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Conferences
البروفيسور كفاح مقبل
استشاري في جراحة الصدر والغدد الصم/ مستشفى سانت جورج/لندن
Highlights From The 25th Annual San Antonio
Breast Cancer Symposium
Professor Kefah Mokbel, MS, FRCS
Professor Associate at Brunel Institute of
Cancer Genetics
Consultant Breast & Endocrine Surgeon at St.
George’s Hospital,
The 14th of December saw the conclusion of the world’s foremost breast cancer conference
; The 25th San Antonio Breast Cancer Symposium 2002 in San Antonio, Texas.
More than 600 papers1 were presented orally or as posters.This conference review will focus
on, and appraise some of the important developments in breast cancer treatment and
biology reported at the meeting
Hormonal Therapy
On behalf of the ATAC Trialists’ Group, Dr A Buzdar presented an updated analysis with a
median follow up of 47 months. The updated analysis showed that anastrozole’s greater
efficacy was maintained over time. In fact the absolute benefit increased from 1.7 % at three
years to 2.9 % at four years for patients with ER-positive disease. The number of first
events for the overall population was 413 (13.2 %) for the anastrozole group, and 472 (15.1 %)
for the tamoxifen group. In ER positive patients, the number of first events was 290
(11.1 %) for the anastrozole arm compared with 345 (13.3 %) for the tamoxifen arm. The new
data provide reassurance that anastrozole superiority is maintained, and predict that
anastrozole’s greater efficacy will continue. Anastrozole reduced the incidence of
contralateral breast cancer by 38 % (p=0.062) in the overall population and by 44 % (p=0.04)
in the ER positive patients compared with tamoxifen. Anastrozole also maintained its
superiority regarding tolerability and adverse effects, except for musculoskeletal side
effects. Reassuringly, there was no further increase in the number of fractures in the
anastrozole arm. The Austrian Breast Cancer Study Group presented BMD data in 278 premenopausal
women with ER and/or PgR positive breast cancer being treated with goserelin plus
tamoxifen +/- zoledronate (4 mg or 6 mg) or with goserelin plus anastrozole +/- zoledronate
(4 mg or 6 mg). The investigators observed a decline in BMD as determined by DXA imaging
(lumbar spine and greater trochanter) in patients receiving tamoxifen or anastrozole
without zoledronate. BMD reduction was significantly greater for anastrozole (p=0.0125).
However, after six months of treatment with zoledronate, the cohorts receiving zoledronate
had significantly higher BMD (p<0.0001). Although longer follow up is required to ensure
that zoledronate benefits are maintained, it would be reasonable to consider zoledronate
therapy (4 mg) in postmenopausal women receiving adjuvant anastrozole, who are at high
risk of osteoporosis.
In a study involving 119 pre- or peri-menopausal women with hormone
sensitive advanced breast cancer randomised to goserelin plus tamoxifen or goserelin plus
anastrozole, the OR was significantly higher for the anastrozole plus goserelin arm compared
with the tamoxifen plus goserelin arm (80 % vs. 53 %, p=0.0023). Furthermore, the time to
death was also significantly longer for the anastrozole plus goserelin group (18.9 vs. 14.3
months, p=0.0001), suggesting that this combination should be considered for the
treatment of pre- or peri-menopausal women with hormone-sensitive advanced breast
cancer.
Dr. Kaufmann et al presented an update of the ZEBRA trial comparing Zoladex (3.6 mg for 2
years) with classical CMF in the adjuvant setting in pre- or peri-menopausal women with
early node positive. After an extended follow up (median=7.3 years), Zoladex was non-inferior
to CMF in patients with ER-positive tumours (HR=0.94, 95% CI=0.75-1.18) in terms of OS
indicating that Zoladex reprents a safe and well tolerated alternative to CMF in this group of
patients. However CMF was superior to Zoladex in patients with ER-negative disease.
Unfortunately we have no data comparing Zoladex with anthracycline-based
chemotherapy which is currently the standard of care in such patients.
In a plenary lecture, Professor R. Nicholson outlined how inappropriate activation of the
EGF, Her-2 and IGF-1 receptors contributed to the development of anti-hormonal resistance of
ER positive breast cancer through ER phosphorylation by protein kinases, by
prolonging cell survival and stimulating cellular proliferation. Blockade of EGFR by new drugs
such as Iressa is likely to prevent or overcome anti-hormonal resistance.Massarweh and
colleagues demonstrated that targeting the EGFR pathway with Iressa (ZD1839) improved
the anti-tumour effect of tamoxifen and delayed acquired resistance in a xenograft model of
breast cancer. Sachder et al presented in vitro and in vivo (animal xenograft model) evidence
demonstrating that a chimeric single chain antibody to IGF-1 receptor down-regulates the
IGF-1R levels. These observations have implications regarding breast cancer therapy by
blocking the IGF-1R pathway.
Chemotherapy
Dr M Citron presented the preliminary results of the C9741 randomised phase III trial comparing
dose-dense with conventional scheduling of sequential or concurrent adjuvant
chemotherapy in patients with node positive breast cancer (n=2005, median age = 50 years,
median number of positive nodes = 3). Filgrastim was given to patients receiving the
dose-dense therapy. After a median follow up of three years, the dose-dense scheduling
(ACx4 followed by Tx4 every two weeks or Ax4 ® Tx4 ® Cx4 every two weeks) was found to be
superior to conventional scheduling (every three weeks) in terms of DFS (RR = 0.74,
p=0.0072) and OS (RR = 0.69, p=0.014) There was no significant difference in DFS or
OS between sequential or concurrent therapy. Furthermore, grade 4 neutropenia was
observed less frequently in the dose-dense arm in which patients received filgrastim support.
Longer-term follow up is required to confirm the dose-dense therapy superiority. The cost
implications arising from the need for filgrastim administration with the dose-dense scheduling
should be taken into consideration. The role of chemo-endocrine therapy for
node-negative breast cancer was the focus of two presentations. The International Breast
Cancer Study Group presented the results of trials VIII (n=1063) and IX (n=1669). After a
median follow up of 5.7 years for trial VIII and 6 years for trial IX, the investigators observed
that classical CMF provided a significant benefit compared with endocrine therapy for
patients with ER negative disease. However, classical CMF added no benefit to endocrine
therapy in women with ER positive disease aged ³ 40 years.
Professor B Fisher presented an up-to-date analysis of six NSABP trials involving 11,699
breast cancer patients with negative axillary nodes. The analysis demonstrated that
chemotherapy benefited patients with ER negative disease and that tamoxifen added no
benefit to chemotherapy in this group of Patients. Furthermore, chemotherapy plus
tamoxifen combination was superior to tamoxifen alone in patients with ER positive
breast cancer aged < 60 years, but not in patients aged ³ 60 years or postmenopausal.
For patients with tumours £ 1 cm in maximal diameter treated with BCS, tamoxifen plus RT
was superior to either treatment alone.
The hypothesis that platinum analogues may act synergistically with trastuzumab against
breast cancer was tested in a phase III randomised trial. Dr N Robert and colleagues
found that a trastuzumab + Taxol + carboplatin combination was superior to trastuzumab +
Taxol in 160 women with Her-2 positive advanced breast cancer in terms of OR (57 %
vs. 38 %, p<0.01) and TTP (13 vs. 7 months, p=0.01) with acceptable toxicity.
Treatment of DCIS
Dr B Cutuli presented the findings of a retrospective study of 1672 women with pure
DCIS treated with BCS, BCS + RT or total mastectomy. The authors confirmed that
mastectomy had the lowest local recurrence rate (1.6 %) after a median follow up of 83
months. Furthermore, RT reduced local recurrence form 26 % to 12.7 %. The
incidence of subsequent metastatic disease was 0.6 %, 1.2 % and 1.3 % for mastectomy,
BCS and BCS + RT respectively. However, the incidence of metastatic disease was 16 % after
invasive recurrence.
The NSABP protocol B-24 study previously
showed that adjuvant tamoxifen reduced the
incidence of all breast cancer events in women
who had BCS for DCIS (RR = 0.63, CI = 0.47,
p=0.0009). However, the ER status was not
included in the previous analysis. Dr Allred and
colleagues presented a subgroup analysis in
relation to the ER status derived from the
NSABP B-24 study. The ER status was
determined for 628 patients who had BCS for
DCIS followed by adjuvant RT. In ER positive
tumours (77 %), tamoxifen significantly reduced
the incidence of all breast cancer events (RR =
0.41, 95 % CI = 0.25-0.65, p=0.0002). This
effect was not seen in patients with ER
negative disease (RR = 0.80, p=0.51).
However, in view of the small number of events
in the ER negative group (n=36), a small
benefit in the group could not be excluded.
Another limitation of this retrospective analysis
is the lack of standardisation of ER testing. In
fact the ER results from contributing institutions
were significantly more likely to be negative
than those from the central reference
laboratory, where ER status was determined by
IHC (p=0.016).
Predictors of response to therapy
The combined determination of uPA and its
inhibitor PAI-1: uPA/PAI-1 was previously
shown to be an independent prognostic
indicator in patients with node-negative breast
cancer. Dr Hanbeck presented new data
demonstrating that the uPA/PAI-1 could also
predict an enhanced response to
chemotherapy. In a study of 3,424 patients
with operable breast cancer, the investigators
observed that patients with high uPA/PAI-1
levels had a significantly better response to
chemotherapy than those with low levels (HR =
0.68, 95 %, CI = 0.53-0.88, p=0.003). This
enhanced benefit occurred over and above the
significant benefit from adjuvant systemic
therapy in all patients. Such results suggest
that patients with high uPA/PAI-1 should be
considered for both chemotherapy and
endocrine therapy.
In a study of 548 postmenopausal patients with
advanced breast cancer randomised to
tamoxifen or letrozole, Dr Ali and colleagues
observed that patients with high serum Her-2
levels had a shorter TTP (HR = 0.56,
p<0.0001) and lower OR (15 % vs. 32 %,
p<0.0001) than those with lower serum Her-2.
However, letrozole was still superior to
tamoxifen when adjustment was made for
tumour burden and serum Her-2 levels.
Protemics
In a plenary lecture, Dr Petricoin outlined the
potential of proteomics technology in diagnosis
and treatment of breast cancer. He
emphasised the need to integrate high
resolution systems into research in order to
improve reproducibility and accuracy of results.
Protein expression by mass spectrometry was
the focus of other oral and poster
presentations. The technology seems to
provide a new method of molecular
fingerprinting of breast cancer and has been
facilitated by the use of laser capture
microdissection and sophisticated
bioinformatics software. Dr Wilson presented
interesting data on the potential application of
proteomics in breast cancer detection using a
blood test. Using a combination of surface
enhanced desorption/ionisation Protein Chip
mass spectrometry with a classification
algorithm, the authors were able to
reproducibly identify the four protein profiles in
blood samples obtained from the 92 women
with breast cancer or normal breast disease,
achieving a sensitivity and specificity of 96 %.
This potential simple diagnostic technique
seems to be at least similar to screening
mammography, although validation of these
preliminary results in larger studies is required.
Breast Conserving Surgery
Dr Poggi presented an update with 18 years of
follow up of the randomised NCI trial comparing
mastectomy with BCS + RT for patients with
stage I and II breast cancer (n=247). The
investigators confirmed that both treatment
options offered similar OS and DFS. However,
patients with early breast cancer in the USA
are still more likely to have mastectomy than
comparable patients in the UK (51 % vs. 42 %,
HR = 1.43, CI = 1.28-1.60). This significant
difference observed in the ATAC study may
reflect patient and/or physician bias and can be
minimised by a greater educational intervention
in the USA.
The Sentinel Node Biopsy
In a poster presentation , Dr E. Rutgers
presented data on the incidence of
extra-axillary SNs in 644 patients (653
procedures). The SN was identified using
intratumoral injection of blue dye (1 ml) and
Tc-99m nanocolloid (0.2 ml) in 96 % of cases.
The SN was found outside the axilla in 191 (29
%) of 653 cases. The internal mammary chain
was the commonest site of extra-axillary SNs
(136 out of 191 cases). The internal mammary
SN was visualised and successfully harvested
in 117 (86 %) of 136 cases, and it was positive
for metastatic disease in 19 (16 %) of 117
cases. The presence of an extra-axillary SN
was associated with non-palpable breast
cancer (41 % vs. 26 %), which may be due to
the fact that non-palpable breast tumours are
located more deeply in the breast. Upgrading
of the nodal status due to the visualisation and
harvesting of the extra-axillary SNs occurred in
16 (8 %) of 191 cases. Omission of
lymphascintigraphy would have resulted in
falsely negative nodal status in 2.5 %. There
was no signification morbidity associated with
harvesting of internal mammary nodes. It
should be borne in mind that the tracer should
be injected intra- or peri-tumourally for the
identification of the extra-axillary SNs, and that
subdermal injection would fail to achieve this
aim.
Dr. Liarsimont and colleagues tried to identify
predictors of non-SN involvement in series of
401 patients who underwent SNB. The authors
observed that the presence of
macrometastasis (>2mm) within the sentinel
node was almost 13 times more likely to be
associated with positive non-sentinel nodes.
The presence of capsular involvement of the
SN was the strongest predictor (odds ratio =
24). When the SN contained isolated tumour
cells detected by IHC, none of the non-SNs
contained metastatic disease. The findings of
this study suggest that axillary node clearance
can be safely omitted in patients with
micrometastasis or isolated tumour cells
(detected by IHC) within the SN.
The use of IHC and RT-PCR was shown to
upstage the SN by 8 % (abstract 518) and 31.3
% (abstract 519) respectively. The significance
of this upstaging regarding patients’
management is currently unknown, and is the
focus of ongoing research.
Abbreviations:
A: anthracycline, BCS: breast conserving
surgery. BMD: bone mineral density,
C: cyclophosphamide, CI: confidence interval,
DCIS: ductal carcinoma in situ. DFS: disease
free survival, EGFR: epidermal growth factor
receptor, HR: hazard ratio, IGF-1R: insulin like
growth factor 1 receptor.
IHC: immunohistochemistry, OR: objective
response, OS: overall survival,
PAI-1: plasminogen activator inhibitor type 1,
RR: relative risk, RT: radiotherapy, RT-PCR:
reverse trascriptase polymerase chain
reaction. SN: sentinel node, SNB: sentinel
node biopsy, T: Taxol,TTP: time to tumour
progression,UPA: urokinase plasminogen
activator.
Reference:
1. No authors listed.
The 25th Annual San Antonio Breast
Cancer Symposium.
Breast Cancer Res Treat;
2002:76S:S1-S180
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