Advances in the Management of Early Stage Breast Cancer–ASCO 2005

May 13-17, 2005 Orlando, Florida Lee Schwartzberg, MD, FACP

Monoclonal Antibody Therapy for ESBC: A New Standard

Progress against cancer does not move at a constant velocity; sometimes there are watershed moments when the pace accelerates. ASCO 2005 was one such milestone in the treatment of breast cancer. In the session titled Monoclonal Antibody Therapy in Breast Cancer, a whole new modality of treatment, targeted biological therapy, became established as an important component of adjuvant treatment. Monoclonal antibody therapy now joins surgery, radiation, cytotoxic chemotherapy and endocrine therapy as an established treatment option for specific patients.

The preceding statements are based on the results of a combined analysis of two NCI sponsored trials of Herceptin® (trastuzumab) added to chemotherapy for HER2-positive tumors. These landmark trials, NSABP B-31 and N-9831, an intergroup trial coordinated by the North Central Cancer Treatment Group, sought to establish the benefit of adding Herceptin to appropriate early stage patients. Herceptin, of course, is already of known value for prolonging the lives of patients with metastatic breast cancer. While originally designed to be analyzed separately, a decision was recently made to analyze and present the results of both trials together because of the great similarity between the studies

[1],[2]This decision resulted in greater statistical power and an ability to present results much earlier than either trial could on its own, based on the prespecified number of cumulative events.

Both trials compared adjuvant chemotherapy with doxorubicin and cyclophosphamide for four cycles at standard doses followed by Taxol® (paclitaxel) as the control arm. B-31 used Taxol 175 mg/m2 every three weeks x 4 cycles while N-9831 used Taxol 80 mg/m2 weekly x 12. The experimental arms added weekly Herceptin at 4 mg/kg loading dose, then 2 mg/kg concurrent with the Taxol followed by Herceptin as a single agent for a total of 52 weeks of monoclonal antibody therapy. N-9831 had an additional arm in which the Herceptin was begun after Taxol was completed. This arm was not part of the combined analysis presented at ASCO.

Eligible patients in both trials were women over age 18 with HER2+ tumors by IHC-3+ and/or FISH+, locally determined. Prespecified cardiac analysis was built into both studies with MUGA scans evaluated after AC then Q 3 months x 3 and Q 6 months afterwards. N-9831 allowed high-risk node negative patients defined as T>1 cm with hormone receptor negativity or tumors >2 cm to participate. Baseline demographics were well balanced across the arms. About half the women were above 50 years of age, approximately half had hormone receptor positive tumors, and 60% had tumors > 2.0 cm in diameter.

Median follow up at the time of the ASCO report for both studies together is 2.0 years, reflecting a 2.4 year follow up for B-31 and 1.5 year follow up for N-9831. The primary endpoint was disease-free survival, and the results are nothing short of remarkable: at four years, patients treated with chemotherapy plus Herceptin had an 87% disease-free survival compared to 69% in the chemotherapy only arm. This represents a hazard ratio of 0.48 with an astounding P value of 3×10-12. When looked at separately, the two studies are extremely similar in outcome with a 5-year disease-free survival 85% for B-31 and 86% in N-9831 for the Herceptin arms compared to 66% and 68%, respectively, for the control arms. Moreover, distant disease-free survival was also markedly improved for patients receiving Herceptin, 90% vs. 81% at 3 years, HR 0.47, p= 8×10-10. At this still short follow up time, overall survival is also improved at 4 years to 91% from 87% with a P value of 0.015. The major toxicity for the addition of Herceptin was, as expected, cardiac dysfunction. Overall, approximately 4% of patients had cardiac toxicity defined as a drop in ejection fraction of >15 points, to below the lower limit of normal (<LLN), or clinical CHF.

A third trial addressing the addition of Herceptin after chemotherapy for HER2 positive breast cancer was a European based trial called HERA. Dr. Martine Piccart-Gebhart presented preliminary results of this study at the special antibody session.

[3]This trial was designed somewhat differently from the NCI sponsored trials in that patients were randomized to receive observation, one year of Herceptin therapy or two years of Herceptin therapy after adjuvant or neoadjuvant chemotherapy of the physicians choice. Accordingly, almost all patients were treated with an anthracycline but only approximately one-quarter received a taxane-containing regimen. One-third of women in the HERA trial were lymph node negative. At a median follow up of 1.5 years, the two-year DFS was 85.8% for Herceptin treated patients compared to 77.4% in the control arm for a hazard ratio of 0.54, P<0.0001. The two-year DDFS was markedly improved with a hazard ratio of 0.51 and the two-year overall survival hazard ratio was 0.76, not yet reaching a statistical significance but certainly encouraging at this early follow up. Symptomatic CHF occurred in 0.5% of patients receiving Herceptin vs. 0% in the observation arm.

Further drilling down on the cardiac issue, Dr. Perez presented a detailed cardiac evaluation of N-9831 in a breast cancer poster discussion session.

[4]Seven percent of women had a drop in EF to <LLN or >15 points from baseline or both and therefore did not receive Herceptin on protocol. In the chemo plus Herceptin arm, 21% of women had a nadir LVEF which was <LLN or >15 points drop from baseline. No clinical cardiac events occurred in the control arm at the interim analysis compared to 3.3% (CI 2-5.1%) patients developing CHF or a drop below the prespecified LVEF boundary prompting an interruption in study drug. Therefore, adding Herceptin to chemotherapy causes a predictable increase in cardiac events but acceptable based on the large clinical benefit. The relatively high incidence of changes in LVEF strongly documents the need to monitor patients carefully during Herceptin therapy.

The total impact of these three trials was recognized by the ASCO audience for their importance with a standing ovation. The addition of Herceptin is associated with greater absolute benefit in the adjuvant treatment of breast cancer than any other single agent in the history of treatment. Moreover, targeting a specific set of breast cancer patients allows this smaller group with a previously worse prognosis to markedly improve their outcome. The net result is an elevation in outcome for all patients. The era of one size fits all adjuvant chemotherapy has ended and the Herceptin results in HER2 positive patients spur us on to find other biological markers for other subsets of breast cancer patients (in addition to endocrine therapy for hormone receptor positive tumors) which will further improve treatment results.

Genetic Analysis of Breast Tumors Matures

As we move to molecularly targeted therapies and diagnosis, it is critical to validate new technology which purports to independently aid prognostic and predictive capabilities. To this end, Dr. Paik of NSABP presented a further analysis of the Oncotype DX test, a 21 gene RT-PCR based gene assay performed on formalin fixed/paraffin embedded tissue. This commercially available test has previously been shown to predict 10-year recurrence rates in LN-, ER+ tumors and has been validated in large data sets from NSABP trials.

At ASCO 2005, updated analysis demonstrated that the recurrent scores is a prognostic factor for this subset of tumors even in the absence of tamoxifen.

[5]Proliferation gene group expression was also associated with recurrence in untreated patients. Moreover, degree of expression of estrogen receptor, as demonstrated by Oncotype test, is a better predictor of benefit from tamoxifen than other methods of determining estrogen receptor. The correlation of increased benefit with higher ER gene expression suggests we should rethink the now common practice of reporting ER as simply positive or negative. Conversely, some patients with high ER levels can still have a high recurrence score since other genes presumably have an important impact on prognosis. Therefore, this additional data confirms the recurrence score is both prognostic of intrinsic tumor behavior as well as predictive for treatment from tamoxifen and has an increasingly important role in the routine clinical assessment of ER+, LN- tumors.

Dr. Habel evaluated the use of the Oncotype test in a population-based, case controlled study using patients from the Northern California Kaiser Permanente database.

[6]The recurrence score was predictive of deaths from breast cancer in ER+ patients independent of treatment with tamoxifen (p=0.002) confirming the earlier results from the NSABP series. These investigators also examined the five genes of the assay associated with tumor proliferation and developed a specific proliferation index. Patients with high proliferation scores and ER- or PR+, tamoxifen negative patients were six fold more likely to die from breast cancer than those with low scores (p=0.001). Progesterone receptor expression in general was strongly prognostic for breast cancer mortality. These results, again, lend confidence that the Oncotype test will be of benefit in the routine evaluation of women with breast cancer outside the clinical trial setting.< /SPAN>

Update on AIs

By now, the use of aromatase inhibitors as a standard part of endocrine responsive early stage breast cancer is well established. Still, questions remain: do all AIs have similar benefits in the adjuvant setting? Are there differences among AIs with regard to side effects?

The first results of the eagerly awaited BIG-98 trial were reported at ASCO 2005.

[7]The most interesting aspect of this four-arm study, comparing sequential tamoxifen/Femara vs. Femara/tamoxifen vs. tamoxifen only or Femara only, will not be available for several years. However, this report of DFS in patients receiving initial Femara vs. tamoxifen as primary endocrine therapy shows a significant benefit for Femara. At 5 years, the DFS for Femara was 84% vs. 81.4% for tamoxifen, a HR of 0.81, p=0.003. All endpoints favored Femara over tamoxifen including OS, DDFS, time to distant recurrence and time to recurrence. Subgroup analysis did not demonstrate any major differences, including the ER/PR+ group which had a HR of 0.84 and the ER+/PR- group with a hazard ratio of 0.83.< /SPAN>

In terms of toxicity, there were more Grade 3-5 cardiac events and more hypercholesterolemia with Femara compared to tamoxifen. Conversely, thromboembolic events and endometrial events, including biopsies and endometrial cancer, were more frequent with tamoxifen. Longer follow up will be invaluable to give a fuller picture at the benefits of AIs vs. potential risks and to evaluate interventions designed to reduce toxicities. Nevertheless, BIG-98 demonstrates that Femara, like anastrozole in the previously reported ATAC trial has clear-cut advantages over tamoxifen. Femara becomes another choice of initial endocrine treatment for postmenopausal women.

One attempt to reduce the most significant toxicity of patients receiving Femara, bone loss, was reported by Dr. Brufsky.

[8]This trial randomized women starting Femara to receive either up front zolendronic acid (ZA) every 6 months vs. delayed zolendronic acid, a potent bisphosphonate, to start when BMD decreased < -2SD or if bone fracture occurred. At 12 months of follow up, the upfront ZA group showed mean increase in lumbosacral BMD of 2.02% while the delayed group showed a mean decrease in BMD of 2.61%, p<0.00. Similar results were demonstrated for BMD of the hip. Serum markers of bone turnover were suppressed by ZA over the 12-month period. ZA was safe and well tolerated. Tentative early interaction with ZA may become a strategy to prevent clinical bone complications associated with long-term aromatase inhibitor use.

Another way to use Femara is in the extended adjuvant setting, i.e. after 5 years of tamoxifen, with benefit of 5% improvement in 4 year DFS documented in the MA-17 trial.

[9]When this benefit became known, patients in the placebo arm were offered Femara. An analysis of factors driving prior placebo-treated patients decision to take Femara was presented.

[10]Younger patients, LN+ disease, and patients with endocrine symptoms while on placebo were more likely to take Femara. In this North American based trial, women from the United States were more likely to opt for Femara compared to Canadian women. Those with flu-like symptoms or longer time on placebo were more likely to decline Femara. Based on these findings, further evaluation of patient preferences for extended AI therapy should be explored.

Lifestyle Change Improves Outcome

One of the most frequently asked questions by women completing adjuvant treatment for ESBC is what else can I do to reduce my risk of breast cancer? Indeed, an entire cottage industry has sprung up with multitudes ready to provide vitamins, herbs, antioxidants and other unproven measures purported to reduce recurrence. As always, evidence based, well-conducted randomized trials provide us with valuable guidance. Dr. Chlebowski presented results of a fascinating lifestyle intervention trial, designed to test the effects of lowering dietary fat in postmenopausal women with breast cancer.

[11]Women with Stage IC-II breast cancer with a >20% fat caloric intake prior to entry were randomized within 1 year of primary surgery to a dietary intervention designed to reduce total fat intake to 15% of total caloric intake. This was accomplished by extensive dietary counseling and group sessions. The control group had dietician contact every 3 months. Almost 2500 women participated in this trial with baseline characteristics generally well balanced between the arms.

An intent-to-treat analysis demonstrated that the dietary intervention did, in fact, cause a reduction in fat consumption to 20.3% of daily calories compared to 29.2% in the control arm (p<0.0001). Even after 5 years, patients in the dietary interaction group were consuming much less fat and had lost an average 6 lbs although weight loss per se was not a trial goal. Most interestingly the primary endpoint, relapse free survival was significantly improved by dieting intervention from 87.6% in the control arm to 90.2% on the study arm, HR 0.76, p=0.34. A subgroup analysis demonstrated most of the benefit accrued to ER- patients, in which 86.4% of intervention patients enjoyed RFS compared to 78.4% in the control arm, HR 0.58, p= 0.018. Based on these results, perhaps the time has come for us to lobby CMS and 3rd party payers to reimburse time for nutritional counseling in our offices, a service currently provided at practice expense.< /SPAN>

Conclusion

The adjuvant treatment of early breast cancer gets more interesting and more rewarding by the year. Population registry databases continue to document an increasing reduction in mortality from breast cancer, beginning in 1990 and continuing to this day. Improvement in breast cancer is undoubtedly due to many factors, including widespread use of mammographic screening. However, there is little doubt that more effective adjuvant therapy, offered now to almost all women with invasive breast cancer, plays a role in this success.

We are truly approaching what Dr. George Sledge termed the breast cancer end game in his discussion of the Herceptin results at ASCO.

[12]A back-of-the-envelope analysis taking into account the new results for addition of Herceptin in the HER2+ group, AI use in the HR+ group, and dietary intervention/fat reduction in the ER- HER2- group suggests that 5 year RFS of >85% for all ESBC patients is within our grasp. Our next task will be to make certain that the clinical trial results translate into real clinical practice.

Thankfully, we have some data from the ASCO QOPI project available that suggests in breast cancer treatment, use of appropriate therapy is indeed being delivered.

[13]We may be on the verge of turning our attention to reducing treatment durations, and lowering toxicity while preserving efficacy, much as has been done in Hodgkins disease. Breast cancer as the new Hodgkins disease I think medical oncologists would welcome that!

References

[1]Romond J. Special Session: Monoclonal antibody therapy in breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005.

[2]Perez E. Special Session: Monoclonal antibody therapy in breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005.

[3]Piccart-Gebhart M. Special Session: Monoclonal antibody therapy in breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005.

[4]Perez E, Suman V, Davidson N, Kaufman P., et.al. Interim cardiac safety analysis of NCCTG N9831 Intergroup adjuvant trastuzumab trial. Proc Am Soc Clin Oncol . 2005;23:17s, Abstract #556.

[5]Paik S, Shak S, Tang G., et.al. Expression of the 21 genes in the recurrence score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer. Proc Am Soc Clin Oncol. 2005;23:6s, Abstract #510.

[6]Habel C, Quesenberry M, Jacobs D, et.al. Gene expression and breast cancer mortality in Northern California Kaiser Permanente Patients: A large population-based case control study. Proc Am Soc Clin Oncol . 2005;23:29s, Abstract #603.

[7]Thurlimann B, Keshaviah A, Mouridsen H., et.al. BIG 1-98: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Proc Am Soc Clin Oncol. 2005;23:6s, Abstract #511.

[8]Brufsky A, Harker W, Beck J., et.al. Zoledronic acid (AZ) effectively inhibits cancer treatment-induced bone loss (CTIBL) in postmenopausal women (PWW) with early breast cancer (BCa) receiving adjuvant letrozole (Let): 12 mos BMD results of the Z-FAST trial. Proc Am Soc Clin Oncol. 2005;23:12s, Abstract #533.

[9]Goss P, Ingle J, Martino S., et.al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349(19):1793-802.

[10]Luk C, Goss P, Pritchard K., et.al. Determinants of preferences for starting extended adjuvant letrozole (L) in postmenopausal women following five years of tamoxifen. Proc Am Soc Clin Oncol . 2005;23:39s, Abstract #642.

[11]Chlebowski R, Blackburn G, Elashoff R., et.al. Dietary fat reduction in postmenopausal women with primary breast cancer: Phase III Womens Intervention Nutrition Study (WINS). Proc Am Soc Clin Oncol . 2005;23:3s, Abstract #10.

[12]Sledge G. Special Session: Monoclonal antibody therapy in breast cancer. Proceedings of the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando, Fla. 2005.

[13]McNiff K, Neuss M, Desch C, et.al. The Quality Oncology Practice Initiative (QOPI): understanding and improving best practices by a community of oncologists. Proc Am Soc Clin Oncol. 2005;23:533s, Abstract #10.

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