The 40th Annual Meeting of the American Society of Clinical Oncology (ASCO) in June 2004 included several reports on the advances in breast cancer. These reports touched on almost every area of this multifaceted disease.  The summaries below are among the most important and potentially practice-changing studies.

• Metastatic Breast Cancer
• HER-2 Positive Disease
• Neoadjuvant Therapy
• Update on Dose-Dense Therapy
• New Agents
• Hormonal Therapy
• Supportive Care
• The Future of Breast Cancer

Metastatic Breast Cancer

While targeted therapies have clearly captured the oncology world’s attention and imagination, the current reality is that cytotoxic chemotherapy remains the standard for the vast majority of cases of metastatic breast cancer.  Efforts continue to define the optimal first-line therapy for metastatic breast cancer (MBC).  There is a need to balance toxicity of treatment with response to therapy in a disease with long chronicity that remains essentially incurable.  When multiple lines of treatment will be employed over a protracted period of time, this balance becomes even more important;  hence, the ongoing and somewhat distracting debate of single agent versus doublet therapy for first-line MBC.  Further fuel to the fire was added at the oral breast session at ASCO 2004. 

Albain, et al.[1] presented interim survival results of a randomized Phase III trial comparing Gemzar® (gemcitabine) and paclitaxel (GT) to paclitaxel (T) alone.  The overall survival hazard ratio was 0.775 (p = 0.18), representing a 23% improvement in survival for GT  (Table 1). 

Table 1

Treatment post first-line progression was similar in both arms except that patients in the paclitaxel arm were more likely to receive Gemzar®.  Importantly, preliminary quality-of-life results demonstrated no severe increase in toxicity for the doublet over single-agent paclitaxel.  This regimen is the second doublet (Taxotere®/Xeloda® being the other) to show a survival advantage in the first-line setting and this trial led to recent FDA approval of Gemzar® for this indication. 

Scheduling chemotherapy drugs correctly can have profound implications in toxicity profile, as well as efficacy.  The taxanes, in particular, have been explored at a variety of dosing schedules and infusion times.  Seidman, et al.[2] reported on the CALGB 9840 trial, which compared weekly administration of paclitaxel to every–three-week dosing in MBC.  The design of the trial was somewhat controversial, as some of the patients in the control arm (every–three-week paclitaxel) were “borrowed” in a pre-specified manner from a previous CALGB phase II trial. 

Nonetheless, patients treated with weekly paclitaxel had improved tumor response (40% vs. 28%) (HR= 1.61, p= 0.017), and significantly better TTP of 9 months versus 5 months (HR=1.45, p = 0.0008).  The overall survival was non-significantly better for weekly paclitaxel (24 months vs. 16 months) (p = 0.17).  A second aim of the trial was to explore the use of Herceptin® (trastuzumab) in HER-2 positive patients with MBC. Herceptin® did not improve response rate (35% vs. 29%), TTP (7 months vs. 6 months), or overall survival (22 months vs. 20 months).  Toxicities differed by arm.  Every-three-week paclitaxel had more granulocytopenia, while weekly paclitaxel had significantly more neurosensory (23% vs. 12%) and neuromotor toxicity (8% vs. 4%).   The authors concluded that weekly paclitaxel was superior to every-three-week scheduling.  Questions still remain on how generalized this conclusion is, given the trial design and the large percentage of patients with HER-2 positive disease in both arms.

HER-2 Positive Disease

For HER-2 positive MBC, Herceptin® plus chemotherapy has a marked survival advantage over chemotherapy alone.  Robert, et al.[3] added Paraplatin® to paclitaxel and Herceptin® based on in vitro synergy.  This trial was updated at ASCO 2004.  Overall response was 52% for the three-drug combination versus 31% for paclitaxel and Herceptin® (p = 0.04) and time to progression was longer, at 10.7 months versus 7.0 months (p = 0.02).  There was a trend towards longer median survival in HER-2 3+ positive patients (42 months vs. 29 months) (p = 0.29).

Perhaps the most striking breast cancer result at ASCO was the report by Buzdar, et al.[4] in a randomized trial comparing paclitaxel followed by FEC versus the same regimen with simultaneous weekly Herceptin® for 24 weeks in HER-2 positive operable breast cancer.  Because of the results, the randomization was halted after 34 patients had completed treatment.  Results are shown in Table 2. 

Table 2

The pathologic CR rate of 65% is likely the highest ever reported for neoadjuvant treatment.  While no clinical CHF was seen, decrease in cardiac injection fraction was seen in both groups.  Accrual continues to the chemotherapy plus Herceptin® arm for safety and efficacy.  These study results must be interpreted cautiously because of the short follow up.  Still, it is another piece of data in a growing body of evidence that Herceptin® plus chemotherapy favorably alters the natural history of HER-2 positive breast cancer. 

Neoadjuvant Treatment

There is growing evidence that patients with ER-negative breast cancer derive the most benefit from neoadjuvant chemotherapy in terms of tumor regression.  Less is known about treating hormone-positive cancers with endocrine therapy.  Semiglazov, et al.[5]  performed a prospective randomized trial comparing neoadjuvant endocrine therapy with Arimidex® (anastrozole) to neoadjuvant chemotherapy in post-menopausal hormone-positive breast cancer.  The endpoints were clinical response rate and breast conservation rate.  Women receiving doxorubicin and paclitaxel had a 76% clinical overall objective response rate compared to an 89.8% response rate after three months of Arimidex®.  Breast conservation was more common in the Arimidex®arm (37.9%) versus the chemotherapy arm (20.6%) (p = 0.054).  Unfortunately, pathologic response rate, usually considered the gold standard in neoadjuvant studies, was not reported.  Neoadjuvant Arimidex® does represent a new alternative for older women with hormone receptor-positive larger tumors wishing down staging and breast conservation. 

Now that we have combinations that are more effective than single agents, which doublet is superior?  We still don’t know the answer to this question.  A randomized trial comparing adriamycin/Taxoter® (AD) to adriamycin/cyclophosphamide (AC) as primary therapy, using pathologic response rate as a surrogate endpoint, showed a 24% pCR with AC versus 21% with AD.[6]  Lymph node positivity was 61% for AC and 66% for AD.  These regimens appear similar in efficacy as neoadjuvant therapy. 

If two drugs are good, are three drugs better?  Comella, et al.[7] studied weekly Platinol®, Ellence®, and paclitaxel (PET) versus every-three-week Ellence® and paclitaxel (ET) in locally advanced breast cancer in the neoadjuvant setting.  There was a trend towards higher clinical response rates in the PET group arm and a significant pathologic CR rate in breast and axilla for 16% of PET treated patients versus 4% of ET treated patients (p = 0.03).  This improved efficacy came at the expense of increased toxicity based on higher rates of severe anemia, mucositis, peripheral neuropathy and GI toxicity in the PET arm.  The trial is ongoing. 

Increasing the number of cycles in neoadjuvant therapy may be an alternative way to improve treatment results.  The Austrian Breast Cancer Study Group[8] randomized operable breast cancer patients to 6 versus 3 cycles of Ellence®, Taxotere® plus G-CSF every 21 days.  The pCR rate was 7.7% with 3 cycles of therapy versus 18.6% for 6 cycles (p = 0.0045).  Negative lymph nodes at surgery were found in 43% versus 57% (p = 0.02), favoring the longer duration of therapy. 

Update on Dose-Dense Chemotherapy

Improved OS and RFS seen in C-9741, a study of dose density, led to profound changes in the use of adjuvant chemotherapy in the United States.  Confirmatory studies are urgently needed.  At the 40th ASCO meeting, a late breaking abstract reported on a phase III trial of dose-dense as well as dose intensified sequential epirubicin, paclitaxel, cyclophosphamide (ETC) versus standard sequential EC followed by paclitaxel (EC-T) every 21 days in 1,169 high-risk women with four or more positive lymph nodes.[9]  At an early reporting time of 17-month median follow-up, the two-year RFS rate was 85% for ETC versus 82% for EC-T.  At 28 months, the OS was 60% versus 43% (p = 0.03). 

While neutropenia and thrombocytopenia were higher in the ETC arm, there was no significant difference in febrile neutropenia and no treatment related deaths in either arm.  These early results are provocative, but the study design was confounded by increased dose intensity, increased dose density and comparing combination versus single agent sequential therapy all at once.  Nonetheless, the strategy was effective without significant worse acute toxicity, similar to C-9741. 

Del Mastro, et al.[10] provided insight into subgroups that may benefit the most from dose-dense chemotherapy.  They retrospectively evaluated their trial comparing FEC every 21 days to FEC every 14 days plus G-CSF in a dose-dense fashion for efficacy by HER-2 status at entry.  The expression of HER-2 was associated with worse EFS (HR=1.55) and OS (HR=2.00).  However, dose-dense FEC completely reversed the negative prognostic effect of HER-2 expression on EFS and partially reversed the negative effect on OS.  Therefore, the potential benefit of dose-dense FEC appeared restricted to HER-2 positive patients.

New Agents

Further experience with nanoparticle albumen-bound (NAB) paclitaxel was reported by Blum, et al.[11]  A weekly schedule of three weeks on and one week off was employed in taxane refractory MBC.  In this heavily pretreated group of patients (median prior regimens = 3, range 1-10), 20% PR rate was seen and 15% of patients had stable or responding disease for more than 24 weeks.  Toxicity was mild, with 8% of patients experiencing Grade 4 neutropenia, but only one case of febrile neutropenia and one case of minimal sensory neuropathy were detected.  NAB paclitaxel was administered over 30 minutes with no pre-medications required.

Another new agent, Ixabepilone, an epothilone B analog, was studied in a daily times five schedule.[12]  Both taxane-naive and taxane pre-treated patients were enrolled.  Observed response rates were over 18% in prior taxane treated and 44% in taxane-naive patients.  Toxicities included 20% Grade 4 neutropenia, 10% febrile neutropenia and 40% mild sensory neuropathy (only 2% Grade 3). 

Hormonal Therapy

Aromatase inhibition has increased in importance and utilization as therapy for MBC and prevention of recurrence in post-menopausal women with breast cancer.  Studies reported at the 40th ASCO meeting continued to reinforce this theme.  Paridaens, et al.[13] performed a trial comparing the steroidal AI Aromasin® to Nolvadex® in first-line hormone receptor-positive MBC.  The median PFS was 10.9 months for Aromasin®, versus 6.7 months for Nolvadex® (p = 0.04) and more patients had objective response with Aromasin® compared to Nolvadex® (43.2% vs. 29.7%).  Toxicity was minimally lower for Aromasin® compared to Nolvadex®.  Thus, Aromasin® joins the armamentarium as a safe and effective treatment for appropriate first-line MBC patients.

The MA.17 trial, previously reported, demonstrated improvement in DFS for Femara® after five years of Nolvadex®.  Whelan, et al.[14] provided an update of the impact of Femara® on QOL, an important unanswered question.  Overall, no significant difference in physical or mental health was observed over 36 months of QOL measurement using the SF-36 scale.  Small percentages of patients (5-8% each) reported decreased quality-of-life for pain, vasomotor symptoms, vitality, sexual function and physical function.

The effect of aromatase inhibition on bone mass remains a concern.  The impact of exemestane on bone was evaluated by assessing bone mineral density (BMD) in early-stage post-menopausal breast cancer patients through a randomized placebo controlled study.[15]  The mean loss in BMD in lumbar spine and femoral neck was similar for exemestane and placebo.  The fracture rate and rate of progression was similar in the exemestane group and the placebo group.  Further analysis of this data set described metabolic differences between patients receiving exemestane and those receiving placebo.[16]  Aromasin® treated patients had marked reduction in circulating estrogen levels but increased bone turnover, as evidenced by increased markers of both bone reabsorption and bone absorption which persisted at a 24-month evaluation time point. 

Thus, none of the third generation AIs has a proven beneficial effect on bone.  Long-term follow up for ongoing AI adjuvant trials are anxiously awaited.

Supportive Care

Several papers addressed the long-term follow-up of previously reported trials utilizing oral or intravenous bisphosphonates in the adjuvant setting.  Three of four studies showed ongoing favorable outcomes for use of oral clodronate or intravenous pamidronate.  Powles, et al.[17] demonstrated an overall survival advantage and reduction in bone metastases at five years for patients receiving two years of adjuvant clodronate.  Jaschke, et al.[18] evaluated adjuvant clodronate for one year in patients with bone marrow micrometastases at diagnosis and demonstrated a persistent overall survival advantage at nine years of follow-up.  Pamidronate given for eight weeks after surgery in patients with four or more positive nodes reduced the incidence of bone mets at five years of follow-up in another trial.[19]  The one negative trial, Saarto, et al.[20], demonstrated no effect on bone metastases or overall survival in node-positive breast cancer patients, but did show increased visceral metastases in the clodronate treated group.  However, as noted by Dr. Alexander Patterson in the poster discussion of these studies, the Saarto trial was not balanced for hormone-receptor positivity and the small size of the trial, combined with the particular analytic methods employed, called into question the strength of the conclusions.

The Future of Breast Cancer

One of the most intriguing events at the 40th ASCO meeting was an integrated education session on genomics in breast cancer.  Advances in molecular biology and genomics now allow an in-depth analysis of genetic events occurring within individual tumors.  How can we capitalize on this knowledge?  Four presentations offered the first steps. 

Neoadjuvant treatment of breast cancer is an attractive model to test predictive techniques since tumor tissue is easily assessable both before and after treatment.  Gianni, et al.[21] used the validated Oncotype DX™ 21-gene RT-PCR recurrence score, as well as an expanded gene set, to assess response to doxorubicin and paclitaxel chemotherapy in locally advanced breast cancer.  Interestingly, patients with a high recurrence score on the 21-gene panel had a higher chance of a pathologic CR.  Eighty-seven genes were identified that correlated with pCR intended to cluster into three groups:  ER related group, proliferation related group and immune related group.  pCR was lower in patients with high estrogen receptor expression.

Hannemann, et al.[22] used cDNA microarrays in 49 patients receiving chemotherapy for LABC to isolate 30 genes distinguishing response to therapy.  Interestingly, patients without response to neoadjuvant chemotherapy had little change in gene expression pre and post therapy compared to those who had a major response.  Yoshimoto, et al.[23] examined cDNA microarrays in 75 patients receiving neoadjuvant chemotherapy and sorted patients into responders and non-responders.  A predictive set of 23 genes was selected for response to paclitaxel.  Microarray expression was ascertained along with RT-PCR.  Validation of the gene set is currently ongoing.

The complexity of tumor gene expression analysis was emphasized by the report of Stec, et al.[24], who analyzed samples in the same patients on two distinct profiling platforms for mRNA expression. 

Distinct predictive marker sets were obtained using the Affymetrix GeneChip versus the Millennium cDNA array.  Accuracy of clustering was not well substantiated across platforms.  This study illustrated some of the statistical difficulties associated with microarrays.  There is little doubt, however, that the technology and statistical capabilities surrounding gene expression testing will continue to develop rapidly.  Clinically useful tests predictive of response to chemotherapy in breast cancer will be available in the near future.  Such capabilities will likely transform the current paradigm of treatment decisions for both early and late stage breast cancer.