Robert Bazell - Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer

To Margot, Rebecca, Josh, and Stephanie

And to the memory of Rebecca Donovan who
taught us the terror of this disease
and courage in the face of it

M y greatest debt is to the people who took the time to educate me about the many facets of this storyespecially the remarkable women with advanced breast cancer, the volunteers for the clinical trials, who shared so much of their own experience. To them and to all the others listed in the Notes at the end, my profound thanks for the time spent, especially for seemingly endless follow-up phone calls and e-mails to which I subjected some.

I want to thank Laura Leber of Genentech for facilitating my access to the many people in the company who were willing to talk with me and for responding to my many inquiries, always with patient, good cheer. John Dreyfuss played a similar, wonderfully helpful role at UCLAs Jonsson Cancer Center.

Ann Godoff, now editor in chief and president of Random House, persuaded me to write this book and managed to continue to serve as its editor while she took on all the management responsibilities. I remain in awe. Suzanne Gluck of ICM not only educated me about the need for a book agent but also taught me how the very best in the trade do it. Amy Bernstein provided invaluable assistance with the writing and editing, as did Ruth Coughlin. My special thanks to Carolyn Schatz, my colleague and good friend of sixteen years, without whose research and writing assistance this project simply could not have happened.

My profound gratitude also to the following people who were kind enough to read this manuscript or portions of it during its various stages of development: Josh Bazell, Hank Fuchs, V. Craig Jordan, Al Rabson, Betty Rollin, Lynn Schuchter, Robert Weinberg, Margot Weinshel, and J. Frank Wilson. Their suggestions helped me greatly, but of course I alone am responsible for all the opinions expressed and any errors that might have been made.

by Dr. Mary-Claire King
American Cancer Society professor of genetics,
University of Washington

A fter the British victory at the Battle of El Alamein in 1942, Winston Churchill said, Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.

He was, of course, correct. Churchills elegant language speaks to many of us who are involved in an entirely different kind of war, the one against the multiheaded, insidious, and complex destruction of normal cellular life that is cancer. This is the story of an important and early victory in that war.

The war on cancer was declared in 1971 by Richard Nixon, the unlikeliest of heroes to many of us who grew up in the 1960s, protesting another war. But in putting enormous public resources into cancer research, Nixon turned out to be prescient. For this war on cancer, the strategy was intelligent, albeit unfaithful to the military analogy that had spawned it. In its dependence on individual investigators who were sought out for their keen tactics and for their willingness to take risks, the war was more guerrilla than top-down strategy. To continue the analogy, it was more American Revolution than Vietnam.

The end of the beginning: The story told herein starts with the identification by Robert Weinberg in 1979 of HER2/neu, a gene involved in multiple cancer pathways. Years of more hard work would reveal that Her2/neu could be a target for a new type of breast cancer treatment.

Why is it that twenty-seven years into the war we are only now declaring the first victorythe end of the beginning? Elegant biology often seems obvious after the fact. Vast collections of ideas were spawned by the war on cancermany of them very good, some so good as to be perceived as hopelessly risky. During its early life, the HER2 project was ridiculed, close to impossible to fund, and nearly abandoned more than once.

The translation of this now-obvious biology into drug development and cancer treatment is a drama too good to be fiction. It is uniquely a story of the late twentieth century, and its heroes are peculiarly American: stubborn and straightforward, they can be seen as mavericks, cowboys, lone rangers. The first of these are the scientists: Dennis Slamon, a UCLA oncologist and cell biologist, the son of a coal miner and grandson of a Syrian immigrant; and Axel Ullrich, one of the first gene cloners, who moved from Germany to California and joined the biotechnology company Genentech in its early days. Between them, Slamon and Ullrich discovered the critical role of HER2/neu in breast-cancer development.

To create a drug based on this biology required a great deal of rigorous immunology, largely carried out by scientists at Genentech. Although these scientists were personally committed to the project, it encountered labyrinthine vicissitudes at the hands of a corporate culture that was concerned with the firms sheer survival. Happily, and certainly not easily, a few people with talent in both science and management emerged from this maelstrom.

The other heroes in this tale are the breast-cancer patients and their partners. It is difficult to imagine a more moving love story than the effective tribute of Bob Erwin to his wife, Marti Nelson, a physician who died at the age of forty from metastatic breast cancer before she could be treated with the antibody. Erwin, along with activists in San Francisco who took their cues from AIDS activists, focused on bringing together Genentech management and breast-cancer advocates into a working alliance. Armed with this knowledge of biology and biotechnology management and propelled by grief over his wifes death, Erwin pushed and persuaded and persevered to establish compassionate use of the antibody.

The expense of proving the usefulness of a drug in phase III trials is daunting. Because the appropriate patients were being treated in many widely dispersed hospitals and because many of their physicians had no previous experience with this sort of trial, putting it together was a logistical nightmare.

Enter Fran Viscolawyer, consumer advocate, breast-cancer survivor, and, as chairwoman of the National Breast Cancer Coalition, an extraordinarily competent organizer. Visco learned the science, decided that the NBCC should support the test, and sent information about the trials to thousands of patients and physicians, paving the way for hundreds of women to sign up.

The phase III trial results, revealed in spring 1998, did indeed prove that Herceptin worked as well as anyone dared hope. Because of this, perhaps fifty thousand breast-cancer patients a year will benefit. As Dennis Slamon has said, This is proof of the principle that we can identify whats broken in a cancer cell and fix it.

This, then, is a fable for our time. It is one with many tragic losses and an ultimately happy ending, or at least one that is hopeful. It is a complex biological mystery; a drama of high finance; a series of nonsentimental, intelligent love stories; and a terrific vindication of stubbornness in a good cause.

In all, it proves that good science makes a great yarn.

D ennis Slamon felt his heart pounding. For years, the six-foot-two, robust doctor with the distinctive mustache had fantasized about this moment, but never had he imagined himself so nervous.