New Directions for Breast Cancer Research: Piccart

HAMBURG—“I can see at least three new directions that carry the potential for significant improvements in the care of breast cancer patients in the coming years,” said Dr. Martine Piccart, winner of the 1997 Hamilton Fairley Award of the European Society of Medical Oncology (ESMO) in her address at the Ninth European Cancer Conference (ECCO 9).

• The development of innovative therapies with new cellular targets made possible by significant advances in molecular biology.
• The potential for increased speed and efficiency in the conduct of adjuvant clinical trials as a result of the recent creation of the European-Canadian Breast Intergroup (BIG).
• The likelihood of improved women’s education, screening, and treatment as a result of increasing awareness among women of the disease.

New Molecular Pathways

Dr. Piccart, who heads the Department of Chemotherapy at Institute Jules Bordet in Brussels and chairs the EORTC Treatment Branch, emphasized the importance of research into molecular pathways of cancer. She pointed to endocrine therapy of breast cancer as an example of an effective therapy with minimal toxicity developed by targeting a specific molecular pathway in the cancer cell.

Newly explored molecular pathways, she suggested, may ultimately prove to be as relevant to the breast cancer cell as the estrogen-receptor mediated signal transduction pathway.

“Anti-signal transduction therapy is no longer science fiction,” she said. She noted that at least three new therapeutic strategies have been developed to interfere with signal transduction mediated by the tyrosine kinase receptor in cancer cells, including antagonism of the receptor itself, ras pathway antagonism, and protein kinase C antagonism.

Reminding the audience that crb2 (or HER-2-neu) is a tyrosine kinase receptor, Dr. Piccart pointed to mounting evidence that overexpression of this protein in breast cancer is correlated with a poor prognosis and with resistance to chemotherapy and hormonal therapy.

The possibility of countering this overexpression by means of an anti-crb2 monoclonal antibody is being tested in an international phase III trial involving women with metastatic breast cancer and Neu gene overexpression. “We are now all eagerly waiting the results of the completed trial which might, if positive, establish an entirely new form of therapy,” Dr. Piccart said.

Anti-ras strategies also represent a clear break from tradition, Dr. Piccart observed. She reported that the EORTC is now launching a phase I clinical trial of an oral inhibitor of ras farnesyl protein transferase. Protein C kinase antisense compounds are undergoing phase I evaluation as well.

This new generation of antitumor agents presents some unique challenges for clinical trialists, she said.

“Investigators may have to abandon objective response rate as one of the primary clinical endpoints in favor of time to progression and pattern of metastatic spread,” Dr. Piccart commented, “since it is likely that some of these new cancer drugs will not be able to induce tumor shrinkage but, rather, could have a favorable impact on the natural history of the tumor.”

For the treatment to be relevant to the individual patient, she continued, “we need pharmacodynamic endpoints to make sure that the target is indeed affected. And finally, the phase I endpoint of the maximum tolerated dose might have to be changed to that of a safe therapeutic dose range.”

Promising approaches to the treatment of metastatic disease, Dr. Piccart said, may include interfering with the process of invasion with agents that inhibit extracellular matrix degradation and blocking tumor neovascularization with agents that inhibit angiogenic peptides, antagonize angiogenic peptide receptors, inhibit angiogenic-peptide-mediated signal transduction, or inhibit endothelial cell proliferation.

While waiting for such agents to reach the clinic, the EORTC Breast Cancer Group is investigating the anti-invasive and antiangiogenic properties of the new pure antiestrogens.

The Group has designed a phase III trial that will randomize patients with biopsy-confirmed breast cancer to receive an intramuscular injection of either a pure antiestrogenic compound or a placebo prior to surgery and adjuvant chemotherapy.

The Hypothesis

“The hypothesis here is that the antiestrogen might counteract early metastatic spread or the growth of distant metastases that could result from the surgical manipulation of the tumor,” Dr. Piccart said.

The researchers think that the pure antiestrogen is a better candidate for this short perioperative use and less appropriate for long-term adjuvant treatment because it lacks the weak estrogenic effects of tamoxifen (Nolvadex).

“If there is a beneficial effect of this compound, it is likely to be small, and therefore we’re going to need a very large patient sample,” Dr. Piccart said. She expressed the hope that the scale of trials permitted by the international BIG collaborative network would eliminate the need for decades worth of repetitive small trials of adjuvant treatment and time-consuming metaanalyses.

Dr. Piccart also acknowledged the contribution of women’s associations as new partners in the fight against breast cancer. “They are now stepping forward to demand improved breast cancer education, appropriate screening, and optimal treatment and care, and I think they are going to help us in identifying some critical issues in breast cancer clinical research and perhaps help us to find increased funding for this research,” she said.

The hope is, she said, that working together, “we may be able to cure more patients or at least convert this lethal disease into a chronic disease such as diabetes, which requires long-term maintenance treatment of low toxicity.”