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American Society of Clinical Oncology 36th Annual Meeting
Day 3 - May 22, 2000

Breast Cancer: Prognosis and Prediction

Melody A. Cobleigh, MD -- Writer: Michelle L. Plante, PharmD

To FISH or not to FISH? That Is the Question

Several interesting papers dealing with HER2/neu detection were presented at today's poster discussion on breast cancer. The most clinically relevant was presented by Dr. Maas and colleagues.[1] Herceptin, an anti-HER2/neu antibody, was approved by the US Food and Drug Administration (FDA) in 1998 for the treatment of HER2-overexpressing breast tumors. The FDA simultaneously approved a test for predicting responsiveness to Herceptin, called Herceptest. Herceptest is an immunohistochemical technique that detects the protein product of the HER2/neu gene on the cell membrane. Patients who are 2+ or 3+ by the Herceptest are candidates for Herceptin.

The response rate to Herceptin as a single agent is 14%[2] in heavily pretreated patients and 26%[3] in patients who have not received prior chemotherapy for metastatic disease. A test with better predictive value for response would be extremely valuable.

Fluorescence in situ hybridization (FISH) measures amplification of the HER2/neu gene. One FISH technique, the PathVysion assay, was approved by the FDA for predicting responsiveness of breast cancer patients to anthracyclines.

Dr. Maas and colleagues compared the PathVysion FISH assay with an immunohistochemical technique in 3 pivotal Herceptin clinical trials. In the heavily pretreated group, the response rate in 2+ or 3+ patients was zero when FISH was not amplified and 20% when it was. In the previously untreated patients, the response rate was 5% (representing one 3+ patient) in unamplified tumors and 41% in amplified tumors.

In the pivotal randomized trial comparing chemotherapy alone with chemotherapy plus Herceptin, there was a significant improvement in response rate, response duration, time to tumor progression, and survival in the group that received Herceptin. Today's abstract showed that only the FISH-amplified patients benefited. The response rate rose from 27% to 54% for FISH-amplified but was unaffected (39% vs 41%) for FISH-unamplified tumors.

Another important finding was that amplification was observed in 3% of patients with negative immunohistochemical tests and in 7% 1+ patients. These women were excluded from the Herceptin clinical trials so it is not possible to know whether they would have responded to Herceptin.

One of the weaknesses of the study is that not all specimens were available for further study. Of the 805 subjects who participated in the 3 clinical trials, 187 did not have additional slides available for study and the assay failed in 78 patients. These studies were performed on slides that were stored for several years. Herceptest was not the method used in the original Herceptin clinical trials. However, the FDA approved Herceptest because it correlated well (79% concordance) with the assay used in the Herceptin clinical trials.

Until now a bewildering array of studies comparing one method of testing vs another have been published. This is the first trial to assess methodology of HER2 testing as it relates to response in the patient. Herceptin is an expensive drug and the FISH assay will save healthcare dollars and direct patients toward appropriate treatment.

To FISH or not to FISH? It seems reasonable to perform FISH testing on any woman who is being considered for treatment with Herceptin. This includes patients whose tumors stain 2+ or 3+ by reliable immunohistochemical methods. Another group that would be reasonable to FISH is the patient whose tumor is 0 or 1+ by immunohistochemistry and has breast cancer with the HER2/neu phenotype. That is, poorly differentiated, ER-negative, and aggressive.

The Needle in the Haystack

The search for clinically occult tumor cells to aid in selection of patients for adjuvant treatment is standard practice in the field of breast cancer. Presently, the most important indicator of distant spread is involvement of axillary nodes. But nodal involvement is not a perfect predictor and at least one third of node-negative patients relapse. About three quarters of women who die from breast cancer develop bony metastasis, so searching the bone marrow for occult tumor cells makes sense. The questions posed by these papers are:

Both Braun[4] and Solomayer[5] conducted prospective cohort studies of consecutively treated patients. Marrow was collected before the primary tumor was removed. Solomayer used tumor-associated glycoprotein 12, whereas Braun tried to circumvent the problem of expression of this antigen on plasma cells and erythroid precursors by using a murine monoclonal antibody against an antigen (2E11) shared by various cytokeratin peptides which are not present in normal bone marrow.

In the study by Braun and colleagues,[4] the presence of cytokeratin-positive cells in the bone marrow was significantly correlated with tumor size and differentiation, and with inflammatory histology. With a median follow-up of 38 months, they found a significant association between cytokeratin-positive (CK+) cells in the bone marrow and distant recurrence. There was no correlation with locoregional recurrence.[6]

The distant disease-free survival (DDFS) and overall survival (OS) rates were 42% and 49%, respectively, for CK+ patients and 91% and 92%, respectively, for the CK cohort. Among 301 node-negative patients, 100 were CK+ and 14% died of breast cancer. Among the 201 CK-, node-negative women, 1% succumbed to their disease. The method has a sensitivity of 1 per million cells and a specificity of 99%. Interestingly, a subset of 150 N0 patients underwent "extended" immunohistochemistry analysis of level 1 axillary nodes and there was no correlation between DDFS or OS, while a significant correlation was observed for CK+ patients in this cohort.

In the initial report by Solomayer's group[7] with a median follow-up of 36 months, 143 women had experienced distant metastasis. In that report, 2E11 positivity correlated with size, grade, and nodal status. In 22 slides, basophilic myelocytes and monocytes were also stained; all patients except 1 displayed tumor cells as well. 2E11-positivity also correlated with locoregional, bone, and non-bone recurrence.

In the current analysis,[5] with a median follow-up of 84 months, 258 women developed distant metastasis. 2E11 positivity retained prognostic significance in the multivariate analysis but this significance was less than in the original report.

Neither paper addressed the issue of whether preoperative manipulation (ie, biopsy) of the tumor has an effect on nodes and marrow. Many patients are now diagnosed by fine needle aspirate or core biopsy. Whether tumor cells dislodged by these processes are innocent passers-by and can be detected by immunohistochemical techniques is unknown. The American College of Surgeons will study the impact of occult tumor cells in bone marrow during its sentinel lymph node trial.

When the Tumor Is Not the Target

Osteoclasts are activated by cytokines secreted by metastatic breast cancer cells in bone. As the bone matrix is degraded, paracrine growth factors are released, further stimulating tumor growth. Bisphosphonates can influence this interaction by inhibiting osteoclast activation. In 1998, Diel and associates[8] reported a randomized trial of oral clodronate (1600 mg) vs no clodronate for 2 years in women with breast cancer who had 2E11+ cells in the bone marrow. In this study, distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P < .001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P = .003). Also, there were fewer deaths in the clodronate group than in the control group (6 vs 22, P = .001). These results were updated in today's poster session.[9] New data were obtained on 288 patients with a median follow-up time of 53 months. The results are summarized in the Table.

  Clodronate No Clodronate P value
Distant metastasis 32 51 0.022
Bone metastasis 20 34 0.044
Visceral metastasis 24 37 0.091
Death 13 32 0.002

Although the arms were balanced for tumor size, nodal status, receptor status, tumor grade, and adjuvant therapy, the analysis was univariate (+/- clodronate). Patients were not treated in a uniform manner and 81% received adjuvant treatment. Reduction in nonosseous metastasis was an unexpected finding in the early report (median follow-up 36 months). In this update with a longer follow-up, the significant differences favoring clodronate held up in all categories except for visceral metastases.

Another group of investigators[10] were unable to reproduce the initial results published by Diel, but their study did not select patients on the basis of bone marrow involvement.

Whether longer follow-up or use of more potent bisphosphonates administered by different routes will be more effective is a subject for future research. Several cooperative group studies are planned to address this question.

In Summary...

Today's session contained some very important new data about HER2-neu testing. FISH testing should be performed on any woman who is being considered for treatment with Herceptin. A number of factors that help to predict response to treatment were also discussed in today's reports.

References

  1. Mass RD, Sanders C, Johnson L, et al. 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.
  2. Cobleigh MA, Vogel CL, Tripathy D, et al. Efficacy and safety of herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy: Program and abstracts of the American Society of Clinical Oncology 34th Annual Meeting; May 16-19, 1998; Los Angeles, California. Abstract 376.
  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. Braun S, Pantel K, Muller P, et al. Cytokeratin-positive bone marrow micrometastases predict poor survival in primary breast cancer independently of lymph node status. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 305B
  5. Solomayer EF, Diel IJ, Hahn M, et al. Tumor cell detection in patients with primary breast cancer, a long-term follow-up study. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 301.
  6. Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342:525-533.
  7. Diel IJ, Kaufmann M, Costa SD, et al. Micrometastatic breast cancer cells in bone marrow at primary surgery: prognostic value in comparison with nodal status. J Natl Cancer Inst 1996;88:1652-1658.
  8. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339:357-363.
  9. Diel IJ, Solomayer E, Gollan F, et al. Bisphosphonates in the reduction of metastases in breast cancer - results of the extended follow-up of the first study population. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 314.
  10. Saarto T, Blomqvist C, Virkkunen P, et al. No reduction of bone metastases with adjuvant clodronate treatment in node-positive breast cancer patients. Program and abstracts of the American Society of Clinical Oncology 36th Annual Meeting; May 20-23, 2000; New Orleans, Louisiana. Abstract 489.

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