- Personality factors and breast cancer - The question of whether there are personality features
that are associated with, or might predispose towards breast cancer just does not go away. It is
an age-old question which can be traced back nearly 2,000 years to the time of Galen, but has
never received a definitive answer from a mix of anecdotal claims and both positive and
negative study results. We presented a summary of one such negative report - Psychological
status and breast cancer - in the May, 1996 issue (volume 2, number 5) of the CancerWeb
Report. In that article, the authors found no connection between breast cancer and a generalized
psychological condition described as distress, but recommended that future studies should look
for more specific conditions than general psychological states. Now comes a new study from
the Netherlands in the October 16, 1996 issue of the Journal of the National Cancer Institute
which claims that anti-emotionality, defined as the absence of emotional behavior or lack of
trust in one's own feelings, shows an association with development of breast cancer. The link is
only weak, with an increased cancer risk of only about 19%, compared with a four-fold increase
for having a first degree relative with the disease, and more than 2 1/2-fold for being childless as
compared with having a child before age 30. A range of 10 other emotional and personality factors
showed no relation to risk at all. The study is to continue for 5 more years of follow-up.
(Bleiker, J Natl Cancer Inst 88:1478, 1996)
- p53 and breast cancer, differences between human and rat disease - Experimental breast
cancers are typically induced in rats by using carcinogens, such as nitroso compounds like NMU
(N-nitroso-N-methylurea) or polycyclic hydrocarbons like DMBA (7,12-dimethylbenz[a]
anthracene). In many cases, tumors growing in experimental animals show similar genetic
changes to those seen in humans, but is this true of breast cancer? In humans, 30-40% of breast
cancers are marked by mutation of the p53 gene, a gene that may help protect against cancer
development. We have alluded to the role of p53 in the Breast Cancer sections of a number of
earlier CancerWeb Reports (see Adjuvant Radiotherapy and p53, December, 1995; p53 and
prognosis, a better test, February, 1996; and prognostic markers, May, 1996), and in this month's
issue there are other articles on p53 in the Bladder Cancer and Cancer in General sections.
The October, 1996 issue of Annals of Oncology includes on page 760 a news item on p53, which
stresses that the reason the gene cannot yet be used generally as a predictor of response is that
there is no commercially-available test to distinguish the abnormal mutant from the normal
protein. A study from Ehime University in Japan, published in the October, 1996 issue of
Molecular Carcinogenesis, found that in contrast to humans, the breast cancers induced in rats
by NMU or DMBA had either none or only 3% of p53 mutations, respectively. These authors
suggest that care should be taken in interpreting the implications of rodent model studies for
human breast cancer. (Kito, Mol Carcinogenesis 17:78, 1996)
- pS2, a marker for response to tamoxifen? - The incidence of breast cancer increases with age,
with one third of patients being over 65. However, the most appropriate treatment for the
elderly remains controversial, with opposing camps supporting surgery or tamoxifen alone as
initial treatment. Both sides claim similar efficacy, and two randomized studies found no
difference in outcome between surgery and tamoxifen. What is clear is that in frail elderly
patients, treatment choice must reflect a balanced consideration of their shorter life expectancy,
the other diseases from which they are suffering, and the risks of surgery. A reliable predictor of
probable response to tamoxifen would be helpful in making treatment decisions. Researchers
from the University of Bordeaux in France looked at 5 breast cancer markers in addition to the
usual clinical features in a group of 208 post-menopausal patients with non-metastatic ductal
breast cancer. In this research, reported in the October, 1996 issue of the British Journal of
Cancer, they found that pS2 protein and the estrogen receptor (ER) were the most useful
predictors of response to tamoxifen. These markers appeared to be independent of each other as
indicators of prognosis. Women could be divided into three groups : pS2 and ER positive, pS2
or ER positive, and pS2 and ER negative, with response rates to tamoxifen of 60%, 45% and
8%. (Soubeyran, Br J Cancer 74:1120, 1996)
Editor's Comment: - These results may help in making logical decisions regarding treatment of
women with tamoxifen. pS2 is a member of the family of trefoil proteins, so-called because of
their three-leaf structure. Abnormal expression of pS2 is associated with breast cancer, and it
may play a role in growth control. Paradoxically, trefoil proteins such as pS2 are also present in
the normal cells lining the stomach and intestine. These are regions of very high cell growth
rates, but there it appears that pS2 and its relatives play a protective role against damage from
acid, enzymes or toxins. Loss or alteration of these proteins is associated with ulceration, and
contrary to the situation for the breast, also with cancer of these organs. For discussions of
experimental studies on these gastrointestinal proteins see the articles in the October 11, 1996
issue of Science, by Chinery, Lefebvre, and Mashimo, on pages 204, 259 and 262, respectively.
- Hormone replacement therapy and tamoxifen may be beneficial even to women at
increased risk for breast cancer - There is a general reluctance to treat women with a history
of or increased risk of developing breast cancer with estrogen replacement therapy for
menopausal symptoms, for fear of further increasing their cancer risk (see also hormone
replacement therapy in women with breast cancer, under Breast Cancer in CancerWeb
Report of March, 1996). Addition of tamoxifen, which antagonizes many effects of estrogens,
to the hormone replacement regimen might protect these women from the effects of estrogen on
the breast. In fact, a group of researchers at the Royal Marsden Hospital in the UK reported 3
years ago that women with breast cancer, treated with a combination of tamoxifen and estrogen
replacement therapy, showed no evidence of rapid progression of their disease (Powles, Lancet
342(8862):60, 1993). The same doctors now found, in a study involving 2,450 postmenopausal
women at increased risk of breast cancer, that the combination can be given safely to minimize
adverse menopausal changes. According to their report in the September, 1996 issue of Annals
of Oncology, tamoxifen treatment reduced serum cholesterol by 13% as compared with 5% for
hormone replacement therapy, and lowered the clotting factors fibrinogen and AT III by 14%
and 8%, respectively. It also produced an annual increase in bone mineral density of 2% in the
femur and 1.5% in the spine. Addition of hormone replacement therapy to tamoxifen treatment
did not produce any further decrease in cholesterol or clotting factor below that given by
tamoxifen alone, but did give an extra 2% increase in bone density in the femur, a very critical
site for fractures to occur. (Chang, Ann Oncol 7:671, 1996)
Editor's Comment: - The results of the studies by this group of doctors are encouraging,
suggesting as they do that a combination of estrogens and tamoxifen can provide benefits to
women suffering from menopausal symptoms without increasing the risk for either breast cancer
or for forming blood clots, both of which are increased by estrogens. Tamoxifen is normally
considered an antagonist of estrogen action, but it also can have some estrogen-like effects as
well. In agreement with the finding summarized here, a study from Michigan State University,
presented at the Midwestern Section Meeting of the American Federation for Clinical Research
in September, 1996, also found that even long-term use of tamoxifen did not increase blood
clotting. (MacDonald, J Invest Med 44:356A, 1996)
- Omega-3 fatty acids and breast cancer - Studies have shown that diets rich in omega-6 fatty
acids such as linoleic acid, which is a major component of peanut, corn, and sunflower oils,
enhance the growth of human breast cancer cells in nude mice, whereas the omega-3 acids, EPA
and DHA, which are abundant in fish oils, inhibit their growth. In an extension of this work, the
same authors from the American Health Foundation in Valhalla, performed surgery on the mice
to remove the main tumors, and found that dietary EPA and DHA (2-4%) inhibited development
and diminished the severity of lung metastases. Writing in the October issue of Clinical Cancer
Research, these researchers suggest that omega-3 fatty acids could play an important role as part
of an adjuvant therapy regimen accompanying surgery for breast cancer. (Rose, Clin Cancer
Res 2:1751, 1996)
Editor's Comment: - The connection between dietary fat and breast cancer has been one of those
on-again off-again relationships, with each change reflecting the results of the very latest study.
Whatever the final outcome on this issue, it should reflect the growing complexity of the overall
diet and cancer problem. The amount and type of fat, presence of specific fatty acids, various
interactions between dietary components, and the presence of other carcinogenic and anti-carcinogenic factors, must all be taken into account. This will require both human studies and
the type of experimental work described in this article.
- Doxorubicin and paclitaxel for advanced breast cancer, effective but toxic - Danish
researchers at Herlev University Hospital in Copenhagen treated 30 women with advanced
breast cancer with doxorubicin and paclitaxel at three different dosage levels. The women had
received previous treatment with adjuvant chemotherapy or hormones. The results, which
appeared in the September, 1996 issue of Annals of Oncology, indicated a high overall response
rate of 83% with 24% complete responses. However, 50% of patients experienced reduced
cardiac function with 20% developing congestive heart failure, all patients had hair loss, and
low white blood cell counts occurred in 77% of the courses. Nausea and vomiting, disturbed
sensations and muscle pain also were common. The doctors concluded that care should be used
with this combination, and the total dose of doxorubicin restricted to 360 mg/m2. (Gehl, Ann
Oncol 7:687, 1996)
- Mitoxantrone and methotrexate, Irish study suggests it is not a good combination as
adjuvant therapy - Adjuvant therapy is frequently given to women treated with surgery for
early breast cancer. The intention is to treat any residual microscopic areas of tumor that cannot
be seen. The frequently-used, standard-dose treatments containing cyclophosphamide, carry
little or no increased risk of secondary cancerous conditions such as acute myeloid leukemia (t-AML), or myelodysplasia (t-MDS), a disturbance in bone marrow function that can predispose
to leukemia. However, new combinations that have been found to be successful in treating more
advanced cancer cases are often used as adjuvant therapy, and these regimens may contain drugs
that do produce t-AML and t-MDS. The September, 1996 issue of Annals of Oncology included
an article by doctors at Trinity College, Dublin who described a 5% incidence of t-AML and t-MDS in 59 patients treated with methotrexate and mitoxantrone. They considered mitoxantrone
to be the likely cause, and concluded that this regimen should not be used for adjuvant therapy,
despite its efficacy against advanced disease. (Cremin, Ann Oncol 7:745, 1996)
- Results of a ten-year study of high-dose chemotherapy with stem cell rescue - A report
presented at the Midwestern Section Meeting of the American Federation for Clinical Research
in September, 1996, showed that high-dose chemotherapy with stem cell rescue benefited a
particular subset among women with metastatic breast cancer. Women (102 in total) with
metastatic breast cancer were first treated with 1-3 courses of regular chemotherapy, and those
who responded to this induction therapy, or whose disease stabilized, went on to receive high-dose chemotherapy with thiotepa and cyclophosphamide with or without carmustine. Stem-cell
rescue consisted of giving transplants of bone marrow or stem cells, cells obtained from the
blood that are capable of multiplying to make new marrow. Patients received bone marrow or
blood stem cells, with or without stem cell mobilization with the help of granulocyte colony-stimulating factor (G-CSF). Median 5-year survival without recurrent disease for those who
achieved a complete response during the initial induction therapy was 33%, compared with only
3% for those who had only a partial initial response. (Laport, J Invest Med 44:395A, 1996)
- Subcutaneous GM-CSF better than continuous infusion - GM-CSF, the granulocyte-macrophage colony-stimulating factor, is widely used to assist bone marrow recovery after
chemotherapy (see for example an article in the November, 1996 issue of the Journal of Clinical
Oncology, vol 14, page 2976, where recovery time was reduced from 6.8 to 2.8 days) or marrow
transplantation. It is also used to mobilize the dividing (stem) cells to be collected for such
rescue procedures. Dose requirements have been defined for GM-CSF, but the efficacy of
different routes of administration has not been compared directly, although the subcutaneous
route is becoming more common because of its convenience. Researchers from Amsterdam,
presented a study comparing two ways of giving the factor in the October, 1996 issue of the
British Journal of Cancer. They treated breast cancer patients with moderately high doses of
doxorubicin and cyclophosphamide, and compared 14 patients given continuous infusions of
GM-CSF with 47 who received the factor subcutaneously. Continuous infusion was
accompanied by more toxicity in terms of fever and low white cell counts requiring antibiotics,
stomatitis, deterioration in performance status, and increased need for transfusions of red cells
and platelets. Response rates for recovery of neutrophils (white blood cell type) were similar for
infusion and subcutaneous treatment, at 86% and 91%, respectively. Lower toxicity and greater
ease of administration make the subcutaneous route preferable. (Honkoop, Br J Cancer 74:1132, 1996)
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