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American Society of Clinical Oncology 36th Annual Meeting
Day 4 - May 23, 2000

HER2, Taxanes, and High-Dose Chemotherapy

George W. Sledge, Jr., MD

Today's oral session represented a look back at 3 "hot-button" topics from the 1990s, still unresolved as we enter the new millennium: HER2 as a predictive factor for therapy of metastatic disease, the use of taxanes in advanced disease, and the use of high-dose chemotherapy and autologous stem cell support.

HER-2: Testing and Therapy

HER2 is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinases and is involved in the growth, invasion, and metastasis of breast cancer. A large body of data generated over the past 15 years suggests that patients with HER2-positive tumors are more likely to relapse and die than those with HER2-negative tumors. More recent data suggest that HER2 status may also be used as a predictor of response to therapy in advanced disease.

Dr. A. Lipton and colleagues,[1] from Penn State/Milton S. Hershey Medical Center, Hershey, Pennsylvania, examined the relationship between HER2 positivity and response to hormonal therapy in 2 randomized second-line trials. They found that patients with HER2-positive tumor had a 24% likelihood of clinical benefit (CR + PR + SD) vs a 44% likelihood of clinical benefit for HER2-negative patients, as well as having a shorter median duration of response and overall survival time. These data are consistent with a meta-analysis of hormonal therapy trials presented at these meetings[2] demonstrating a negative impact of HER2 positivity on response to metastatic hormonal therapy.[1]

Dr. Lipton's trial is of particular interest because of the means used to test for HER2. HER2 is a transmembrane receptor, and the external membrane domain of the protein may be sheared off, allowing measurement in the blood, as was performed in this trial. By contrast, testing in the past has been performed largely with either immunohistochemistry or fluorescence in situ hybridization (FISH), both of which are commonly performed on the primary tumor. Unpublished data suggest that tumors with the most striking membrane expression (3+ by immunohistochemistry) are the tumors most likely to shed HER2 into the blood, as might be expected. The potential advantage of the serum approach employed is that it might allow one to obtain important clinical information in a setting where the original tumor block may have disappeared from the pathology archives, or when the metastatic disease is not easily accessible for biopsy. Unfortunately, this test is currently available only as a research test.

Dr. Lipton's study (and the related meta-analysis by Dr. De Laurentis) raises an important question: Should HER2-positive, ER-positive patients receive hormonal therapy as initial therapy for their disease? Here is where the art of medicine becomes important. If the patient has a strongly ER- and PR-positive tumor with low-volume, indolent, metastatic disease, hormonal therapy still seems a reasonable initial approach. But for patients with symptomatic multiorgan disease, particularly those with what might be termed a "visceral crisis," the better part of valor would seem to call for beginning therapy with a chemotherapeutic regimen.

Dr. C. Vogel and colleagues,[3] from Aventura Comprehensive Cancer Center, Aventura, Florida, reported the results of a multi-institutional trial of trastuzumab as first-line therapy for HER2-positive metastatic disease. The authors examined 2 dose levels of trastuzumab and found similar response rates for the 2 doses. The response rate for the overall group was 26%, with median time to progression of 3.5 months for the standard-dose trastuzumab arm, and a median survival time of 22.9 months.

Of crucial importance in this trial, all patients responding to trastuzumab were positive at the 3+ level by immunohistochemistry. A related study, presented yesterday by Dr. Bob Mass[4] of Genentech, South San Francisco, California, demonstrated that virtually all responding patients tested positive for HER2 by the FISH technique. Indeed, the overall response rate in this trial for FISH-positive patients was 41%, a response rate that places trastuzumab in the activity range of the most active single chemotherapeutic agents that we currently possess. This is not to say that single-agent trastuzumab is the preferred approach for the FISH-positive patient; a prospective, randomized trial has demonstrated that the combination of up-front chemotherapy with trastuzumab provides a significant survival advantage. These data do strongly suggest that the only patients who should be considered for therapy with trastuzumab are those who are FISH-positive or 3+ by immunohistochemistry.

The Return of the Taxanes

Actually, the taxanes never left. But they have returned to ASCO every year in the past decade, demonstrating the continued interest in this versatile family of agents. Today's session examined the substitution of cyclophosphamide with paclitaxel in anthracycline-based regimens. Dr. H. J. Luck and colleagues,[5] from Medical University Hannover, Hannover, Germany, reported on a German trial comparing epirubicin + paclitaxel with epirubicin + cyclophosphamide, whereas Dr. Bignanzoli and colleagues[6] reported an EORTC trial comparing doxorubicin + paclitaxel with doxorubicin + cyclophosphamide. The results are shown in the Table below.

  German EORTC
RR TTP OS RR PFS OS
Epi-Taxol 46 39w 73w      
Epi-CTX 40 32w 88w      
Adria-Taxol       58% 6m NR
Adria-CTX       54% 6m NR

RR = objective response rate; TTP = time to progression; PFS = progression-free survival; OS = overall survival; NR = not reported

These data are perhaps not surprising, if not outright disappointing. The initial hope of many was that up-front use of the taxanes might affect the overall survival of patients with metastatic breast cancer. This has not been the case in these trials. Why not? Previous randomized trials have demonstrated that salvage taxane chemotherapy offers a statistically significant survival advantage. It is unsurprising that patients failing on an anthracycline-cyclophosphamide combination and then receiving salvage taxane therapy would fare equally well with regard to survival as did patients receiving initial anthracycline-taxane therapy. These studies offer further support to the concept that there is nothing magical about combination chemotherapy in the setting of metastatic breast cancer; sequential single-agent therapy is likely to provide the same overall survival benefits as more toxic combinations.

High-Dose Chemotherapy for High-Risk Node-Positive Disease

The last year has not been propitious for advocates of dose-intensive chemotherapy in breast cancer. First, last year's ASCO meetings were saturated with high-dose chemotherapy trials that could only be described as unpromising. The one striking exception to the litany of distressing data involves a trial by Dr. Werner Bezwoda of South Africa that has since been proven to be fraudulent. Some have been depressed by these events, and some have rejoiced. Sensible observers have noticed that not all the data are yet in, particularly for patients with high-risk node-positive disease. The Tuesday session demonstrated that high-dose therapy, while still on life support, should not be declared officially dead.

Dr. Rodenhuis and colleagues,[7] Netherlands Cancer Institute, Amsterdam, reported the results of the NWAST trial in patients with 4+ axillary lymph nodes. This large (n = 885 patients) Dutch trial randomized patients to receive fluorouracil, epirubicin, and cyclophosphamide (FEC) either alone or followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb) and autologous stem cell support. The abstract submitted to ASCO was a promissory note, providing no efficacy data and contributing to the suspense of the presentation. As presented at ASCO, the results involved a subset of the whole: only the first 289 patients entered on the trial were analyzed. An analysis involving the whole population will be performed in 2002.

Nevertheless, the results of this trial should give comfort to supporters of the dose intensity hypothesis, perhaps the first positive data in several years. With a 3-year median follow-up, relapse-free survival is 62% in the standard arm vs 77% in the high-dose arm; in terms of overall survival, 79% of the standard arm patients are alive compared with 89% of transplanted patients. Early transplant-related mortality was rare (about 1%). These results are difficult to interpret, given the short follow-up, the fact that only the first 289 patients have been analyzed, and the fact that the data presented on the whole group look somewhat less encouraging. Nevertheless, this represents a superbly conducted and important trial. The emerging results from this trial will play an important role in our understanding of the role of high-dose chemotherapy in breast cancer.

An approach short of high-dose chemotherapy and autologous stem cell support was presented by the Australia-New Zealand Breast Cancer Trials Group, an organization that has provided consistently high-quality studies over the years. In this trial, patients with metastatic breast cancer were randomized to receive either high-dose epirubicin and cyclophosphamide (150 and 1500 mg/m2 x 3 cycles) or standard-dose epirubicin and cyclophosphamide (75 and 750 mg/m2 X 6 cycles). Best overall response, progression-free survival, and overall survival were statistically similar in both arms, and unsurprisingly the high-dose arm was associated with greater toxicity and impaired quality of life. These trials complement previous NSABP trials (B-22 and B-25) that have failed to show a value for dose intensification in the adjuvant breast cancer setting.

References

  1. Lipton A, Ali SM, Leitzel K, et al. Elevated serum HER-2/neu level predicts decrease response to hormone therapy in metastatic breast cancer. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 274.
  2. De Laurentiis M, Arpino G, Massarelli E, et al. A metanalysis of the interaction between Her2 and the response to endocrine therapy (ET) in metastatic breast cancer (MBC). Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 300.
  3. Vogel C, Cobleigh M, Tripathy D, et al. First-line, non-hormonal, treatment of women with HER2 overexpressing metastatic breast cancer with Herceptin (trastuzumab, humanized anti-HER2 antibody). Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 275.
  4. Mass RD, Sander C, Charlene K, Johnson L, Everett T, Anderson S. The concordance between the Clinical Trials Assay (CTA) and fluorescence in situ hybridization (FISH) in the herceptin pivotal trials. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 291.
  5. Luck HJ, Thomssen C, Untch M, et al. Multicentric phase III study in first line treatment of advanced metastatic breast cancer (ABC), epirubicin/paclitaxel (ET) vs epirubicin/cyclophosphamide (EC). A study of the AGO breast cancer group. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 280.
  6. Bignanzoli L, Cufer T, Bruning P, et al. Doxorubicin (A)/taxol (T) versus doxorubicin/cyclophosphamide as first line chemotherapy in metastatic breast cancer (MBC): a phase III study. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 282.
  7. Rodenhuis S, Botenbal M, Beex L, et al. Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin in operable breast cancer with 4 or more axillary lymph nodes. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 286.

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