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ASCO 1998: A Commentary

Massachusetts General Hospital and Dana-Farber/Partners Cancer Care, Boston, Massachusetts, USA

Correspondence: Bruce A. Chabner, M.D., Massachusetts General Hospital and Dana-Farber/Partners Cancer Care, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114, USA. Telephone: 617-724-3200; Fax: 617-724-3166; e-mail: chabner.bruce{at}mgh.harvard.edu

The American Society of Clinical Oncology (ASCO) occupies a central place in the professional and social life of cancer specialists. In this once-a-year happening we have the opportunity to see close colleagues from the past and reflect on the state of our profession, including clinical research and the more practical aspects of our existence and survival as practitioners. Robert Mayer, the outgoing ASCO President, and the Program Chair, Margaret Shipp, did a masterful job of creating a well-organized, informative, and exciting four days in Los Angeles.

ASCO is an organization in evolution. While clinical research is still its main mission, the financial and organizational aspects of cancer care occupy an increasingly important place in this meeting, as reflected in the program itself and in the dominating presence of the drug companies on the exhibit runways. Nonetheless, the quality of the scientific sessions was outstanding.

For those who were not in attendance, or those who would like to reflect on the meaning of what they heard and saw, we offer the following comments on selected papers:

• The most important paper of the meeting came from NSABP, which reported that tamoxifen profoundly reduced the incidence of breast cancer in "high-risk" women on the national prevention trial initiated six years ago by the National Cancer Institute [1]. Tamoxifen reduced the number of new tumors by 45%, after a median follow-up of four years. What should be emphasized, however, is that the balance of negative and positive events in the two arms of the study was less positive.
  

Other aspects of the study deserve consideration in weighing benefits and risks. While the endometrial cancers were all early stage and presumably curable, one-half of the breast cancers in the tamoxifen group were ER^–, as compared to one-sixth of those in the control group, and presumably at higher risk for relapse. One possible explanation for this finding is that tamoxifen provided selective pressure for outgrowth of ER^– clones by causing selective regression of the pre-existing ER⁺ tumors. Will the ER⁺ tumors recur once tamoxifen is stopped?

On the plus side, there were additional benefits of the drug. The tamoxifen group had a 47% reduction in the number of non-invasive breast cancers and a 33% reduction in fractures of the hip, wrists, or spine.

Overall, the results were clearly positive, but how they apply to subgroups of the study population remains uncertain. Is it worth treating almost 7,000 women with an average of four years of tamoxifen at a total cost of perhaps $30 million for the net benefits observed?

The discussant, Kent Osborne, of the University of Texas, San Antonio, offered the opinion that all women at similar risk to the study population should be so treated. We certainly agree that tamoxifen is reasonable for young women with a strong family history of breast cancer, or with a history of atypical hyperplasia or lobular carcinoma in situ. However, do the results justify treating all women over age 60, a category that made up 30% of the women in the study? The evidence is not yet convincing that this is the correct course, given the higher incidence of side effects, particularly endometrial cancers and pulmonary emboli, in the older women. Longer follow-up and a more detailed cost-benefit and toxicity-benefit analysis would lead to greater confidence in recommending the drug for all women over 60.

A second trial in breast cancer prevention, sponsored by Eli Lilly, raised additional possibilities [2]. Evista (raloxifene), an estrogen antagonist approved for its positive effects on osteoporosis, reduced the risk of breast cancer in women over age 50 by 76% after only three years of follow-up. Endometrial cancer seems to be absent from its side-effects, and clotting events are "rare." Thus, Evista may become the drug of choice for older women who have not undergone a hysterectomy. NSABP plans to compare Evista and tamoxifen in a prevention trial.

• We may realize important clinical benefits from the discovery of the Her-2/neu oncogene, which is overexpressed in 20% to 30% of human breast cancers. Previous work indicated that Her-2/neu overexpression in primary breast cancer specimens is associated with a high rate of disease recurrence after adjuvant chemotherapy. Now it appears that the same may be true for its effect on adjuvant tamoxifen. An Italian group analyzed the impact of this factor on tumor recurrence and survival in a group of patients randomized to receive tamoxifen or no further therapy [3]. Patients with ER⁺, Her-2/neu^– tumors clearly benefitted from tamoxifen adjuvant therapy, while those with ER⁺, Her-2/neu⁺ tumors had a higher rate of recurrence and lower survival as compared to untreated controls. These results imply that Her-2/neu should be assessed routinely in the adjuvant setting in deciding whether to use tamoxifen. Secondly, the findings suggest that Her-2/neu in some unknown way confers independence from hormonal control, and may unmask an agonist role for tamoxifen.
  

In a related paper, a national study group supported by Genentech revealed the results of their large randomized trial of chemotherapy, either taxol or doxorubicin/cyclophosphamide, with or without the Her-2/neu monoclonal antibody (herceptin) in patients with advanced breast cancer [4]. The antibody/chemotherapy group had a strikingly more positive response rate (62%) as compared to chemotherapy alone (36%), and a significantly longer time to progression. The only negative and puzzling finding was a significantly higher rate of cardiotoxicity in the antibody/anthracycline-treated group as compared to those receiving anthracyclines without antibody. Why the antibody should enhance cardiotoxicity is unclear.

Herceptin deserves approval for marketing, and represents an important conceptual advance in the therapeutic use of monoclonals. Many questions are unanswered; for example, are the actions of the drugs and antibody independent, or truly synergistic? It is impossible to tell from these data, in that the antibody by itself has a 20% response rate in advanced breast cancer.

If the combination of drugs and monoclonal is synergistic, what is the mechanism of this interaction? Prior studies suggest that Her-2/neu closely resembles the epidermal growth factor-receptor and may function as a receptor for an as yet unidentified growth factor. Blocking its function with antibody may sensitize cells to DNA damage by lowering the threshold for apoptosis. The trial provides a significant impetus for testing combinations of cytotoxic drugs and other signal pathway inhibitors, such as farnesyl transferase inhibitors, raf antisense molecules, flavopiridol (an inhibitor of cell cycle dependent kinases), and other candidate anticancer drugs. At a clinical level, it will certainly lead to trials of antibody/drug, and, in particular, antibody/taxane combinations in both adjuvant and advanced breast cancer.

• Is CAF better than CMF for adjuvant therapy of breast cancer? A recently completed intergroup study in "high-risk" node-negative breast cancer patients (hormone receptor negative, or tumors >2 cm, or tumors with a high S-phase fraction) seems to indicate that there is a slight advantage for CAF, with a 2% to 3% improvement in disease-free (86% versus 84%) and overall survival (92% versus 90% at five years) [5]. However, this improvement was realized at the expense of greater acute toxicity, especially myelosuppression and nausea and vomiting, and the potential for late cardiac toxicity. In low-risk node negative patients (ER⁺ or PR⁺, <2 cm tumor, and low S-phase fraction), not treated with adjuvant therapy, overall survival was 96% to 97% and disease-free survival was 88% to 89%. While these survival figures are impressive, there is room for improvement. In the good-risk group, given the minimal toxicity of either tamoxifen, CMF, or the combination, most oncologists would now treat the smaller, ER⁺ tumors with at least tamoxifen, if not both.
  
• One plenary abstract proved controversial. While most of us believe that PSA screening for prostate cancer does lower the death rate due to this disease, particularly in men under 70, the question remains unproven. A paper from Laval University in Quebec did little to settle the issue [6]. In this trial, two-thirds of the men were offered PSA screening, while one-third was not. However, three-fourths of those who were offered screening declined to be tested and were then added to the control group. What happened to the intent-to-screen rule? The control group had a much higher rate of death due to prostate cancer, but many of the controls were "dropouts" from the screening group. The results were thus ambiguous at best, and the value of screening remains uncertain.
  
• Other papers provided additional evidence that anthracyclines and taxanes may not be cross-resistant in breast cancer. Austen Doyle from the University of Maryland has cloned a new drug-resistance transporter specific for anthracyclines and mitoxantrone, but which does not affect taxanes or vincas [7]. The transporter was first isolated in breast cancer cell lines, and is found in few normal tissues other than placenta. It could explain the lack of cross-resistance between taxanes and doxorubicin in breast cancer, but much more information is needed regarding its expression in clinical breast cancer.
  

An important paper from Vienna supports the hypothesis that p53 status is a major determinant of drug response in breast cancer [8], but with strikingly different effects on anthracyclines and taxanes. Resistance to anthracycline-based regimens was associated with p53 mutation in six of six resistant patients, while partial or complete response in 15/15 patients was associated with wild-type p53. The opposite relationship was observed for a paclitaxel-containing regimen, for which there were no responders in 20 patients with wild-type p53, but five of 11 patients with mutant p53 tumors had partial or complete responses. Thus, mutant p53 status seems to negate response to anthracyclines but sensitizes tumors to taxanes. This information adds to the rationale for combining these two classes of drugs.

• Do we actually help our patients in terms of quality of life and survival with second-line chemotherapy for metastatic disease? Cunningham reported the results of a multicenter randomized non-blinded clinical trial comparing CPT-11, 350 mg/m² every three weeks and best supportive care for patients with a good performance status and 5-FU-resistant metastatic colorectal cancer [9]. Unfortunately, the two groups were not stratified for performance status, and the CPT-11 group had significantly more patients with a performance status of "0." The median survival was significantly better for the CPT-11 group (9.2 months versus 6.5 months), as was the time to deterioration in performance status. Adverse effects of treatment were modest, and included diarrhea and neutropenia. A quality-of-life analysis suggested improvement with therapy, making CPT-11 a standard second-line option for selected patients with favorable performance status who fail 5-FU.
  
• A CALGB randomized study found significant benefit to the use of subcutaneous azacitidine in patients with symptomatic myelodysplastic syndrome. One hundred seventy patients requiring transfusions or with rising peripheral blast counts were randomized to receive subcutaneous azacitidine 75 mg/m²/day for seven days, 28-day cycles, or best supportive care [10]. Crossover to the treatment group was allowed after four cycles for worsening clinical status. An intent-to-treat analysis showed 61% of patients in the treatment group responded, with a decreased transfusion requirement or disappearance of peripheral blasts, compared with only 5% in the supportive care group. Median survival was 23 months in the treatment group and 14.5 months in the observation group. The observation group had a high percentage of patients develop AML (11%), suggesting the possibility of unequal randomization. Cytogenetics, an important prognostic factor in this disease, was not used to stratify patients or determine responses. Nevertheless, azacitidine represents the only treatment besides bone marrow transplantation that appears to alter the natural history of MDS. Quality of life steadily improved on this treatment, which should be considered a standard in future randomized trials for this frustrating disease.
  

1. Wickerham DL, Costantino J, Fisher B et al. The initial results from NSABP protocol P-1: a clinical trial to determine the worth of tamoxifen for preventing breast cancer in women at increased risk. Proc Am Soc Clin Oncol 1998;17.
2. Cummings SR, Norton L, Eckert S et al. Raloxifene reduces the risk of breast cancer and may decrease the risk of endometrial cancer in post-menopausal women. Two-year findings from the multiple outcomes of raloxifene evaluation (MORE) trial. Proc Am Soc Clin Oncol 1998;17:2a.
3. Bianco AR, De Laurentis M, Carlomagno C et al. Twenty-year update of the Naples gun trial of adjuvant breast cancer therapy: evidence of interaction between c-erb-b2 expression and tamoxifen efficacy. Proc Am Soc Clin Oncol 1998;17:97a.
4. Slamon D, Leyland-Jones B, Shak S et al. Addition of Herceptin to first-line chemotherapy for Her-2 overexpressing metastatic breast cancer markedly increases anticancer activity: a randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 1998;17:98a.
5. Hutchins L, Green S, Ravidin P et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102. Proc Am Soc Clin Oncol 1998;17:1a.
6. Labrie F, Dupont A, Candas B et al. Decrease of prostate cancer death by screening: first data from the Quebec prospective and randomized study. Proc Am Soc Clin Oncol 1998;17:1a.
7. Doyle LA, Yang W, Abruzzo LV et al. Characterization of transfectants of breast cancer resistance protein, a novel ATP-binding cassette transporter that contributes to the multidrug-resistance phenotype of mcf-7/ADRVP breast cancer cells. Proc Am Soc Clin Oncol 1998;17:200a.
8. Berruti A, Bottini A, Brizzi MP et al. p53 expression and reduction in kinetic cell activity in predicting clinical complete response to primary chemotherapy in breast cancer patients. Proc Am Soc Clin Oncol 1998;17:102a.
9. Cunningham D, Pyrhonen S, James RD et al. A phase III multicenter randomized study of CPT-11 versus supportive care alone in patients with 5-FU-resistant metastatic colorectal cancer. Proc Am Soc Clin Oncol 1998;17:1a.
10. Silverman LR, Demakos EP, Peterson B et al. A randomized controlled trial of subcutaneous azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. Proc Am Soc Clin Oncol 1998;17:14a.

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