Frontiers in Breast Cancer Research, Diagnosis& Therapy

9/18-9/19/97

The audience was composed of researchers primarily, many from NIH, physicians from around the country, a few nurses, genetic counselors, administrators and Ann Fonfa and Helen S.(one of the founders of the New Horizon committee at SHARE.

The first session was held on Genetics and Public Policy. As activists we have discussed these issues many times, for the researchers and some physicians this was new ground.

Most of the talks centered around genetic counseling with an emphasis on confidentiality. A survivor spoke, Mary Jo Ellis Kahn(co-chair, Heredity Susceptibility Working group of the National Action Plan on Breast Cancer). She spoke on how it felt to be in a "high risk" family. One of her daughters does not want to know her status and one does. Family issues involve alienation of those with the gene from those without-called survivor guilt.

She discussed the problem of the lack of clinical trials or studies of younger women. Nothing is known about follow-up through mammography over a 20-30 year period(high risk young women) or the results of prophylactic mastectomy as a preventive.

Another issue was possible genetic testing in utero(an issue even for clinical trials). This obviously could be used to halt pregnancies.

Cost was discussed, Medicare pays $65 for genetic testing. Even private companies are not fully reimbursing test subjects.

One physician questioned whether it was ethical to withhold results from insurance companies. The speaker suggested using another doctor or another name to avoid having to report at a time when there are no laws to protect patients. I suggested that there was an ethical problem with insurance companies who would use this information in a discriminatory way. There is no real confidentiality as hundreds of people actually have access to the medical records(especially in the age of computers).

An important point made in this discussion-the severity of the disease cannot be predicted in women with the susceptibility genes(BRCA1, BRCA2). They do not necessarily get the most aggressive cancers. In ovarian cancer, current thinking indicates there may even be a benefit conveyed. This is very important because the only preventive currently offered is bi-lateral prophylactic mastectomy. If a woman was destined to develop Stage 1 breast cancer, she might want to keep her breasts and do the generally accepted treatment. Additionally, there is a new way of looking at penetrance. It had been accepted that women with these genes had an 85% chance of developing breast cancer. That is reduced to 65% now. In ovarian the numbers have gone from 40-60% to 15% chance.

A chemopreventive mentioned in this context is the use of Vitamin A-retinoids to prevent cancer in the contralateral breast which has been shown to work as well as tamoxifen. (Milan study)

A. Kallioniemi, M.D. on the staff of the Human Genome Research Institute spoke about CGH which is comparative genomic hybridization. It is felt that this method of looking at DNA amplification sites may significantly contribute to knowledge of the progression of breast cancer. There may be a common stemline but often a very distant relationship between primary and metastatic lesions. Perhaps not a direct precursor but a product relationship-to be explored.

Francis Collins, director of the National Human Genome Project spoke about the many as yet unidentified gene mutations that may affect breast cancer. He recommended checking out the NIH home page: www.nih.gov which has useful information. He mentioned the Center for Inherited Disease Research at Johns Hopkins, Baltimore, MD which is run by 8 groups and offers help in reviewing clinical trials in this area. For clinicians, he mentioned a recent JAMA article March 26, 1997 Wylie Burke, MD, PhD. et al "Recommendations for follow-up care of individuals with an inherited predisposition to cancer".

The second session was entitled: Molecular Biology & Biochemistry.

Dr. Frank Rausher, III of the Wistar Institute spoke about BAP1 a carboxy -terminal hydrolase which binds to BRCA1. He said it may be involved in enhancing BRCA1 to mediate growth suppression This research was sponsored by the Susan G. Komen Foundation.

Dr. Robert Clark spoke about antiestrogen resistance. He talked about a steroidal compound ICI 182,780 (Faslodex)that may or may not be cross resistant to tamoxifen. His abstract states: "Antiestrogens induce responses in approximately 70% of all breast cancers that express the nuclear receptors for estrogen(ER) and progesterone(PgR). Despite the high response rate, a significant proportion of patients, particularly those with metastatic disease, will recur." He said that ICI 182, 780 appears to be pure antiestrogen and is probably not going to cause endometrial problems. It was felt that antiestrogen binding sites could confer resistance to tamoxifen but not confer resistance to ICI 182, 780(meaning it could work with more women).

Dr. Mark Danielsen, Ph.D. said that it was generally accepted that most if not all breast cancers are initially dependent on estrogen in order to grow. This has led to the development of endocrine therapies for treatment of estrogen-receptor positive disease. However some tumors progress from dependent to independent(this has been observed in prostate cancers also). Researchers are seeking to understand this. It seems that based on data from his work, they predict that women with estrogen positive breast cancer but who do not express a tumor suppressor Retinoblastoma(pRB) would be less likely to respond to tamoxifen and its ilk. There possibly are multiple mechanisms that lead to inactive estrogen receptors.

A talk given by Dr. Jerry Shay, Ph.D. was about the role of p53 and telomerase. P53 is a tumor suppressor gene which can be silenced in one of several ways. This is considered the first stage in how normal breast cells obtain unlimited division potential. The second stage refers to "upregulation" of telomerase(a ribonucleoprotein complex that is a repeated DNA sequence protecting the end of a chromosome) which is a critical 'event'contributing to unlimited cell growth.

His study was conducted to determine when telomerase could be detected in the progression to breast cancer. This knowledge may be able to be used diagnostically or as a treatment. 91% of the breast tissue specimens from women with advanced breast carcinoma showed telomerase activity while non of the control group(women without breast cancer) did. It has to be stressed that this is a very preliminary finding. "There is much that remains to be understood and additional validation studies will be required before knowledge of telomerase activity will be useful in a practical sense for decisions regarding patient management." The references offered on this research include papers from 1988. There were 42 references listed!

The next speaker was Dr.Marti Jett on Studies of Therapeutic regimens which target bioactive lipids in breast cancer. "The importance of this study is that it will be a mechanism to identify which drugs are inducing apoptosis(cell death) or are arresting cells in specific phases of the cell cycle and reveal additional therapeutic, diagnostic and intervention strategies to use in combating breast cancer".

The second day offered more on Molecular Biology & Biochemistry.

L. Wakefield, Ph.D. spoke about the TGF- system in the genesis and prevention of breast cancer. These are transforming growth factors which are inhibitors of epithelial cell growth(breast cells). They may also act as tumor suppressors in the colon and pancreas. This substance has been researched since 1987.

The conclusions: "...the biological activities of TGF- are complex, and it appears that if the tumor cell loses responsiveness to TGF-s, locally increased TGF- levels may actually promote tumor genesis(growth). Thus, strategies to increase TGF- levels in a preventive or therapeutic setting must be coupled to a knowledge of the TGF- response status of the target cells. " She stated that development of a pharmacologic to increase expression locally in the mammary gland or to restore TGF- response is a rational new approach to chemo prevention. Retinoids(Vitamin A) and Deltoids(Vitamin D) appear to regulate this substance.

This concept of a substance working both for and against tumor growth seems to occur often. Researchers are finding a similarity in this. Sometimes a substance is actively suppressing tumor proliferation and later in the development may aid growth of tumor cells.

Dr. Edison Liu, M.D. spoke about protein kinases in breast cancer. These are like electrical switches that tell cells to grow, differentiate and change shape. He showed charts on the affect of high dose chemotherapy on patients with higher expression of Her-2. There was a better rate of survival by a few months for patients in that category, relative to the survival of women with lower expression of Her-2. Doses were being tested in this study-women without Her-2 overexpression showed no difference in survival at any of the dose levels. He did state that women who overexpressed Her-2 and p53 tended to have the least good survival rates. "The data suggests that only narrow subgroups of breast cancer patients respond to specific therapies, underscoring the potential clinical utility of molecular profiling in treatment selection."

Pat Steeg, Ph.D. Chief, Womens Cancers Section, Lab. of Pathology, NCI spoke about a substance called Nm23. The reduced expression of Nm23 significantly correlates with poor prognosis. It is found in breast and ovarian cancer and some others.

On the second day, there was another discussion on genetic testing. This time Dr. Neil Holtzman spoke. He is the Director, Genetics & Public Policy Studies Chair, Task Force on Genetic Testing-NIH/DOE. He made a very strong point that we keep in mind laboratory errors. He showed that 32% of biotech companies are doing genetic testing and 9% of non-profit organizations are also engaged in some level of testing.

If a lab plans to sell a kit or have other laboratories do their test, they need FDA approval or an IRB. If they offer direct laboratory services, FDA has declined to become involved. The vast majority of organizations developing tests do submit to quality assurance but a minority do not even do that. He then went on to speak about the brochures offered consumers for genetic testing. He said: 100% describe the condition; 60% describe treatment options; 50% test performance; 25% discuss the intended use/purpose; 35% offer interpretation of how it's done; and 15% discuss risks and benefits. He said that 4 labs currently offer BRCA1 and 2 testing. Myriad, Oncor Med etc.

There was no real information about risk reduction from prophylactic mastectomy because very little is known. There is very little data on that or the effects of mammography or radiation. There are inconsistencies among the labs and very little review of quality or the nature of the test. Many studies are needed. He said activists input is required. 30-40% of medical schools have no coursework on genetics currently. It is important to insist that medical boards have specific questions on genetic testing issues so that courses will be offered. And, of course all the issues usually raised on this topic including the fact that there may be other areas for mutation on the gene and are not yet discovered.

Dr. R. Brem spoke about Breast Imaging. She said that breast cancer accounts for 29% of cancers in women and 16% of all deaths. As we know, there is no method of prevention. In 1970 7.9 million mammograms were performed annually, in 1996 it rose to 29+ million. This is about a 50% compliance level nationally in contrast to the 90% for pap smears. In 1970 about 40% of tumors were 1 centimeter or less. In 1990 that rose to 75%. In 1972 2% were in situ, in 1988 it was 30%.

She mentioned the factors that reduce the success of mammography: dense breasts(found in younger women and women on HRT/ERT); post surgical(due to scarring) and women with implants.

The new possibilities include digital mammography, computer aided diagnosis, MRI(expensive), scintimammography and ultrasound. She reminded the audience that only 25-35% of breast biopsies are malignant! In the case of fine needle aspirants, 15-77%(a ridiculous figure) gave insufficient samples.

She described large core biopsy, ultra and stereotactic as well as vacuum assist(mammatone) and ABBI. This last consists of a woman lying face down on a table, her breast is dangling through a hole. The computer generates and image in 3 seconds with digital viewing. A needle is guided into the mass digitally. A sample is taken and goes to surgical pathology. It is FDA approved for biopsy only. The system can remove a less than 2cm tumor completely in one pass, leaving it intact. This is felt to reduce the risk of random cancer cells escaping into the blood stream. There is no breast compression and a real time viewing of the needle in the breast can take place. Patient acceptance is 91% according to Dr. Brem.

Mammatone yields a 30% larger sample and works better with microcalcifications. Up to a 15mm are is excised. A titanium clip can be placed where the tumor sample was taken out.

Atypical hyperplasia cannot be core biopsied.

She reminded the audience that a second reading of any mammogram usually yields up to 15% better detection. Operator error has a large effect.

Computer aided diagnosis involves a mammogram actually placed into a reader in a computer. It is seen on a viewer. The program usually counts the number of spots, the distances, etc. This method picked up 30% more breast cancer up to one year earlier according to a study. The final diagnosis is still up to an radiologist. Dr. Brem suggested that full field digital mammography would be an excellent tool.

The scintimammography is a nuclear medicine exam for diagnosis. The patient lies on her back, an injection is given in the contralateral(opposite)arm. The image appears onscreen 5 minutes later. It has an 83% predictive value. Negative readings are 89% accurate. When viewing the axillary, it is 90% correct for positive findings and 84% for negatives. The resolution is not good enough for anything under 7mm.

An MRI has a 99.7% negative correlation and an 83.7% positive. (from a 1992 study at Kaiser Institute). It is useful in viewing multifocal disease and axillary nodes.

A presentation was made by Dr. Bernard Fisher-a review of clinical trials and their value. He said that trials are misunderstood by clinicians, patients and researchers. (leaving who to understand them?) They are used for hypothesis testing, obtaining a natural history, evaluating therapy and conducting clinical research.

Trials should provide a rational role for: establishing clinical practice guidelines and play a role in health care delivery. The first clinical trial was conducted in England in 1948 and in the U.S. in 1958. He gave a brief history of the beliefs affecting breast cancer treatment and related these alternative hypotheses: no orderly pattern of dissemination of tumor; systemic disease by time of diagnosis; variations of local-regional therapy unlikely to affect survival.

1972 saw the first trial on systemic treatment. The 1985 NIH Consensus conference called for chemotherapy for node positive women regardless of their ER status and whether pre or post-menopausal. For node negative women, no therapy was recommended.

He discussed the trial B14 that yielded information on tamoxifen. He reiterated that they found no benefit for tamoxifen after 5 years. He said patients did better on placebos after that time.(talking about survival)

He mentioned B-04 which compared radical mastectomy with total mastectomy and total mastectomy with radiation. It is now 20 years out and shows no difference in any arm in terms of survival or distant disease-free survival. B-06 compared lumpectomy with total mastectomy and lumpectomy with radiation. Again, they found no difference in survival or distant disease-free survival. However, there was a higher recurrence rate without radiation. 40% without versus 10% with radiation.

He spoke about preoperative chemotherapy saying that the breast tumor was reduced in 80% of patients. This allowed the opportunity to offer lumpectomy as treatment. The number of node negative patients increased by 37%. But again, no change in distant disease-free survival was shown. A paper will be published on this method. He said there were many trials now on preop chemotherapy. There has "never been a study that demonstrated when to give chemotherapy".

Dr. Wiliam Dooley's talk was about a patient empowerment model used in his breast center. The idea began with "What if we allow patients to define what is best for them?" They began monitoring patient satisfaction with outcomes. Patients are allowed to make a decision about lumpectomy versus mastectomy because "there is no medical difference in survival". The survey they used with patients showed that the critical time was at first encounter between a doctor and patient, that it encompassed all components of care. It was important for all family members to know the expectations of others within the system.

Dr. Dooley stated that the surgery section was told to encourage the patient's support team, define its current role and define disease specific role, telling the patient what is normal, what to expect and what is abnormal. They were told never to let patient concern be unanswered. They also found that anesthesia caused many problems for patients including nausea and vomiting. Changes were made.

They also taught arm exercises, gave patients time to think over their decisions and did pre-counseling on pathology results over the phone.(Patients did not get told to come see the doctor as soon as possible with diagnosis withheld until then). Post-treatment slump was handled by lifestyle counseling at that point. They also offer out-patient mastectomy if desired. When surgeons and other participants were given feedback, they took a while to adjust to their new roles but Dr. Dooley is confident that they will remain ahead of SEER statistics in all patient related areas.

Dr. Gary Kelloff, Chief, Chemoprevention Branch, Div. Cancer Prevention & Control, NCI explained that since the 1960's, chemoprevention has meant the inhibition or reversal of carcinogenesis(before malignancy) by intervention with chemical agents. He showed a time line that indicated that atypical hyperplasia in the breast might take 14-18 years to become DCIS and then another 6-10 to become carcinoma.

There are currently 39 chemopreventive clinical trials in phase II/III. These substances are pharmaceutical products including: Vitamin A(retinoids, D(deltoids), orange peel(modified citrus pectin) and lavender oil(perillyl alcohol congeners), curcumin(spice turmeric), Ibuprofen, lycopene(tomatoes), indole-3-carbinol(cruciferous vegetables), seleniumethione, and green tea (for colon) and SERM(serum estrogen, i.e. toremifene), DHEA analog and NSAID's,

He said they are indeed studying these products in combination as well. The idea is to see how they effect mutagenesis(beginnings of malignancy)apoptosis(programmed cell death), differentiation(more is better) and proliferation. They are using populations with DCIS and LCIS to see if they are modulated by the chemopreventive agents. This way it is felt they could have shorter, less costly trials as these biomarkers could serve as surrogate trial endpoints.

Dr. Sheldon Feldman of Benedictine Hospital, Kingston, NY spoke about his experience with sentinel node biopsy. Using gamma probe localization in the non-randomized multicenter clinical trial, sentinel node resection and complete axillary dissection on 56 patients with invasive breast cancer. They were able to identify sentinel nodes in 51 of the 56. 13 of these patients had node involvement but 4 of them were false negatives (all four had large excisional biopsies). They also failed to find sentinel nodes at all in 5 patients. Their"early findings suggest that large volume excisional biopsy may cause lymphatic distortion making gamma probe localization less reliable". They are now "prospectively evaluating patients with diagnosis made by core needle biopsy to assist if in the larger group the false negative rate will be reduced." No false negatives have been found in patients who had core biopsies. Many cancer centers and hospitals are now offering sentinel node biopsy as an alternative to axillary node dissection. In Stage 1 women, no further surgery would be required. Obviously the risk of lymphedema would be greatly reduced especially if they do not then have radiation.

Interestingly, the first sentinel node presentation was given at Sloan by Ramon Cabanas in 1976.

Lee Pai, M.D. spoke about recombinant immunotoxins. These "are a class of potent targeted cytotoxic agents composed of a bacterial or plant toxins linked to an antibody targeting moiety." LMB-1(1st generation) is one. It has shown excellent anti-tumor activity in vitro and in nude mice bearing tumors. erb-38, a single chain immunotoxin was made to react with Her2/neu. Approximately 30% of women with breast cancer overexpress Her2/neu. In ovarian cancer, it is about 25%. A Phase I clinical trial using erb-38 will open for patient accrual fall of 1997 at NCI Medicine Branch, Bethesda, MD. Tumors must express Her2/neu with no neutralizing antibodies.

M.J. Kennedy, M.D. of Johns Hopkins spoke about the future of breast cancer chemotherapy. "Systemic combination chemotherapy administered to women with breast cancer in the adjuvant or metastatic setting has to date had only a modest impact (my emphasis)on clinical outcomes". "For women with involved lymph nodes this translates into an absolute improvement in survival of about 6% at ten years after diagnosis. While these absolute numbers are small, the public health impact of such therapy can be substantial due to the frequency of this malignancy".

Dr. Kennedy proposed 3 strategies: Optimize currently available drugs; Introduce new agents; adopt new strategies. He then stated that dose response in breast cancer is "rather shallow". He said that NSABP Protocol 22 & 25 demonstrated that higher doses of cytoxan(cyclophosphamides) do not get better results but can lead to leukemia. The group that may benefit from high dose chemo is the 30% of patients who express c-erbB2(also called Her2/neu). When these women also overexpress P53, the best results ensue.

He also said that although several small randomized studies suggest that stem cell support may prolong disease-free survival, but has not yet been conclusively demonstrated for women with metastatic disease. Some good results reported may be due to patient selection or improved efficacy.

A small randomized study of high-dose chemo administered in an adjuvant setting has recently been reported in abstract form and no improvement in outcome has to date been observed. But the future role of high-dose therapy will be determined by the results of several large intergroup randomized trials currently accruing patients. Currently the disease-free range after BMT is 10-15% to 5 years. He also pointed out that if studies are stopped early, they can show better benefits.

The combination of adriamycin and taxol showed high response but high levels of congestive heart failure. Taxotere response is lasting 6 months on average. It is compatible with adriamycin.

He indicated that doxcil(liposome delivery) may act the same as a lower dose of adriamycin.

His conclusions: A high response to chemotherapy in resistant disease is seen but no real increase in actual survival. "The available data suggest that the residual burden of truly resistant cells is sufficiently large and capable of sufficiently rapid regrowth that the median duration of remission remains around a year at most. The challenge for cytotoxic therapy in the decade to come will be to improve on remission duration."

He did say that he felt that an improvement in remission duration will require combining with more biologically based treatments.

He mentioned bisphosphonates(pamidronate=aredia) can be used to reduce mets to the bone as well as work on hypercalcemia and vertebral deformities. (FDA did approve aredia for off-label use on June 13th of last year. There has been physician resistance.) A Dutch study has shown that giving pamidronate prophylactically prevented metastases to the bone.

I asked a question about a technique I had read about that uses the patients tumor cells to suggest what chemos may be appropriate. The response was that these methods will tell which chemo will not elicit a response. The labs I heard about are in California. Rational Therapeutics is one and Nichols Lab is another. He said this should be looked at more strongly.

I also asked about the effects of Coenzyme Q10 in protecting the heart from damage from adriamycin. He did not know of studies but believed there were some.

There was a brief discussion of matrix metalloproteinase in synergy with chemotherapy. A study in rats(Sledge et al) indicated that there was evidence of much less lung metastases than expected after its use.

The last speaker, Dr. Gage spoke about findings in DCIS. It is known that the 20 year follow-up of incidence shows that 17% of DCIS turns to cancer. 48% of patients presenting with breast cancer had DCIS in the second breast. The natural history is not well understood. There are few long term treatment results available. And, of course, optimal treatment is still debatable, as we do not know which patients will benefit from mastectomy and which from lumpectomy. There is an increase in incidence, so findings are critical. When a recurrence does occur after treatment, 50% of them are invasive cancer. Radiation is used to reduce local recurrence. 50% of recurrences are still found to be invasive. The risk of recurrence is said to be 10% over 10 years. The actual risk of mortality may be 2%.

Conclusions: In this section I would like to highlight several factors that struck me very strongly.

1) How very long it takes from the conception of an idea until it is accepted as a treatment, or leads to a study. An example is the introduction at Sloan Kettering of a paper on sentinel node biopsy in 1976! Also see the discussion by Jerry Shay, Ph.D. on telomerase.

2)Rarely is a study is accepted from any other country until its has been duplicated here in the United States. A new example is a study in Milan that indicates that retinoids (without side effects) may be used to prevent cancer in the contralateral breast instead of tamoxifen (which has some degree of dangerous side effects).

3)It was very interesting to hear that ovariectomy as a treatment for breast cancer was proposed in 1896.

4)Research that I had done prior to this conference indicated that in 1922 a British surgeon looked at less radical mastectomies and offered a study to his colleagues. He was totally laughed at and disregarded. It took 50 years for this idea to come to fruition. Even Halstead began rethinking the radical procedure named after him way before it was discontinued!

5) Regarding the ABBI tool for biopsies, the patient lies face down. This is a good development in many ways. I proposed this when I first viewed radiation equipment. How much better it would be for the body if radiation was external to the degree possible. Larger breasted women would benefit most but there should be a way to do this.

6)Chemoprevention is using many of the natural, non-toxic products that the "alternative" world has touted for many years. This crossover was not mentioned but is striking to me. Funding has been minimal in this and any other prevention-oriented area.

7)Advocates know a lot about what is going on. I did not feel totally at sea most of the time. Although the most research oriented presentations went over my head, eventually sense can be made of them. Researchers and physicians(clinicians) may not know as much about genetic testing as we do, for example. There is so much to keep up with and most of them are excessively busy in their daily practice.

8)It is important to note that women at high risk due to genetic susceptibility do NOT necessarily develop more aggressive cancers. This means that daughters of mothers who died of breast cancer may not need the most aggressive treatments(which most are currently offered automatically).

9)We were welcomed, as advocates by the majority of people at the conference. I prefaced each of my comments with a remark that I was a breast cancer patient/activist. As usual, I handed out a paper called Random Thoughts to provoke discussion on some issues of importance. Many came up to me to comment on how glad they were that Helen and I were there. We definitely had an impact. Other women have told me of the positive effect they found when participating in panels, etc. We may not yet have any real power, but our ability to influence is growing.

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