NEW YORKDramatic advances in the treatment, detection, and
prevention of breast cancer are occurring because of research efforts
of the past 30 years, experts emphasized at the International
Roundtable on Breast Cancer: Todays Choices, Tomorrows
Chances for a Cure, sponsored by the American-Italian Cancer
Foundation and the Susan G. Komen Breast Cancer Foundation.
We can calculate that 350,000 women are alive today because of
the use of tamoxifen [Nolvadex], said V. Craig
Jordan, PhD, DSc, Diana Princess of Wales Professor of Cancer
Research and director, Lynn Sage Breast Cancer Research Program,
Robert H. Lurie Comprehensive Cancer Center, Northwestern University.
Current tamoxifen research and clinical trials, Dr. Jordan reported,
are focusing on prevention of breast cancer in high-risk women. These
trials have shown, he said, that tamoxifen taken for 5 years reduces
breast cancer in high-risk women by about 50%. The women who
take tamoxifen have half as many breast cancers as those who do
not, he observed.
In the adjuvant setting, Dr. Jordan noted, 5 years is the standard
duration for tamoxifen in the United States. When stopped at that
point, he added, the patient continues to be protected for at least 5
years by an action that is not understood at this point.
It is almost like an invisible hand that keeps protecting the
person, he said, so you dont need to continue the
patient on tamoxifen. The 5-year duration of treatment is,
however, more effective than 2 or 3 years, he stressed.
Tamoxifen, the first agent shown to prevent breast cancer, is now
being tested against raloxifene (Evista) in the STAR (Study of
Tamoxifen and Raloxifene) trial for which Dr. Jordan is the
scientific chairman. Raloxifene, he noted, was developed to treat and
prevent osteoporosis, but encouraging preliminary data suggest it may
also prevent breast cancer.
Other chemoprevention research efforts, Dr. Jordan said, include
planned clinical trials in Italy with a reduced dosage of tamoxifen.
The International Breast Cancer Intervention Study, headquartered in
the United Kingdom, he added, is planning a trial in postmenopausal
women of aromatase inhibitors, the next generation of agents
that control the metabolism of estrogen.
Research on selective estrogen receptor modulation, he suggested, may
eventually produce compounds that fool the brain into thinking
theyre estrogen, so you can prevent breast cancer without
Breast Screening Innovations
For Susan M. Love, MD, adjunct professor of surgery, UCLA, and
founder and CEO of SusanLoveMD.com,
the Website for Women, the research challenge is to move breast
screening to the precancerous setting. What were doing
with mammography, she said, is detecting cancers that are
already there rather than figuring out who is headed toward cancer
and reversing it.
The road to breast cancer, Dr. Love explained, probably begins in the
lining of the lactiferous ducts with the development of atypical
cells and hyperplasia. It occurred to me that milk comes out
the duct, and maybe we could go in the other direction . . . to
sample the lining of the duct, she said. Toward that end, she
is exploring the use of catheters to extract cells from ducts.
In her research, she found early work by George Papanicolaou,
renowned for developing the Pap smear for cervical screening. He
was actually the first one to think of suctioning a little bit of
fluid from the breast ducts and looking at it for abnormal
cells, she said.
In this 1950s research, she noted, Dr. Papanicolaou did, in fact,
find atypical cells. He just didnt know what to do about
it, she observed. It wasnt until the 1970s that
researchers showed that women with atypical cells had a higher
risk of getting breast cancer down the road, she said.
Dr. Love is also interested in defining which ducts are most likely
to harbor precancerous cells. Clinical trials have begun, she
reported. I think it holds a lot of promise, she said.
If it succeeds, we can start to pick out who should get
chemoprevention and then follow them to see if it works.
Biologic markers are another potential way to detect patients who are
at risk of developing breast cancer, Dr. Love noted. Can
we, she asked, find a blood test like PSA for breast
cancer? There are some candidates that look promising in very small
studies and that need to be studied in much larger groups.
Larry Norton, MD, head of the Division of Solid Tumor Oncology and
director of the Lauder Breast Center, Memorial Sloan-Kettering Cancer
Center, said that thanks to molecular biology, analysis of small
tissue samples may reveal an individuals risk for breast cancer
and also factors that make their disease unique.
Expression profiling, a growing branch of science, he explained, is
directed toward finding out what it is within the cells that
makes the tumor click. These findings, he noted, then can be
used to devise new weapons against those specific abnormalities.
The cascade of molecular events involved in signaling cells to
divide, Dr. Norton said, is beginning to be understood more clearly.
One target identified in this research is tubulin, a molecule that
divides the DNA into little packets full of chromosomes,
and then pulls them apart. Taxanes, such as paclitaxel (Taxol), he
said, attack tubulin.
In addition, research is showing that tubulin is a constituent of
blood vessels that helps them retain rigidity. A whole new class of
drugs, Dr. Norton suggested, can be developed to attack the
neo-angiogenesis associated with cancers. That looks to me
extremely promising, he said.
This research may also open a new avenue of treatmentmetronomic
therapy. Its premise, he explained, is to keep tumors small by not
allowing them to grow. Although not eradicated, the tumors would
cease to be a threat to their host environments.
The intimate relationship between cancer cells and the immune system,
Dr. Norton noted, has prompted research on vaccines. Those tried for
breast cancer in the past have not worked well, he indicated, because
they aimed at a specific target rather than striking at the
tremendous heterogeneity in cancer cells. What you
need is a polyvalent approach, he said, that will use a variety
of antibodies to attack different cells.
A pilot study with a multivalent vaccine for breast cancer, he
reported, will be conducted this year. The next step will be a large
multi-institutional study to see if this vaccine can complement
adjuvant drug therapy to prevent cancers from growing back, he said.
Adjuvant systemic therapy currently saves more lives than any other
medical oncologic procedure, asserted Aron Goldhirsch, MD, director,
Department of Medicine and Radiotherapy, European Institute of
A recent report, he noted, showed that adjuvant therapy lowered
mortality in all age groups, but especially in the young and middle-aged.
Nonetheless, administering such therapy after tumor removal is
difficult because you cant see the results with your
eyes, Dr. Goldhirsch said. There is no diagnosable sign
of tumor, and you must rely on results of trials in the past that
this is indeed a suitable treatment.
Dr. Goldhirsch looks forward to the development of niche treatments
in which each type of breast cancer will be treated in a specific way
based on biologic knowledge. The Breast International Group (BIG), he
reported, has been formed to conduct trials to rapidly answer
questions about niche treatments.
Even without such targeting, Dr. Goldhirsch said, great progress has
been made in improving chemotherapies. As an example, he cited the
increased understanding of the interaction between combination
chemotherapy and endocrine therapy.
Neoadjuvant therapy to shrink cancers prior to surgery seems a
very good idea, Dr. Gold-hirsch said, but must take into
account the chemosensitivity of the tumor. A randomized trial, he
noted, found that such therapy was very good at reducing the
size of the tumor and allowing more women to have breast-conserving
surgery, but it didnt change the efficacy of tumor control.
Milestones in Surgery
A pioneer of breast-conserving surgery, Umberto Veronesi, MD, PhD,
Italys Minister of Health, headquartered in Milan, observed
that surgery for breast cancer today is totally different from
30 years ago.
At that time, he and several other surgeons challenged the need for a
total mastectomy for women with small tumors and began performing
quadrantectomies or lumpectomies. Every year now, he
said, there are some 300,000 women who have their breasts saved.
Another sea change in breast cancer surgery, Dr. Veronesi said,
occurred 5 years ago with the introduction of sentinel lymph node
biopsies. This procedure, he noted, allows sparing of the lymph nodes
in 70% of women, resulting in much less surgeryand less sequelae.
Today, Dr. Veronesi, who founded the European Institute of Oncology,
is involved in a new radiotherapy approach for women who have
quadrantectomies. Instead of postoperative radiotherapy extending for
5 or 6 weeks, the entire dose of radiation is delivered
intraoperatively with a specially designed linear accelerator.
We give 22 Gy in a single dose, which is equivalent to 55 Gy
with fractionated dosing, he said. Because the skin is not
irradiated, he said, side effects of radiation are eliminated.
The rationale for the new approach, Dr. Veronesi explained, sprang
from a review of 2,000 cases showing that 92% of recurrences were in
the same area as the original tumor. As a result, he asserted,
irradiation of the entire breast is not needed, and we may
concentrate radiation to the quadrant where the tumor was originally.
Dr. Veronesi and his associates began using the intraoperative
approach a year ago in a small group of patients. So far, the results
are very good, he said. Everything suddenly becomes
simple, he observed. We remove the tumor. We remove the
sentinel node. We give the radiotherapy. This way, in 1 or 2 hours,
all of the treatment is given to the patient. The next day the
patient is at home, and she doesnt need anything more.