Monica Zangwill, MD

Paul Ehrlich, MD, wins the Nobel Prize for his idea that antibodies could be used like magic bullets to treat disease.

Georges Köhler, PhD, and César Milstein, PhD, uncover the technique for producing monoclonal antibodies. The pair win the Nobel Prize in physiology or medicine in 1984.

Dennis Slamon, MD, PhD, and his colleagues publish data showing the link between HER2 overexpression and an aggressive type of breast cancer that affects 20 to 25 percent of the 213,000 women diagnosed with breast cancer each year.

Genentech scientists humanize an antibody directed at HER2 that comes to be known as Herceptin.

Phase III trials for Herceptin completed. Results show that Herceptin in combination with chemotherapy slows the progression of cancer and increases tumor shrinkage in metastatic disease.

Development begins for a diagnostic kit to screen breast cancer patients for HER2 overexpression.

Genentech submits application for FDA approval of Herceptin.

Phase III trials initiated to evaluate Herceptin in the adjuvant setting for breast cancer.

Data from a phase III trial is published in 

 that shows a 25 percent increase in survival rate for women with HER2-positive metastatic breast cancer who receive Herceptin and chemotherapy compared with chemotherapy alone.

FDA approves use of FISH (fluorescent in situ hybridization) gene amplification test for HER2 gene.

Data from three large trials of Herceptin used in the adjuvant setting, presented at the annual meeting of the American Society of Clinical Oncology, show the drug reduces the risk of recurrence by 50 percent in HER2-positive breast cancer patients.

Genentech submits application to the FDA for approval of Herceptin with chemotherapy in early-stage HER2-positive breast cancer in the adjuvant setting.

Articles

A timeline of important Herceptin developments.

Pathway to Herceptin Success

Geary Corves knows a thing or two about the sun and skin cancer. Now 80 years old, he's had more than 30 small skin cancer spots removed over the past 40 years. "I noticed something on my forehead," he recalls about the first time he saw a dermatologist. "It was some kind of sore." Corves' doctor used radiation to remove that first lesion, which turned out to be basal cell carcinoma. Since then, Corves has seen great changes in the medical community's understanding and treatment of skin cancer.

More than one million people will get skin cancer this year, estimates the American Cancer Society. The majority of skin cancers come in two forms: melanoma, which arises from cells in the skin called melanocytes and accounts for approximately 4 percent of all skin cancers, or nonmelanoma skin cancer, which arises from cells in the skin called keratinocytes and accounts for approximately 95 percent of all skin cancers. Other rare forms of cancer, like cutaneous lymphoma or Kaposi’s sarcoma, make up the remaining skin cancers. 

Nonmelanoma skin cancer is divided into two kinds, depending upon which type  of keratinocyte the malignant cells start in. Basal cell carcinomas comprise  approximately 75 percent of all nonmelanoma skin cancers and originate from  keratinocytes in the basal (bottom) layer of the epidermis, the outer covering  of the skin. Basal cell carcinomas usually occur on the face, head, neck or  other skin areas that tend to be exposed to the sun. Squamous cell carcinomas  stem from keratinocytes in the uppermost layer of the skin and account for the  other quarter of nonmelanoma skin cancers. A precancerous lesion called actinic  keratosis often precedes squamous cell skin cancer. People with numerous actinic  keratosis lesions have about a 10 percent risk of squamous cell cancer in their  lifetime. Squamous cell cancer also sometimes presents as a superficial  malignancy called Bowen’s disease. Unlike basal cell cancer, which rarely  metastasizes, squamous cell cancer runs a 5 to 10 percent risk of spreading  throughout the body. 

Over the next few decades, experts expect an increasing number of nonmelanoma  skin cancers will be found, says Vernon Sondak, MD, chief of the cutaneous  oncology program at H. Lee Moffitt Cancer Center and Research Institute in  Tampa. Much of the increase will be related to the greater amounts of current  sun exposure.  You know, 150 years ago people went out in the sunshine totally  clothed from head to toe with big floppy hats, no matter how hot it was, says  Dr. Sondak. During the second half of the past century, however, sun tanning  became very popular and wearing tank tops, shorts and bikinis became acceptable.  As people increased their sun exposure throughout the 20th century, more  nonmelanoma skin cancers developed. Furthermore, while nonmelanoma skin cancers  most often affect people over 50, more men and women are being diagnosed under  age 40.

When I was a kid I spent a great deal of time in the sun, says Corves. He  says that every summer he would burn, then get very dark. At 19 years old he  entered the military and spent a couple of years in India out in the sun without  a shirt. Being fair-skinned and light-haired, Corves skin was particularly  susceptible to the damaging rays of the sun that trigger the skin cancer  process.  I pushed my skin to the limits, he says.

Dermatologists now know that sunlight can directly damage the skin. Sunlight  carries three types of ultraviolet (UV) radiation—waves of electromagnetic energy that  move through the air. UVA radiation has a wavelength of 280 to 320 nanometers  (one nanometer equals one-billionth of a meter), UVB radiation has a wavelength  of 320 to 400 nanometers and UVC has a wavelength of 200 to 290 nanometers. Most  sunlight that reaches Earth’s surface consists of about 90 percent UVA and 10  percent UVB (the ozone layer completely absorbs UVC). Artificial light from  tanning beds and salons also release UVA and UVB.

UVA and UVB both have a relationship to skin cancer, says Desiree Ratner, MD,  director of dermatologic surgery at the Melanoma Center at Columbia University  Medical Center in New York. She explains in an article in 

 that the electric and magnetic components of UV radiation  can penetrate the skin and damage protein or DNA components of skin cells. In  fact, scientists have discovered that UV radiation can induce specific changes,  or mutations, in certain tumor-suppressor genes, the most common of which is  called p53. If a skin cell has one of these damaged, or mutated, p53 genes, it  will probably just die. But, if the skin cell has two of these mutated p53  genes, either because of chronic sun exposure or because the person was born  with one damaged gene already, then the skin cell will undergo abnormal growth  that may lead to cancer. UV radiation can also decrease the  skin cells immune system and, thereby, lessen the skin's ability to detect or  kill off abnormal and mutated cells.

Although the complete effects of UV radiation on skin cells remain unknown,  chronic sun exposure appears to be the biggest risk factor for nonmelanoma skin  cancer.  The more sun exposure you have, the more likely you are to get  nonmelanoma skin cancer, says Dr. Sondak. This may be in contrast to melanoma  where occasional sunburns, perhaps even one, appear to increase the chance of  malignant melanoma. Nonmelanoma skin cancers appear most commonly  on sun-exposed areas, but may occasionally develop in places on the body that  get little sun.

Like Corves, Kathy Bilodeau, a 56-year-old from Connecticut, spent a lot of  time in the sun as a kid.  I grew up in California. I didn't think anything of  it, she says. Unlike Corves, however, Bilodeau has olive-colored skin and dark  hair. About 10 years ago, Bilodeau developed a wart-like growth on her forehead  that would break off and bleed but kept returning. Nonmelanoma skin cancers may  present in many different forms, from small sores to large bumps, which  dermatologists learn to recognize.

After several months, Bilodeau went to see a dermatologist, who removed the  lesion and diagnosed it as squamous cell carcinoma. Since then she has visited  the doctor every six months for total body skin checks. Four other small  cancerous spots have been detected and removed.

Other risk factors, besides sun  exposure, can also make someone more susceptible to developing nonmelanoma skin  cancer. As Corves and Bilodeau experienced, getting one skin cancer greatly  increases the chance of developing another skin cancer, which may be of any  type, including melanoma.

Like Corves, fair skin or light hair heightens susceptibility of developing  nonmelanoma skin cancer. Living in a sunnier climate, higher altitude or closer  to the equator can increase susceptibility, as does smoking, exposure to arsenic  or ionizing radiation and sunbed use. Also, people who have had an organ  transplant or who must take immunosuppressive drugs like steroids for a long  time develop nonmelanoma skin cancer more easily than other people. Recently,  scientists discovered that a common virus, called human papillomavirus, may also  be involved in triggering some nonmelanoma skin cancers.

Genetics plays a big role in risk for nonmelanoma skin cancer. Scientists  have recently traced a genetic defect involved in initiating nonmelanoma skin  cancer to chromosome 9. The genetic defect involves a protein called patched  homologue 1 (PTCH1) that fights the development of tumor cells. PTCH1 is part of  a chain reaction in skin cells called the sonic hedgehog pathway, which has been  detected in some basal cell cancers, says Chrysalyne Schmults, MD, assistant  professor of dermatology at the University of Pennsylvania.  When this pathway  is altered you end up with abnormalities in how rapidly cells proliferate, says  Dr. Schmults. Experiments in mice suggest that the PTCH1 defect may make the  hedgehog pathway more susceptible to the damaging effects of radiation.  Continued research into the genetics of nonmelanoma skin cancer should enhance  the development of preventive methods and treatment strategies for these  conditions. 

Nonmelanoma skin cancers are highly curable with fewer than 3,000 deaths each  year, but they still require treatment, says Dr. Sondak. Nonmelanoma skin  cancers can look disfiguring, they can be a site for infection and, if  neglected, they will grow larger and may spread to other parts of the body.  Removing nonmelanoma skin cancer completely and getting all its roots out will  usually cure it, says Dr. Sondak. Fortunately, he adds, many effective  treatments exist.

One of the most common methods to treat small and superficial nonmelanoma  skin cancers, called electrodesiccation and curettage, involves drying or  burning the spot with electricity and then scraping it off. Other small lesions  or precancerous spots may be destroyed by cryotherapy, which freezes off the  malignant skin. Because these techniques destroy the unwanted skin, the doctor  has no tissue sample to examine under a microscope after the procedure, making  it hard to know if all the malignant cells were removed. For small, superficial  lesions, however, microscopic analysis may not be that important.

A dermatologist or surgeon can surgically cut, or excise, larger nonmelanoma  skin cancer lesions right out of the skin. Excised tissue can be examined under  a microscope to make sure the whole tumor has been removed, but a lot of  surrounding normal skin is frequently cut off with the excised lesion, leaving  large scars that may require plastic surgery or treatment with a laser for  repair.

A more sophisticated surgical method to remove nonmelanoma skin cancers,  called Mohs surgery, was developed in the 1950s. During Mohs surgery, named for  its inventor Frederick Mohs, MD, a specially trained dermatologist or surgeon  removes thin slices of the cancerous area, one by one, and examines each slice  under a microscope until no tumor cells remain. This technique can be time-consuming,  but Mohs surgery is an ideal approach when the nonmelanoma cancer is someplace  where you would like to get the tumor out completely and take a minimum amount  of normal tissue around it, says Dr. Sondak. Skin cancer experts frequently  recommend Mohs surgery for lesions on the tip of the nose, on the edge of the  ear or in the middle of the cheek.

Donna Groon, a 53-year-old teacher who lives on the New Jersey shore, had a  nonmelanoma skin cancer removed by Mohs surgery three years ago.  I had a scaly  mark on my nose that would peel and bleed but just wouldn't go away, she says.  After a biopsy revealed basal cell carcinoma she underwent Mohs surgery to  remove it.  I was very pleased with the results and I have had no recurrence,  says Groon, who underwent laser surgery after Mohs to improve the look of her  skin.

Some people have many small but superficial nonmelanoma skin cancers or  precancerous spots. Topical ointments applied directly on the skin can get rid  of some of these lesions. A cream of 5-fluorouracil (5-FU), a chemotherapy drug,  can burn off precancerous lesions or superficial skin cancers. Corves tried the  5-FU cream four or five times, but it can be messy and burn other areas of the  skin if not carefully applied.

Dermatologists are excited about a new topical  agent called Aldara (imiquimod). Aldara causes a powerful immune response  on any skin it touches and is currently approved for treatment of superficial  basal cell carcinoma and actinic keratosis.  Basically, says Dr. Sondak, the  patient's own immune system rushes in to attack this cream and destroys all  these other cancer cells.  While Aldara shows promise for some small nonmelanoma  skin cancers, it is not as effective as surgical methods for removing larger  skin tumors.

Yet, more options exist for treating nonmelanoma skin cancers. For people who  can't undergo surgery, radiation may be offered. Radiation for nonmelanoma skin  cancer works similarly to radiation for other cancers and usually requires daily  treatments for several weeks. Photodynamic therapy, another nonsurgical method  to treat nonmelanoma skin cancer, involves applying Levulan Kerastick (5-aminolevulinic acid, or 5-ALA) to the skin under a specialized light that  activates the acid to destroy cancer cells. Like other topical treatments,  photodynamic therapy appears most effective for small nonmelanoma cancers or  precancerous areas, says Dr. Schmults. 

Novel approaches to treating nonmelanoma skin cancers appear on the horizon.  Cyclopamine, a drug that blocks the changes to the hedgehog pathway that induce  nonmelanoma skin cancers, is in phase I testing. Another ointment called  Dimericine, made up of a DNA repair enzyme called T4 endonuclease V, or T4N5,  seems to help prevent early skin cancers in susceptible people. An initial study  of Dimericine in 30 people found it significantly decreased the development of  precancerous spots. A phase II trial testing Dimericine as a preventive agent  for nonmelanoma skin cancer is currently under way.

Although many options for treating nonmelanoma skin cancer exist and new  approaches are expected in the future, most experts feel prevention should be  the message when talking about skin cancer.  If you protect yourself, you can  lessen the risk of developing skin cancers over time, says Dr. Ratner. But  dermatologists also recognize that people need not be afraid of the sun. Even  nonmelanoma skin cancer survivors want to enjoy themselves in the sun.

Last year Groon spent seven days in Arizona on vacation. She wore hats and  sunblock with SPF 30 and returned home without a tan. But she still went outside  and rode horseback in the desert.  I did it all, she says, without taking a  risk. It can be done. 

Treating and preventing the nation's most common cancer.

Nonmelanoma Skin Cancer: Saving Your Skin

While most people love the feeling of the warm sun on their faces,  they also hate the intense discomfort of sunburn. Sunburn occurs when prolonged  exposure to the sun’s UV radiation causes irreparable damage to skin cells. Skin  cells contain melanin, which can safely absorb UV rays of the sun. But the  capacity of melanin to absorb UV radiation can be quickly overwhelmed in intense  sunlight. UV rays that are not absorbed by melanin can damage DNA inside the  cell, destroy skin cells and stimulate inflammation, resulting in the redness,  pain and itching of sunburn.

Many things can affect a person’s ability to sunburn, including:

: People with fair skin, light hair and blue eyes are the most susceptible to sunburns because their skin contains the least amount of melanin. Skin of any color, however, can get burned with prolonged exposure to intense sun.

 Certain medications can make the skin  more sensitive to getting a sunburn, even in people who don’t usually burn. Many  of these medications are quite common, including antibiotics like Cipro (ciprofloxacin), anti-anxiety medicines like Xanax (alprazolam) and even some  chemotherapeutic agents like methotrexate.

 Uncommon genetic disorders, like  albinism and xeroderma pigmentosum, can increase susceptibility to sun damage  and sunburns. People with these conditions need to be extremely careful about  protecting their skin in the sun.

Although many popular remedies for sunburn exist, few of them have  been tested in objective scientific studies to evaluate their effectiveness.  Here’s what we know about a few common treatments:

Nonsteroidal anti-inflammatory drug (NSAID) pain  relievers:

 Studies suggest that taking an oral NSAID, like ibuprofen,  may shorten the course of sunburn if the medicine is taken before the redness of  the skin develops or even before exposure to the sun. NSAIDs taken after redness  will reduce pain but have little ability to reverse the injury to skin cells.

Some clinical studies  show that aloe vera gel, which contains some anti-inflammatory chemicals, may  help healing of thermal burns due to heat, but there is no data on its effects  on sunburn. Like other moisturizers or emollients, however, aloe vera gel  provides temporary soothing of the discomfort of sunburn.

Applying  anti-inflammatory corticosteroid ointments to the skin before redness develops  may reduce the total time you have a sunburn. Using corticosteroid ointments  once the sunburn is full blown also soothes the symptoms of itching and pain.

 Oral or topical antihistamines,  such as Benadryl (diphenhydramine), can reduce itching associated with sunburn.  Oral antihistamines also have a sedating effect that may help when pain prevents  restful sleep.

No  scientific studies have shown that using topical anesthetics, like Solarcaine (lidocaine) or Lanacane(benzocaine), on the skin lessen the sun’s damage, but  the cooling feeling of these sprays and lotions should temporarily reduce the  pain of sunburn.

While these remedies will relieve symptoms, most sunburns will  heal on their own within three to five days. Rarely, severe sunburns will result  in blistering, swelling, fevers, chills and/or weakness that require further  medical attention.

Many things can affect a person’s ability to sunburn, including medication and skin tone, but once you get a sunburn, there are certain ways to relieve the pain. 

Sunburn Reasons & Remedies

There are certain emotional moments that we all remember. The birth of a  child. The death of a grandparent. The first time the doctor said, “Cancer.” For  Jen Levinson, a 39-year-old breast cancer survivor from Ponte Vedra Beach,  Florida, one of those moments came in a most unlikely place.

Levinson was diagnosed with stage 2 breast cancer in 2000. Shortly after her  mastectomy she joined a clinical trial of a new anti-cancer drug called  Herceptin (trastuzumab). Five years later, Levinson attended the 2005 meeting  of the American Society of Clinical Oncology to hear the results of the study.  Sitting in the audience as the data was unveiled, she says, was one of the most  moving experiences of her life. “When they talked about the amazing results, ”  she says, “it was really incredible.”

What Levinson heard that day was that Herceptin, when given after surgery to  women with HER2-positive breast tumors, could reduce the risk of cancer  recurrence by almost 50 percent. This was big news. And, as it turns out,  Levinson was not the only one excited by it. Within days, doctors and patients  around the world applauded the news. Few other cancer drugs had yielded such  profound results in clinical trials.

Doctors say the success of Herceptin, which can be used for the 20 to 25  percent of breast cancer patients who are HER2-positive, is astounding. But,  like other great advances in cancer treatment, the path to success was not easy.  Herceptin’s rise to prominence actually took many years and required much hard  work by numerous doctors and thousands of patients.

Back in the 1970s, scientists noticed that certain genes in animal tumors  were involved in turning normal cells into cancer cells. Looking at similar  genes in humans, doctors made some interesting discoveries. They found that one  gene, called the HER2 gene, (HER stands for human epidermal growth factor  receptor) that is present in normal breast cells was overly abundant in some  malignant cells.

With more investigation, doctors learned that the HER2 gene can create a  protein receptor that sits on the outside of cells. This HER2 receptor helps  trigger the chain reactions that cause the cell to abnormally divide and grow.  George Sledge, MD, an oncologist and researcher at Indiana University, says,  "HER2 is involved in pretty much everything you would be interested in for  cancer, including growth, invasion, and metastases.” Further research on those  malignant cells with extra copies of the HER2 gene revealed that not only did  they have more copies of the HER2 gene, but whereas a typical breast cell has  about 50,000 HER2 receptors on its surface, a breast cancer cell can have as  many as 1.5 million receptors.

HER2 is involved in pretty much everything you would be interested in for  cancer, including growth, invasion, and metastases.

In the 1980s doctors began to measure HER2 in the tumors of women who were  newly diagnosed with breast cancer. Using an immunohistochemical (IHC) analysis  that measures the receptors on the outside of the cell or a fluorescent in situ  hybridization (FISH) analysis that measures the copies of HER2 genes inside the  cell, doctors can look for HER2-positive cells in breast tumors. Tumors with a  2+ or 3+ reading on IHC are currently considered to have too many copies of the  HER2 protein receptor (referred to as “overexpression”) and are HER2-positive. A  positive FISH analysis, which registers an excessive number of copies of the  HER2 gene (referred to as “amplification”), is also considered  HER2-positive.

As doctors began testing more women for HER2 in the 1980s, they found that  women with HER2-positive tumors had a worse prognosis than women with  HER2-negative tumors. Women with HER2-positive tumors tended to have recurrences  of their cancer or developed metastases more frequently than women who were  HER2-negative. This early finding was disappointing. But, early on, some  scientists saw a silver lining in this dark cloud. All those little copies of  HER2 were just sitting on the cell like ducks in a row waiting for a specialized  drug that targeted just the HER2 receptor—a drug that homed in on those cells  with excess HER2 receptors, effectively picking them off and dismantling their  cancer-causing apparatus. It was a great idea but one that required creating a  new drug in the lab out of monoclonal antibodies, drugs that attach to proteins  on the surface of cancer cells and interrupt the cell’s growth signals. A few  years later, Herceptin was born.

"Herceptin targets HER2 receptors outside of the cell,” says Sledge,  which allows it to specifically attack cancer cells. A bonus effect of the  targeted mechanism of Herceptin is that it does not affect other fast-growing  cells like those in the hair follicles or stomach lining.

After the initial studies with women who had advanced breast cancer showed  very promising results, the Food and Drug Administration approved Herceptin in  1998 for metastatic HER2-positive breast cancer. Although the drug was approved  for weekly use, clinical trials have found Herceptin to be just as effective  when given every three weeks and tripling the approved dose to 6 milligrams per  kilogram of body weight.

In the early 2000s several phase III clinical trials began to test Herceptin,  which costs up to $60,000 a year, as first-line treatment after surgery for  women with early-stage HER2-positive breast cancer. Levinson joined one of these  clinical trials in 2000. “I enrolled in N9831,” she says about the designation  of her trial, and was randomized to the arm that got Herceptin.” In the NCCTG  (North Central Cancer Treatment Group)-N9831 trial, Levinson had an equal chance  of being placed in one of three groups. All three groups received standard  chemotherapy with Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide)  followed by Taxol (paclitaxel). One group got Herceptin for one year starting  at the same time as the Taxol treatment; a second group got Herceptin for one  year but did not start the drug until chemotherapy was completed; and a third  group, called the control arm, only received chemotherapy. Levinson was one of  approximately 2,700 women who participated in the trial.

A similar clinical trial called NSABP (National Surgical Adjuvant Breast and  Bowel Project) trial B-31 began in February 2000. This trial, which treated more  than 2,000 women with early-stage HER2-positive breast cancer, had two groups.  Both groups received Adriamycin and Cytoxan followed by Taxol, but only one of  the groups also got one year of Herceptin, which was started at the same time as  Taxol.

Because the B-31 and N9831 trials were so similar, the trials’ investigators  pooled their results for analysis and presented them at last year’s ASCO  meeting, where Levinson heard them. Like everyone else, the investigators were  amazed with the results. “The differences between the groups were huge,” says  Edith Perez, MD, a principal investigator of the N9831 trial. “Herceptin really  improved outcomes when added to chemotherapy.”

A large international trial called HERA (Herceptin Adjuvant Trial), which was  also discussed at last year’s ASCO meeting, found almost exactly the same  results as the American trials. The HERA trial, which involved almost 5,100  women, provided more good news because it showed that giving Herceptin  immediately after chemotherapy could still reduce the risk of recurrence.

When the data from these three trials (N9831, B-31, and HERA) were released at  ASCO, the future for many women with HER2-positive breast cancer turned around  almost overnight. Levinson could sense it when she heard the results. “I felt so  lucky to have been part of that trial because it was groundbreaking.” No longer  did having a HER2-positive tumor mean a poor prognosis. Herceptin could beat  HER2-positive breast cancer in many of the 250,000 women diagnosed with the  disease around the world each year. Genentech, the maker of Herceptin, filed for  additional approval of the drug in mid-February for early-stage HER2-positive  breast cancer. If the application receives priority review status, the FDA will  have to make a decision by August.

The latest study results ushered in a new era in treatment of HER2-positive  breast cancer. But questions remain. The American trials gave Herceptin with  adjuvant (after surgery) chemotherapy. The international trial gave Herceptin  after chemo was finished. Which was better? In general, giving combinations of  drugs at the same time is more effective because the cancer cells are  essentially surrounded and pummeled from all directions. But giving one drug at  a time tends to reduce side effects. Herceptin was effective in both scenarios,  which led to the question of whether it should be given to women with  early-stage disease who finished chemotherapy months beforehand.

"Theoretically, you should still get an effect from  Herceptin as you go out further from initial treatment,” says Debu Tripathy, MD,  director of the Komen/University of Texas Southwestern Breast Cancer Research  Program in Dallas. “Although, that effect may diminish the further you go out,”  he adds, "and at some point you cross the line where the benefits are smaller  than the risks.” But, no one knows where that crossover line may lie, and that  line may be in a different place for women who are at high risk for recurrence  versus low risk. Continued monitoring of the women from the clinical trials may  eventually provide more answers. Patients who are interested in starting  Herceptin will need to have a one-on-one discussion with their doctors to weigh  their own risks and benefits. For women who finished chemotherapy more than a  year ago, the possible benefit of taking Herceptin is unknown.

Also still under investigation is how long the drug should be given. While  most trials tested one year of Herceptin therapy, other trials are testing  longer as well as shorter durations of treatment to determine how to most  effectively prevent breast cancer recurrence. Duration of treatment may also  affect the likelihood of cardiac toxicity, which, according to the clinical  trial results of 2005, occurs in 1 to 4 percent of women on Herceptin.

A large clinical trial called BCIRG 006 (Breast Cancer International Research  Group) tested whether different Herceptin and chemotherapy combinations could  decrease the chance of cardiac side effects. Diane Nathan, a 55-year-old from  Delray Beach, Florida, entered the BCIRG 006 trial in 2003 after a routine  mammogram found a 1.2-centimeter HER2-positive breast tumor. “I was thankfully  randomized to an arm with Herceptin,” she says.

The BCIRG 006 trial had three groups for comparison. Nathan was in the group  that received chemotherapy with Adriamycin and Cytoxan followed by Taxotere (docetaxel) plus Herceptin. The second group received chemotherapy without  Herceptin, and the third group was given carboplatin, Taxotere, and Herceptin.  Nathan continued taking Herceptin for a year and underwent numerous heart tests  to monitor her heart function. “I found Herceptin to be a very tolerable drug,”  she says. She had no heart damage and no significant side effects. Plus, she has  not developed a recurrence or metastases since her diagnosis.

Nathan’s experience contributed to the results of BCIRG 006, which were  released at the San Antonio Breast Cancer Symposium in December 2005. The trial  data again showed that Herceptin decreased the risk of recurrence by almost 50  percent. The trial also revealed that the risk of heart damage was less when  Herceptin was given without Adriamycin. The data suggest the benefits of  Herceptin can be obtained despite removing Adriamycin, a drug that belongs to a  class of older chemotherapy drugs called anthracyclines, which can raise the  risk of heart damage. However, studies suggest that anthracycline-containing  Herceptin regimens should be used to treat a specific subgroup of HER2-positive  breast cancer patients—the approximately 40 percent of patients whose tumors  co-amplify a gene called topoisomerase II alpha. The topo II alpha gene and HER2  gene are located close to each other on chromosome 17, which can sometimes  result in amplification of a large segment of the chromosome that includes both  genes. Because topo II alpha is a known target for anthracyclines, doctors can  determine the best Herceptin combination for each patient.

Herceptin has ushered in a new wave of targeted treatment for breast cancer.  In fact, new drugs that target other parts of the HER2 receptor or HER2 chain  reaction are already in the works. A drug called Tykerb (lapatinib) targets the  portion of the HER2 receptor that sits inside the cell as well as the HER1  receptor, also known as epidermal growth factor receptor (EGFR). Preliminary  data from a phase II study of Tykerb in women with advanced or metastatic  HER2-positive breast cancer showed positive results. Tykerb may be filed for FDA  approval in breast cancer within the next year. The drug also appears to  penetrate into the brain, which may allow it to work for women with brain  metastases.

Oncologists expect that Tykerb may actually be most effective when given in  combination with Herceptin. “The hope is that if you give the old ‘one-two  punch’ on HER2 by targeting both the outside and the inside portions of the  receptor, you will get more effectiveness than just targeting either alone,”  says Sledge. A phase I trial demonstrated that combining Tykerb and  Herceptin was well-tolerated and safe in women with advanced or metastatic  HER2-positive breast cancer. Armed with these early promising results, larger  studies are currently under way to assess Tykerb in combination with  Herceptin.

Another drug called Omnitarg (pertuzumab) blocks the HER2 receptor from  setting off the chain reactions that lead to cancer growth. Omnitarg, however,  is still in the very early stages of development and may actually turn out to be  more effective in other types of cancer besides breast cancer.

The overwhelming success of Herceptin has motivated doctors to look for more  specific targets in breast cancer tumors, including targets in women with  HER2-negative cancers. “There is more work ahead,” says Perez, “but it’s  been wonderful to see the product of research and the product of volunteerism of  patients.”

Nathan and Levinson are also grateful for all the hard work that was put into  their treatment. Levinson, who restarted Herceptin after a recurrence of breast  cancer in 2003 and is now disease-free, strongly advocates participating in  clinical trials. “People with breast cancer are not all the same and there’s no  one-size-fits-all solution, so it’s only with clinical trials that we’re going  to get the answers,” she says. More trials and more research are under way.  Herceptin appears to be only the beginning.

In general, giving combinations of drugs at the same time is more effective because the cancer cells are essentially surrounded and pummeled from all directions. But giving one drug at a time tends to reduce side effects.

Eight years after its approval, Herceptin emerges as the best weapon against  HER2-positive breast cancer.

Monica Zangwill, MD

Pathway to Herceptin Success

Nonmelanoma Skin Cancer: Saving Your Skin

Sunburn Reasons & Remedies

Herceptin in the Spotlight

Latest News