Taxotere combination significantly increased the percentage of women living with no signs of cancer at seven years, as compared with the anthracycline combination.”

Based on these results, TC should now be a standard nonanthracycline combination for early breast cancer. In addition, TC may be preferable because of its lack of cardiotoxicity.

Study Shows Lapatinib (Tykerb) Combination Reduces the Size of Brain Tumors Associated with HER2-Positive Breast Cancer

Metastatic breast cancer is the second most common type of cancer to develop brain metastases. Approximately 10% of newly diagnosed breast cancer patients have locally advanced and/or metastatic disease; 20% to 85% of patients (depending on initial stage, tumor biology, and treatment strategy) diagnosed with early breast cancer develop recurrent and/or metastatic disease.

Diane Palmieri, PhD, Laboratory of Molecular Pharmacology, Women’s Cancers Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, moderated a poster session during which preliminary results of the extension arm of a phase II study of lapatinib in patients with HER2-positive breast cancer were presented.

Lapatinib is an oral small-molecule inhibitor of the HER2 (ErbB2) tyrosine kinase receptor. Stimulation of HER2 is associated with cell proliferation and with multiple processes involved in tumor progression and metastases. Overexpression of this receptor has been reported in a variety of human tumors and is associated with poor prognosis and reduced overall survival. On March 13, 2007, the United States Food and Drug Administration approved Tykerb (lapatinib) in combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors over-express HER2 and who have received prior therapy (including an anthracycline, a taxane, and trastuzumab).

In this preliminary analysis, 18 patients (37%) experienced a 20% or greater volume reduction in brain metastases—without progression of disease outside of the brain, increase in corticosteroid requirements, or worsening of neurological signs or symptoms&mdash;and a median reduction in brain metastases of 4.8 cm3. Of these 18 patients, 10 (20% of the total cohort) experienced a 50% or greater volume reduction in brain metastases, with a median reduction in the volume of brain metastases of 7.1 cm3. As of September 2007, three patients remained on the parent study with lapatinib monotherapy, and of the 51 patients enrolled in the extension arm with lapatinib plus capecitabine, eight remained on this combination.

Of the 51 patients enrolled in the extension arm, 10 (20%) who received lapatinib plus capecitabine experienced a partial response, and 20 patients (39%) achieved stable disease. The disease progressed in 15 patients (29%) who received the combination. The status of six patients (12%) was unknown at the time of reporting.

The most commonly reported Grade 1/2 adverse events include hand—foot syndrome (37%), diarrhea (34%), nausea (22%), vomiting (12%), anorexia (12%), and nail disorder (12%). The most common Grade 3 adverse events include handfoot syndrome (8%), nausea (8%), vomiting (6%), diarrhea (4%), and fatigue (2%).

This analysis provides important information because up to one-third of women with HER2-positive metastatic breast cancer may develop brain metastases during the course of their disease.

Clinical Use of Trastuzumab (Herceptin) in Metastatic Breast Cancer in Germany: A Five-Year Review

Christian Jackisch, MD, Klinik für Gynäkologie und Geburtshilfe, Klinikum Offenbach GmbH, Offenbach, Germany, presented the results of a prospective observational study performed to characterize the clinical use of trastuzumab in Germany over a five-year period.

Data for a total of 910 patients (of whom 908 were evaluable) were recorded in 142 centers. The median duration of documented therapy was 49 weeks. Information on long-term outcomes, progression-free survival (PFS), and overall survival (OS) was retrieved in a subgroup of 485 patients in whom the treatment documentation had been finalized before July 2004. Subjects were stratified into three groups: (1) single-drug therapy with trastuzumab (N = 102; 11% of total cohort); (2) trastuzumab combined with chemotherapy, with or without endocrine therapy (N = 715; 79% of total cohort); and (3) trastuzumab combined with endocrine therapy only (N = 91; 10% of total cohort).

Median age was 57 years. Mean relapse-free interval was 2.7 years; 37% of patients were receptor negative. At the start of trastuzumab treatment, 9% suffered from locally advanced cancer only. The incidence of liver (40%) and lung (30%) involvement was greater in Group 2, while the majority of Group-3 patients suffered from bone metastases. A total of 45% of patients had previously received one to four chemotherapy regimens for metastatic breast cancer. Seventy-nine percent were pretreated with an anthracycline.

Overall survival was 56% overall, 45% in Group 1, 59% in Group 2, and 38% in Group 3. The respective OS medians were 30, 27, 28 and 44 months, based on 299 reported deaths. Based on 417 events in 485 patients with long-term observation, the estimated median PFS was 9.8 months overall, 7.1 months in Group 1, 10.1 months in Group 2, and 11.9 months in Group 3. Treatment was generally well tolerated. Grade 3/4 cardiovascular toxicity was reported in seven patients—two in group 1, four in Group 2, and one in Group 3.

These results provide an interesting glimpse at trastuzumab usage patterns. Trastuzumab is used in a variety of combinations. Response rates are within the expected range, but were also remarkably high after previous palliative chemotherapy. In Group 3 (trastuzumab plus endocrine therapy only), response rates were lower, but OS reached almost four years.

Clinical Significance of Polysomy 17 in the HER2 N9831 Intergroup Adjuvant Trastuzumab Trial

Recent preliminary findings suggest an association between chromosome 17 number anomalies and trastuzumab benefit in patients with metastatic breast cancer. To further elucidate the nature of this association, Monica M. Reinholz, PhD, Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota and colleagues performed a study evaluating the correlation between HER2 gene copy, chromosome 17 number anomalies, and outcome (disease free survival [DFS]) in patients treated with or without trastuzumab. In a general session, Dr. Reinholz presented the results of the study.

This analysis included 1,888 patients from the HER2 N9831 Intergroup Adjuvant Trastuzumab phase III clinical trial who were or were not or treated concurrently with trastuzumab. Disease-free survival was the primary endpoint of the study.

P

P

P

in situ

Patients who did not receive trastuzumab and had polysomy 17 (p17) had a 34% lower DFS rate ( = 0.04) than the non—trastuzumab-treated patients who had normal 17 (n17). Patients whose tumors were amplified with p17 and with n17 and were treated with trastuzumab had improved DFS, with hazard ratios of 0.52 ( = 0.006) and 0.37 ( = 0.0004), respectively. The investigators noted an insufficient number of events to address the efficacy of trastuzumab in patients with monosomy 17 (m17), small clone amplification, or duplication fluorescent hybridization results.

The investigators concluded that patients treated with standard chemotherapy only and who had p17 benefited more than those who had n17, whereas both groups of p17 and n17 patients benefited from trastuzumab, as compared with standard therapy with similar 3- and 5-year DFS rates. These results suggest that chromosome 17 number status is not predictive of trastuzumab response.

Role of Anthracycline-Based Therapy in the Adjuvant Treatment of Breast Cancer: Efficacy Analyses Determined by Molecular Subtypes of the Disease

The use of anthracycline-based therapies for the adjuvant treatment of high-risk breast cancer has now become a common, standard part of clinical practice.

Dennis J. Slamon, MD, PhD, Division of Hematology/ Oncology, David Geffen School of Medicine at the University of California at Los Angeles, and colleagues performed a systematic review of published data from randomized, controlled, adjuvant chemotherapy trials reporting HER2 subtype (i.e., HER2-positive vs. HER2-normal breast cancers). Dr. Slamon presented the results of the systematic review in a general session.

The investigators noted that the incremental efficacy benefit attributed to anthracycline-based therapies is restricted to the HER2-positive subgroup. They cited a recent analysis of the BCIRG 006 (HER2 ) and 005 (HER2-) studies, which revealed that topoisomerase IIa (topo IIa) amplification is confined to cancers that contain the HER2 amplicon.

In more than 1,600 HER2-negative samples, there was not a single topo IIa—amplified case. Conversely, deletion of topo IIa was found in 5% of HER2-positive and 3% of HER2-negative tumors. An analysis of the effect of topo IIa co-amplification demonstrated that the improved efficacy imparted by an anthracycline—compared with a non–anthracycline-based regimen&mdash;is restricted to HER2/topoisomerase IIa (topo IIa) co-amplified cancers. These cancers, said Dr. Slamon, constitute 35% of HER2-positive cancers. In these cancers, the efficacy resulting from an anthracyclinebased regimen alone was similar in magnitude to the addition of trastuzumab to adjuvant therapy.

The investigators reach the important conclusion that use of anthracyclines in the adjuvant treatment of all breast cancer is not supported by the existing data. Given the known long-term cardiac and leukemogenic toxicities of anthracyclines and the lack of an incremental benefit in non-HER2/topo IIa co-amplified cancers (which represents approximately 92% of the overall breast cancer population), other approaches to the adjuvant treatment of breast cancer should now be adopted.

Distant Metastasis: Upfront Letrozole Resulted in Fewer Early Relapses

Previous studies have demonstrated that in patients with operable breast cancer, there is an early peak of recurrence at around two years.^3,4 In these studies, there are no data regarding the type of recurrence or whether this can be prevented by adjuvant therapy.

In a poster session, Julie C. Doughty, MD, Consultant Breast and Endocrine Surgeon, Department of Surgery, Western Infirmary, Dumbarton Road, Glasgow, Scotland, and colleagues looked at 4,245 postmenopausal women with estrogen receptor—positive (ER ) operable breast cancer. Recurrence was defined as locoregional, contralateral, and distant. Cumulative rates of recurrence types were calculated using Kaplan–Meier survival analysis and annual hazard rates of overall recurrence, and each type of recurrence was plotted over five years.

Cumulative rates of recurrence type (with 95% confidence intervals) were as follows: distant 2.5 years 4.5% (3.8—5.1), locoregional 2.5 years 1.0% (0.7–1.3), contralateral 2.5 years 0.5% (0.3–0.8). An initial peak in overall recurrence rates of 4.2% was seen at two years. The annual recurrence rates of distant recurrence peaked at 3.2% at two years. The annual hazard rates for locoregional and contralateral recurrence never exceeded 1% over the five years following diagnosis, and no initial peak at two years was evident.

Annals of Oncology

Dr. Doughty and colleagues concluded that their findings are in keeping with a recent study published in the , which found that upfront letrozole resulted in significantly fewer early relapses than tamoxifen, even after adjusting for significant prognostic factors.⁵ This study also demonstrated that distant recurrence is the predominant type of recurrence in the first two years following surgery for operable ER breast cancer.

Patients receiving letrozole demonstrated a pronounced reduction in distant recurrence in the first two years compared with tamoxifen (87 events vs. 125 events). Various aromatase inhibitor (AI) treatment strategies are in use. Implementing an AI after an initial two to three years of tamoxifen fails to address this peak of distant recurrence at two years and the potential breast cancer-associated mortality. Until the results of the Breast International Group 1-98 sequencing arms become available, only women with low-risk ER breast cancer should not receive an upfront AI.

REFERENCES

1. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.

2006;24:5381-5387. Erratum in:

2007;25:1819.

2. Chan S, Romieu G, Huober J, et al: Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast cancer (MBC) patients (pts): Results of a European phase III study [abstract].

2005;23(16 suppl):A581.

3. Saphner T, Tormey DC, Gray R: Annual hazard rates of recurrence for breast cancer after primary therapy.

1996;14:2738-2746.

4. Houghton J, on behalf of the ATAC Trialists’ Group: Using anastrozole as initial adjuvant treatment prevents early recurrences and reduces adverse events: Updated data from the ATAC (Arimidex, TAM, Alone or in Combination) trial.

2005;23(16 suppl):24S. Abstract 582.

5. Mauriac L, Keshaviah A, Debled M, et al: Predictors of early relapse in postmenopausal women with hormone receptor—positive breast cancer in the BIG 1-98 trial.

2007;18:859-867.

J Clin Oncol J Clin Oncol J Clin Oncol J Clin Oncol J Clin Oncol Ann Oncol