- Assessing the likelihood of lymph node metastases from loss of apoptosis - Apoptosis, the
genetically programmed death of cells, is a process that is complementary to cell division in
regulating cell numbers. Two genes in particular, bcl-2 and p53, appear to exert an opposing
role in determining the occurrence of apoptosis, with bcl-2 extending the life of cells and p53,
specifically the normal (wild) type, favoring apoptosis. A group of researchers at the Oncologic
Research Institute in Barcelona, Spain, examined the expression of these two genes as their
protein products, and also the status of tumor cell division and death, in 116 tumor specimens
from patients having breast cancers of 2 cm or less in size (T1) with or without lymph node
metastases. Their findings appeared in the November, 1996 issue of Clinical Cancer Research.
Patients who showed marked loss of apoptosis were about 5 times more likely to have lymph
node metastases than those with no such loss. Expression of bcl-2 was strongly associated with
loss of apoptosis and with the presence of metastases, most especially in the less obviously
malignant grade I and II tumors, and in those which proved negative for p53. (Sierra, Clin
Cancer Res 2:1887, 1996)
- More on blood vessel numbers as an indicator of response to treatment - In the July, 1996
issue of the CancerWeb Report (Volume 2, Number 7), under the heading Breast Cancer -
Microvessel numbers as a predictor of tamoxifen efficacy, we discussed a European study of
the value of measuring the number of tiny blood vessels - microvessels - formed by the process
of angiogenesis as an indicator of the success of treatment of breast cancer with tamoxifen.
Angiogenesis, the development of new blood supply through the growth of vessels and
microvessels, is a critical factor in determining whether a tumor grows, remains static, or
disappears. In the December 4, 1996 issue of the Journal of the National Cancer Institute,
doctors at the University of Chicago analyzed data from 167 breast cancer patients who had
mastectomies between 1941 and 1987. These women had node-negative disease, and received
no further treatment after surgery. Preserved specimens were examined for numbers of
microvessels with a cut-off point of 15 at 400X magnification. Overall disease-free 20-year
survival was 74.8%, but this figure rose to 93.1% for those with a low count, and was only
68.9% for those with high counts. The microvessel index as a predictor of response, provided
information that was independent of that given by the other predictors, tumor size and grade.
(Heimann, J Natl Cancer Inst 88:1764, 1996) (For more on angiogenesis see also under Cancer
in General - A clue to a method to attack tumors by blocking their blood supply?- in this
month's CancerWeb Report issue)
- Ornithine decarboxylase, another potential marker for breast cancer prognosis - The
polyamines are substances that play a vital role in cell division in general, including the specific
case of breast cancer cells. Ornithine decarboxylase (ODC) is a critical enzyme needed for the
synthesis of polyamines. Researchers at the Pennsylvania State University in Hershey,
Pennsylvania, reported in the November, 1996 issue of Clinical Cancer Research that levels of
ODC in tumor specimens provided a good indication of disease prognosis. They measured ODC
along with other enzymes involved in polyamine metabolism, but found increased levels of ODC
alone to show a highly significant relation to poor disease-free and overall survival, and also to
relate to earlier death following a recurrence of the cancer. In fact, ODC activity appeared to be
an indicator that was independent of other prognostic features, and superior to the number of
positive lymph nodes as an indicator of overall survival. (Manni, Clin Cancer Res 2:1901, 1996)
Editor's Comment: - Regular visitors to the CancerWeb Report site may wonder why so much
attention is given in issue after issue to markers of prognosis. The answer is that effective
treatment for cancer is most often intrusive, stressful, and toxic, some treatments more so than
others. Particularly intensive therapy should be reserved for those with the most life-threatening
forms of disease who require extreme measures, while within the limits of providing effective
treatment, those patients with a more favorable prognosis should be spared needless discomfort
and toxicity. To ensure that the right decisions are made it is necessary to identify, evaluate, and
apply all reliable indicators of stage and prognosis. ODC is one such potential prognostic
indicator that may define a particular subset of breast cancer patients with a higher risk of
recurrence and the likelihood of shorter potential survival who should, therefore, receive the
most intensive available treatment to eradicate their disease.
- Negative lymph nodes, just how good an indication of prognosis are they, and is there a
better indicator? - Dissection and detailed examination of the lymph nodes in the armpit area to
determine whether they harbor cancer cells is common practice in treating breast cancer.
Negative nodes, the absence of tumor cells, are taken as indicating a good prognosis, in contrast
to those cases whose nodes are positive for tumor. However, 30% of patients with negative
nodes relapse within 10 years, and between 10% and 20% of patients with distant metastases do
not have tumor-positive lymph nodes. Three recent articles are of great interest in this regard. A
report from the Charing Cross Hospital and Westminster Medical School in London, appearing
in the November, 1996 issue of the British Journal of Cancer, suggested that present techniques
are just not sensitive enough to really prove the absence of tumor cells. These doctors examined
lymph nodes from 75 patients judged by conventional microscopic examination to be node-negative, and found, using a very sensitive enzyme procedure called PCR (polymerase chain
reaction) to measure nucleic acid associated with producing the cancer marker keratin 19, that
23 of them (30.6%) had evidence of lymph node involvement. While this is promising, there are
problems with adopting the use of PCR technique. It is not widely available to doctors, it would
be necessary to adapt automated techniques to handle large numbers of samples, and it is not
something that can be done and have results available while the patient is still on the operating
table. As a possible alternative, a second article by researchers at the University of Heidelberg
in Germany suggested that examination of the bone marrow may provide a better guide than
negative lymph nodes. In their report in the November 29, 1996 issue of the Journal of the
National Cancer Institute, they found that by using an immunological test for a component of
tumor cells they were able to find cancer in bone marrow samples from 31% of patients who had
been tested and found to have negative lymph nodes. Since the technique only identified tumor
in 55% of those who were lymph-node positive, it obviously requires more study. That lymph
node examination should not be abandoned impulsively, is emphasized by a short report from
researchers at the University Hospital of South Manchester in the UK in the November, 1996
issue of the British Journal of Cancer. They found that with the possible exception of grade I
cancers, which do not appear very malignant when examined under the microscope, removal and
examination of lymph nodes is necessary for all cases detected at first incidence screens, no
matter how small the tumor may be. (Schoenfeld, Br J Cancer 74:1639, 1996; Diel, J Natl
Cancer Inst 88:1652, 1996; Holland, Br J Cancer 74:1643, 1996)
Editor's Comment: - There is no question that dissection of lymph nodes adds to the trauma of
surgery for women suffering from breast cancer. It would clearly be an advantage if there were a
reliable new alternative procedure which safely reduced the need for extra surgery to remove
lymph nodes, but it is evident that there is as yet no safe and reliable alternative. The bone
marrow study is of great interest, but the marker used did not identify all node-positive patients.
Perhaps another tumor marker should be explored for greater reliability. Meanwhile lymph
nodes continue to be the best indicator we have.
- More on lymph nodes; what if the positive nodes are few in number? - A report published in
the December, 1996 issue of the Journal of Clinical Oncology suggested that for patients with
less than 4 positive nodes, and whose original tumors are 2 cm or less in size, the outcome is the
same as for patients with negative nodes. This study involved 501 women with breast cancer
treated between 1927 and 1987 at the University of Chicago. Doctors found that the 20-year
disease-free survival rates for women with one positive node were 81% for a tumor less than 2
cm in size, compared with 59% if the tumor were larger than this. For those with 2 or 3 positive
nodes the corresponding survival figures were similar, 73% and 53%, respectively. These
figures were essentially identical with the survival rates achieved in women with no positive
nodes, who had disease-free survivals of 79% and 64% for tumors smaller or larger than 2 cm,
respectively. (Quiet, J Clin Oncol 14:3105, 1996)
- Canadian study fails to identify patients who do not require radiation after conservation
surgery - Breast-conservation surgery is now common, and post-operative radiotherapy appears
to reduce the risk of recurrence, but is there a group of patients who do not need this additional
therapy? The answer from the Ontario Clinical Oncology Group, published in the November 20,
1996 issue of the Journal of the National Cancer Institute, is clearly no. Looking at 837 patients
with negative nodes treated between 1984 and February, 1989, these researchers found that the
disease had recurred in 35% of the non-irradiated patients, versus 11% of those who received
radiation, but similar numbers of patients had died (24% and 21%) in the two groups. The most
important factors for a poor prognosis were age less than 50, tumor size greater than 2 cm, and
poor tumor nuclear grade, but an analysis based on these factors was unable to identify any
subgroup with a very low risk of recurrence who might not need radiotherapy. This study is also
in agreement with others in showing that radiation does not increase survival even though it
reduces local disease recurrence. (Clark, J Natl Cancer Inst 88:1659, 1996)
- Tamoxifen, two more studies suggest that 5 years of treatment is optimal - It is generally
accepted clinical practice to follow surgery with the drug tamoxifen for early breast cancer
which is positive for estrogen receptors, and without positive nodes. Although in animal studies
continuous use of tamoxifen gave the best results, there is some evidence that the drug may
increase the risk for a patient to develop a second cancer. There may also be a higher incidence
of other side-effects like blood clot formation. This makes the indefinite use of tamoxifen
controversial. The November 6, 1996 issue of the Journal of the National Cancer Institute
included the reports of two trials, one by the National Surgical Adjuvant Breast and Bowel
Project in the US comparing 5 years with more than 5 years of tamoxifen, the other a Swedish
study comparing 2 and 5 years of the drug. The Swedish study of postmenopausal women aged
less than 75 with early breast cancer found that 5 years of tamoxifen gave an 18% reduction in
recurrence and mortality compared with the two-year group. The estimated 10-year overall
survival was 80% after 5 years of tamoxifen for those who were recurrence-free at 2 years,
versus 74% for those who received drug for only 2 years. The US study involved an initial 5-year period of tamoxifen or placebo, with reassignment of those disease-free after this period on
tamoxifen to either further tamoxifen or placebo; the study ran for 10 years. Overall and
recurrence-free survival rates, respectively, were 80% and 69% for tamoxifen versus 76% and
57% for placebo; there was also a 37% reduction in cancer developing in the opposite breast.
After a further 4 years of tamoxifen or placebo, those in whom the drug was discontinued after 5
years had better disease-free (92% versus 86%) and overall (96% versus 90%) survival rates.
There were increases in incidence from 0.4% to 1.7% for troublesome blood clots, and from
0.2% to 1.5% for endometrial cancer rate in those receiving tamoxifen, but overall incidence
rates for second cancers were similar for tamoxifen (5%) or placebo (4%). These studies agree
that 5 years is an optimal period for tamoxifen treatment to continue. (Fisher, J Natl Cancer
Inst 88:1529, 1996; Swedish Breast Cancer Cooperative Group, J Natl Cancer Inst 88:1543,
1996)
- Protecting women against the adverse effects of chemotherapy on the heart - Among the
most effective anticancer drugs are the so-called anthracycline antibiotics such as doxorubicin
(Adriamycin) and epirubicin. Unfortunately, the side-effect which limits the maximum doses of
these drugs that can be given is cardiac damage, in which heart muscle cells are eventually
killed, making the heart less efficient at pumping blood, and resulting in a condition resembling
congestive heart failure. Researchers at several cancer centers in Italy described their work on
an antidote to this side-effect in the December, 1996 issue of the Journal of Clinical Oncology.
They reported that a 10:1 ratio of a drug called dexrazoxane in conjunction with epirubicin
reduced the incidence of adverse heart effects in 160 patients with advanced breast cancer from
23% down to 7%. Other side-effects and the benefit to the patients in terms of disease-free
survival were unaffected. (Venturini, J Clin Oncol 14:3112, 1996)
Editor's Comment: - The importance of this finding extends well beyond breast cancer, since the
anthracyclines are used to treat such a wide range of tumors. Cardiac side-effects are more
serious than most other adverse effects of chemotherapy such as hair loss or reduced white blood
cell counts, since unlike these troublesome problems, damage to the heart is not reversible.
Dead heart muscle cells are not replaced. The ability to give a higher dose of drug because of
the wider safety margin may make a great difference in the response of many cancers to
chemotherapy.
- Pamidronate effective in reducing bone complications of breast cancer - Breast cancer is one
of the tumors (prostate cancer is another) that form bone metastases in most patients with
advanced disease. Bone is normally maintained by an equilibrium between cells that stimulate
bone formation (osteoblasts) and cells that break down the bone (osteoclasts). In this way, small
areas damaged by stress are removed and replaced, extra bone is formed where needed, and the
skeleton is maintained in a healthy state. Tumor cells release a factor which stimulates the
osteoclasts causing them to increase bone breakdown, which allows tumor to infiltrate and grow
into the bone. For the patient this causes pain, reduced mobility and function, and fractures. A
report in the December 12, 1996 issue of the New England Journal of Medicine describes the
use of the drug pamidronate to relieve this painful condition. An international team (the Aredia
Breast Cancer Study Group) found that in 380 women with Stage IV breast cancer, monthly
infusions of pamidronate extended the time for first occurrence of skeletal problems from 7 to
13 months, lowered the incidence of bone damage from 56% to 43%, and significantly reduced
both the increase in pain and the deterioration in function associated with progressing disease.
(Hortobagyi, New Engl J Med 335:1785, 1996)
- Fat and breast cancer, reconsidering the quality of epidemiological data - A rather technical
discussion of the issue of dietary fat and breast cancer appeared in the December 4, 1996 issue
of the Journal of the National Cancer Institute. In it, Dr. Prentice from the Fred Hutchinson
Cancer Research Center in Seattle, developed a model for dietary studies which stressed the
importance of errors in dietary assessment. The data used to develop his model was taken from
a study done between 1985 and 1988 which involved 303 women in Cincinnati, Houston, and
Seattle, and in which 4-day food records and food frequency questionnaires, both self-reporting
measures, had been used to assess dietary fat intake. Without any allowance being made for
error, there was a 3- to 4-fold increase in risk for the highest versus the lowest 10% of fat intake.
This risk fell to 1.4- to 1.5-fold when random error (noise) was acknowledged, and further
consideration of potential systematic error in measurement reduced the risk ratio to about 1.1.
Self-reporting methods for determining fat (or other ) dietary intake may be inadequate for use in
studies, casting doubt on many reported findings of an association of fat intake and breast
cancer. (Prentice, J Natl Cancer Inst 88:1738, 1996)
Editor's Comment: - The implications of this study for those investigating the relationship of
dietary fat and breast cancer are that the most widely-used methods for determining food intakes
are not good enough, and that the researchers should have more control over the actual diet, or
find a better way of finding out what the actual diet may be. This is much easier said than done,
since any method of stricter control will escalate the cost of a study, and may be impracticable
for any but a very selected population anyway.
- Induced abortion and breast cancer, a new Dutch study - In contrast to spontaneous abortion,
where studies have almost uniformly found no increased risk for breast cancer, reports regarding
induced abortion have been more variable. Six studies showed no association between having
an induced abortion and subsequent breast cancer, five showed an increased risk, and one
showed a decreased risk of cancer. All but two of these studies had a case-control design in
which women with breast cancer and a matched group without the disease were questioned
about whether they had ever had an abortion. These studies are generally thought to be less
reliable than cohort studies in which groups who have had the procedure are followed-up to see
if they develop cancer. This is because of what is known as reporting bias resulting from the
fact that healthy controls are less likely than breast cancer patients to report on controversial,
emotional issues like abortion. Now comes a Dutch case-control study which addressed the
relationship to abortion in 918 women with breast cancer, and also looked at reporting bias by
comparing regions of the Netherlands that differ in attitudes towards abortion. As reported in
the December 4, 1996 issue of the Journal of the National Cancer Institute, there was an overall
90% increase (risk ratio 1.9) in the risk of cancer among women with children who had a history
of induced abortion. The relationship was very strong (risk ratio 14.6) in the southeastern region
of the country which is mainly Roman Catholic, and weak (risk ratio 1.3), and not statistically
significant in western areas, suggesting a bias in reporting. There was no additional increase in
risk associated with induced abortion in women who had no children, and no group of women,
with or without children, showed any association between breast cancer and spontaneous
abortion. The same pattern was seen also in a survey of oral contraceptive use, in which healthy
women from the southeastern region underreported duration of use by 6 months more than those
in the western region, as checked against documented prescription records. (Rookus, J Natl
Cancer Inst 88:1759, 1996)
Editor's Comment: - In discussing their findings, the researchers concluded that induced abortion
does not produce an appreciable increase in the risk of breast cancer, most reported association
being due to reporting bias. A similar conclusion was reached by a Swedish study (Lindefors-Harris, American Journal of Epidemiology 134:1003, 1991). US rates of induced abortion are
five times greater than in the Netherlands due, according to the Dutch researchers, to availability
of additional birth control modalities such as the "morning-after" pill. Despite more widespread
recourse to induced abortion in the US, which might be thought to show less reticence regarding
the procedure, it is underreported by about 40% (Jones, Demography 29:113, 1992). The logic
of suspecting that there is a relationship between induced abortion and breast cancer is based on
the stimulation of breast tissue that occurs during the first trimester. Subsequently, stimulated
tissue matures and differentiates and becomes less subject to cancer formation. Termination of
pregnancy when the breast is stimulated and undergoing extra cell proliferation might leave the
tissue more susceptible to carcinogenic factors.
[ CancerWeb Home
| Comments
| CancerWeb Report Index ]