Biology 207Spring 2004
Biology of Cancer
Her-2: Summary of Chapters 7-12
THE PATIENTS
Mary Bonesco
--1991, age 47 identified benign cysts
--2 years later found lump in breast--very large tumor
--no risk factors
--found first oncologist condescending--walked out
--refered to new oncologist with connections with Her-2 phase II trials
--first prescribed chemotherapy to reduce tumor size
--modified radical mastectomy
--started to look into bone marrow transplant treatment
--cancer returned along mastectomy scar 3 weeks after surgery
--opted to join Her-2 trial with option to choose other therapies if it failed; 11 week treatment period.
--documented her recovery with photographs--complete remission
Marti Nelson
--an MD in ob/gyn also married to a PhD biologist
--diagnosed with breast cancer at age 33 in 1987
--had surgery and asked for chemotherapy before chemo was routinely given
--recurrance of cancer 3 years later; chemotherapy repeated with different mixture
--nausea side effect
--recurrance of cancer in 1993 along mastectomy scar, radiation treatments, cancer found to have metastasized
--pathologist identified the cancer immediately but tried to hide it from the patient
--fought to have access to Her-2 treatment; was Her-2 positive, but died before she could try the treatment
Kathy Crooks
--1994 diagnosed with inflammatory breast cancer at age 43
--inflammatory breast cancer in rare form of the disease tha causes skin to turn red and the breast to swell rapidly; put on mixture of chemo drugs.
--had lumpectomy that didn’t remove all of the tumor followed by a modified radical mastectomy. Cancer had spread to lymph nodes. Also had follow-up chemotherapy and radiation therapy.
1995--cancer free based on tests
1996--cancer had recurred and metastasized to her lungs; her doctor got her into the phase III trials for Her-2.
Saw no improvement after several weeks; guessed she was on placebo and asked to be switched to Her-2. With Her-2, she started to improve.
1997--brain metastasis; required radiation treatment of brain tumors
Later, her cancer returned to other organs, although the brain tumors were under control. Put on cisplatin and herceptin and is in remission.
Anne McNamara (cont.)
--Recurrance of cancer in lymph nodes
--High dose chemotherapy/Bone marrow transplant option--self donor
(autologous bone marrow transplant=ABMTs)--insurance coverage?
$100,000-300,000 cost
--switched to CAF combination therapy, more extreme side effects
--went through with the transplant
--heard about Her-2 in 1995 in Boston Globe article
--had her tumor tested--turned out to be Her-2 positive
--Jan. 1996 entered “649” group receiving antibody and no chemotherapy
--within 9 months most of her tumors had regressed
--in 1997, her cancer had again recurred; pushed for modifying the Her-2 protocol; in a modified treatment involving interferons and continued Her-2 treatment, she is again is remission.
THE CLINICAL TRIALS
Phase I: Determine toxicity. Slamon/UCLA 15 patients
Phase II: Test dosages and effectiveness. UCSF/Larry Norton at Sloan-Kettering (NYC) 43 patients 22/43 cancer continued to progress; 14/43 disease stayed same; 11/43 drug provided some benefit; 1 complete remission UCLA tested Her-2 antibody +cisplatin (chemotherapeutic drug): 1/2 showed benefit; 1/4 strongly responded to treatment.
Phase III: Test drug on many patients in anticipation of its release. Many sites
Costs in excess of $100 million. Usually only can be carried out by large pharmaceutical companies. Requires large supplies of drug to be tested, thus new plant needed.
Special problems with Her-2 phase III trials:
--Genentech inexperienced at getting pharmaceutical products through this phase
--lack of staff oncologists
--unethical to use Her-2 without adjuvant chemotherapy as chemotherapy known to have some effectiveness?
--choice of cisplatin as chemo agent--cisplatin alone could not treat breast cancer
--opted for different chemotherapeutic agents in phase III--CA
--protocol submitted ”648” 450 patients 1/2 CA +Her-2 antibody; 1/2 CA + saline “double-blind test” meaning neither patients and investigators know which treatment each patient receives. Two smaller trials, 100 patients each, to ask if antibody alone was effective in treating disease unresponsive to chemotherapy “649” and to test on women who were willing to try the Her-2 treatment but not chemotherapy “650”.
--648 trial (key trial) slow to enroll patients
--added a taxol treatment subgroup to the 648 trial, which increased enrollment
--trial still was failing, had to be redesigned; here patients and doctors would know who was getting the antibody; an outside panel looked at results
--started a PR campaign and enlisted NBCC organization
--both 648 and 649 trials ultimately provided data in support of FDA application
--649 study--213 patients; 8 had complete response; 26 had partial response; in at least 30% tumors did not grow.
--648 study--49% taking Herceptin and chemotherapy saw 1/2 or more of their cancer disappear; only 32% with chemotherapy alone saw same response. Best results were in combination with Taxol.
Drawbacks of Her-2
--only works on Her-2 positive tumors (25-30% of tumors)
--can’t treat metastases in the brain
--can worsen the cardiac muscle weakening side affect of adriamycin treatment
--fever and flu-like symptoms from the first treatment (40%) can be controlled with Tylenol and Benadryl.
THE BREAST CANCER ACTIVISTS
“compassionate access” to new chemotherapeutic drugs, Her-2
role in designing phase III trials
BCA: Breast Cancer Action
ACT-UP: AIDS advocacy organization of Bay Area
Tactics: fax/phone zap on Genentech
funeral procession on campus of Genentech (Her-2 developer)
request meeting with company
NBCC: National Breast Cancer Coalition: lobbied for breast cancer funding in Congress
Activists achieved: Her-2 treatment lottery--patients must be Her-2 positive, must agree to be treated in hospital based experimental program. >300 women had access to drug before FDA approval through this vehicle; data from these women helped gain
FDA approval
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