ANTHRACYCLINE THERAPY,
BENEFITS HER2+ PATIENTS MORE THAN HER2- PATIENTS AND OTHER AGENTS SHOULD
BE CONSIDERED FOR ADJUVANT TREATMENT IN EARLY STAGE BREAST CANCER
[13] Role of anthracycline-based therapy in the adjuvant
treatment of breast cancer: efficacy analyses determined by molecular subtypes
of the disease.
Slamon DJ, Mackey J, Robert N, Crown J, Martin M, Eiremann
W, Pienkowski T, Bee V, Taupin H, Villalobos I, Lindsay M-A, Riva A, Hurvitz S,
Glaspy J, Pauletti G, Sauter G, Press M. Cancer International Research Group
(CIRG), Edmonton, AB, Canada
Background: The use of anthracycline-based therapies for the
adjuvant treatment of high-risk breast cancer has now become a common standard
part of clinical practice. The evidence supporting this approach was initially
controversial but finally thought to be resolved when the
Materials and Methods: We performed a systematic review of
published data from randomized, controlled adjuvant chemotherapy trials
reporting HER2 subtype, i.e. HER2 positive vs. HER2 normal breast cancers. In
addition, the analysis of two recent and separately conducted adjuvant trials
of HER2 positive and HER2 normal breast cancers respectively, that were further
sub-classified by whether or not they contained co-amplification of the
topoisomerase II alpha (topo IIa) gene were included.
Results: The published data demonstrate a remarkably
consistent finding. Specifically, the incremental efficacy benefit attributed
to anthracycline-based therapies is restricted to the HER2 positive subgroup. A
recent analysis of the BCIRG 006 (HER2+) and 005 (HER2-) studies reveals that
topo IIa amplification is confined to cancers that contain the HER2 amplicon.
In >1,600 HER2 FISH negative samples there is not a single topo IIa
amplified case. Conversely, deletion of topo IIa was found in 5% of HER2+ and
3% of HER2 tumors respectively. An analysis of the impact of topo IIa
co-amplification demonstrates that the improved efficacy imparted by an
anthracycline vs. a non anthracycline-based regimen is restricted to the
HER2/topo IIa co-amplified cancers. These constitute 35% of the HER2+ cancers.
In these cancers the efficacy resulting from an anthracycline-based regimen
alone was similar in magnitude to the addition of trastuzumab to adjuvant
therapy.
Conclusion: The use of anthracyclines in the adjuvant treatment of all breast cancer is not supported by the existing data. Given the known long-term cardiac and leukemogenic/MDS toxicities of anthracyclines and the lack of an incremental benefit in non HER2/topoIIa co-amplified cancers (which is 92% of the overall breast cancer population), other approaches to the adjuvant treatment of breast cancer should now be adopted.
ADRIAMYCIN IS SHOWN TO REDUCE RECURRENCE
[3077] Annual hazard rates of recurrence for early breast
cancer. What has changed in the last 10 years? Results from the NORA study.
Cazzaniga ME, Mustacchi G, Pronzato P, De Matteis A, Di
Costanzo F, Nardi M, Barberis G, D'Aprile M, Rulli E, Floriani I. Az Osp
Treviglio-Caravaggio, Treviglio, Bergamo, Italy
BACKGROUND: 10 years ago, Saphner et Al (J Clin Oncol 14:
2738-2746, 1996) analyzed 3585 breast cancer (BC) patients (pts) in terms of
annual hazard rates (HRs) of recurrence; 2661 (74.2%) were N+ve, 429 (11.9%)
high-risk N-ve, 1965 (54.8%) were treated with CMF-based chemotherapy (CHT),
650 (18.1%) with anthracycline-based CHT, with or without tamoxifen (T) and 87
(2.4%) with T alone. The remaining pts were followed up. For the entire group,
highest HRs of recurrence occurred during first and second year (13.30.7).
PURPOSE: to analyze in a cohort of early BC pts
prospectively followed up for a median interval of 3.4 years whether the
widespread of adjuvant therapy and the use of more active regimens, mainly
3-drug anthracycline-based, have induced modifications in the magnitude of
recurrence peaks or in the appearance time.
METHODS: NORA is a cohort study aimed at investigating
treatment modalities and clinical outcome in 3515 early BC pts radically
resected in 71 oncological Italian centers. 56.5% of the pts were N-ve and
17.1% had >4 positive axillary nodes. Results concerning treatment details
have been already published (Cazzaniga ME et Al, Ann Oncol 17: 1386-1392,
2006). Adjuvant medical treatment was delivered in 97.8% of the cases. Briefly,
1234 (35.1%) were treated with anthracycline-based CHT and 82 (2.3%) with
taxanes, with or without T or aromatase inhibitors (AIs). CMF was delivered in
963 pts (27.3%). 3433 pts (97.7%), for whom full data concerning relapse are
available, were analyzed in terms of annual HRs of recurrence, defined as the
fraction of pts who recur during a 1-year interval.
RESULTS: for the entire group, the peak hazard of recurrence
occurred in the interval from 3rd to 4th year (HR=3.4 0.5). The peak hazard of
recurrence in all pts traditionally considered at high risk (N>10; T4)
remained in the interval from 1st to 2nd year (18.2 3.6, 11.5 3.8,
respectively), even if in some cases 2-3 fold reduced in comparison a decade
ago. Details are listed in Table 1.
CONCLUSION: our results suggest that the widespread of
adjuvant systemic therapy and the use of more active drugs, mainly
anthracyclines, have delayed and reduced the peak hazard of recurrence in some
groups of early BC pts. High risk pts showed a significant reduction of
recurrence number but not a delay in the time of appearance.
CANCER TREATMENT RELATED BONE LOSS AND THE USE OF ZOLENDRIC
ACID TO IMPROVE BONE MINERAL DENSITY
[27] The effect of zoledronic acid on aromatase
inhibitor-associated bone loss in postmenopausal women with early breast cancer
receiving adjuvant letrozole: the Z-FAST study 36-month follow-up.
Brufsky A, Bosserman L, Caradonna R, Haley B, Jones M, Moore
H, Dong M, Warsi G, Lacerna L, Perez E. Z-FAST Study Group; Novartis
Pharmaceuticals, East Hanover, NJ
Background: Aromatase inhibitor (AI) therapy effectively
increases disease-free survival in postmenopausal women (PMW) with ER+ and/or
PR+ BCa. However, the use of AIs in this patient population results in nearly
complete ablation of estrogen production which can lead to accelerated bone
loss and increased fracture risk. The Z-FAST study evaluates the efficacy and
safety of Zoledronic acid (ZA) in preventing AI associated bone loss in PMW
with early breast cancer (EBC) who are receiving adjuvant Letrozole (LET)
therapy.
Material and Methods: 602 PMW with stage I-IIIa ER+ and/or
PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized to upfront ZA (4 mg IV
q 6 mos) vs delayed ZA in 94 centers in the US and Canada. The delayed group
receives ZA when either the post-baseline T-score decreases to <-2 or a
clinical fracture occurs. All patients (pts) are treated with calcium and
vitamin D. The primary endpoint, the percent change in lumbar spine (LS) bone
mineral density (BMD) at 12 mos, was reported at ASCO 2005. The results of 36
mos follow-up are reported here.
Results: Baseline characteristics were similar between
groups. At 36 mos, the upfront ZA group (n=189) showed a mean increase of 3.72%
in LS BMD while the delayed group (n=188) showed a mean decrease of 2.95%,
resulting in an absolute difference of 6.7% (p<0.001). The upfront group
(n=189) showed a mean increase of 1.66% in total hip (TH) BMD while the delayed
group (n=187) showed a mean decrease of 3.51%, resulting in an absolute
difference of 5.2% (p<0.001). The overall difference in LS and TH BMD
between the two groups was 8.2% and 6.7%, respectively, when BMD data in the
delayed group was excluded after pts started ZA. Among pts with baseline T
score between -1 and -2, 40.4% of upfront pts (7.6% of delayed pts) returned to
normal T score (T score >-1) and 13.4% of delayed pts (2.1% of upfront pts)
became severely osteopenic (T <-2). 15% of delayed pts had a decrease in BMD
that required initiation of ZA. Fractures occurred in 5.6% of upfront pts and
6.3% of delayed pts. 199 upfront pts and 191 delayed pts had baseline and 36
mos spinal x-rays. 0.5% upfront pts and 0.52% delayed pts had a radiological
fracture detected at 36 mos. The study was not designed to detect a significant
difference in the fracture rate between treatment arms. Administration of ZA q
6 mos for up to 36 mos was safe and well tolerated. No serious renal adverse
events and no confirmed osteonecrosis of the jaw cases were reported. Disease recurrence
was reported in 9 (3.0%) pts in the upfront group, and 14 (4.7%) pts in the
delayed group (p=0.24).
Discussion: The 36 mos follow-up of the Z-FAST trial show
that the overall difference in the percentage change in BMD between the upfront
and delayed ZA treatment groups, at both LS and TH, progressively increased
from baseline through 36 mos. These data demonstrate that ZA 4mg IV q 6 mos is
effective in preventing bone loss associated with adjuvant AI therapy in PMW
with EBC.
BREAST MRIS DETECT CANCER BETTER
[1001] Effect of magnetic resonance imaging on the clinical
management of women with newly diagnosed breast cancer.
Newstead GM, Abe H, Jansen SA, Shimauchi A, Sennett CA,
Schmidt RA, Zak L, Olopade O, Jaskowiak N. University of Chicago; University of
Chicago, Chicago, IL
Background: Magnetic resonance imaging (MRI) has been shown
to identify multifocal, multicentric and contralateral breast cancer, not
identified by clinical examination, mammography and ultrasound. Although the
biological importance of additional areas of disease identified by
histopathology has been questioned, we sought to evaluate the contribution of
MRI to the initial staging of newly diagnosed breast cancer patients, and to
document the effect of MRI assessment on patient management.
Materials and Methods: MRI has been routinely and
non-selectively used for breast cancer staging at our institution since 2002.
We identified 459 consecutive patients with 465 newly diagnosed breast cancers
who underwent MRI between July 1 2002 and December 31 2006. Excluded were
patients with clinical findings of inflammatory cancer. All patients were
assessed by clinical examination, bilateral mammography (MG) and ultrasound (
Results: Analysis of the MRI staging data with pathology
review, demonstrated secondary disease to be present in 106 (23.1%) patients,
mean age 51.2 years (5 years younger than mean age of all). Distribution of
additional disease: multifocal n=58 (12.6%), multicentric n=27 (5.9%),
contralateral breast n=21(4.5%). Additional cancer histology: IDC n=36 (33.9%),
IDC + DCIS n=26 (24.5%), DCIS n=29 (27.4%), ILC n=15 (14.2%). Management
change: More extensive cancer surgery with breast conservation n= 86 (81.1%),
mastectomy rather than conservation n=10 (9.4%) and Neoadjuvant chemotherapy
n=5 (4.7%).
Conclusion: MR imaging offers more precise assessment of
tumor extent than mammography or ultrasound imaging. Therapeutic management was
changed in 23.1% patients (n=106), resulting in a change from breast
conservation to mastectomy in 9.4% patients.
PRIOR USE OF HRT INCREASES ODDS OF
LOBULAR
[1055] Impact of hormone replacement therapy on breast
cancer: Womens Healthy Eating and Living (WHEL) study experience.
Parker BA, Flatt SW, Mortimer JA, Natarajan L, Gold EB,
Bardwell WA, Jones LA, Hollenbach KA, Pierce JP. University of California, San
Diego, La Jolla, CA; University of California, Davis, Davis, CA; The University
of Texas, Houston, TX
Prior hormone replacement therapy (HRT) has been associated
with an increased incidence of breast cancer. Conflicting information exists
regarding the impact of prior HRT on subsequent breast cancer development. We
utilized data from the Womens Healthy Eating and Living (WHEL) Study to
determine the natural history of breast cancer in women who reported HRT prior
to their diagnosis of breast cancer. Our aim was to determine the features of
breast cancer, the severity of vasomotor symptoms, and the disease-free
survival in women with breast cancer and reported prior HRT as compared with no
reported prior HRT. The WHEL Study is a multi-institutional randomized trial of
dietary change to a diet high in vegetables and fruits in Stage I-IIIA breast
cancer patients within 4 years of diagnosis. Baseline data regarding tumor
characteristics, demographics, and the Thoughts and Feelings questionnaire
regarding vasomotor symptoms were analyzed. A total of 1544 patients randomized
to the non-intervention group were included in this analysis. We used bivariate
statistics to assess the association of reported prior HRT with covariates,
logistic regression to analyze tumor histology, and a proportional hazards
model for disease-free survival. A total of 706 patients reported prior HRT
including 453 who received combined estrogen and progesterone HRT for a mean of
6.8 years and 216 women with estrogen alone HRT for a mean of 9.3 years. The
results of our analysis indicate that patients reporting prior HRT as compared
with no prior HRT were older (mean 57 versus 48 years), had a higher incidence
of lobular cancer (10.2 % versus 6.2%), had lower grade tumors (18.4% Grade 1
versus 13.6%), were more likely to report hot flashes (74.9% versus 60.6%),
were more likely to report night sweats (58.3% versus 48.0%), were more likely
have ER+PR+ tumors (63.6% versus 59.3%), and had a greater likelihood of being
disease-free at 7.3 years follow-up (84.7% versus 81.3% as of June 1, 2006). In
multivariate models, reported prior HRT weakly predicted lobular histology of
the original primary tumor (OR = 1.53, 95% CI = 0.99 2.36) but did not predict
disease-free survival (HR 0.78, 95% CI = 0.58-1.06). However, the significant
predictive effect on disease-free survival of low tumor stage, low tumor grade
and presence of hot flashes remained. These results add to reports suggesting
that prior HRT is associated with an increased incidence of lobular histology
at diagnosis. In our study, prognosis was similar regardless of prior reported
HRT.
HER2 POSITIVE PATIENTS WHO GET LUMPECTOMIES ARE MORE LIKELY
TO GET LOCAL RECURRANCES THAN THOSE WHO OPT FOR MASTECTOMIES
[1060] The prognostic significance of human epidermal growth
factor receptor-2 over-expression for the development of local recurrence after
newly diagnosed breast cancer.
Gabos Z, Thoms J, Hanson J, Ghosh S, Deschenes J, Mackey J,
Abdulkarim B. Cross Cancer Institute, Edmonton, AB, Canada; University of
Alberta, Edmonton, AB, Canada
Background: Human epidermal growth factor receptor-2 (Her-2)
over-expression occurs in 20-30% of invasive breast cancer and results in
aggressive disease and high-risk of recurrence. The impact of Her-2
over-expression on the risk of local recurrence is unclear.
Objectives: In this population-based study, we have
investigated the incidence of local recurrence in newly diagnosed breast cancer
patients with Her-2 over-expression.
Methods: Newly diagnosed breast cancer patients between
01/1998 and 12/2003 with uniform Her-2 testing were identified from a cancer
registry. A total of 460 Her-2 over-expressing patients were reviewed. A random
sample of 500 patients with Her-2 negative disease was also reviewed. Patients
were excluded if there was a breast cancer diagnosed before 01/ 1998 or other
cancer. A total of 266 Her-2 positive and 338 Her-2 negative patients were
included for this analysis. The groups were stratified based on surgical
treatment, lumpectomy versus mastectomy. The association between histological
features and local recurrence was evaluated with univariate and multivariate
analyses.
Results: In patients treated by lumpectomy, Her-2
over-expression was the only factor to be associated with increased risk of
local recurrence, on both univariate and multivariate analysis, hazard ratio
7.4 (95% CI, 1.6-33.9, p=0.01). In patients treated by mastectomy it was not
associated with increased risk of local recurrence.
Conclusions: In our population-based study, Her-2/neu
over-expression is significantly associated with increased risk of local
recurrence in newly diagnosed breast cancer patients treated by lumpectomy. In
patients treated by mastectomy, Her-2 over-expression is not associated with an
increased risk of local recurrence.
BETTER DRUG COMBO TO PREVENT DELAYED NAUSEA AND VOMITING
FROM CHEMOTHERAPY
[1086] Dexamethasone, metoclopropamide and omperazole
combination is simple, safe and effective for delayed nausea and vomiting
control in adjuvant chemotheray for early breast cancer.
BACKGROUND: Delayed nausea and vomitting in chemotherapy are
the most frequently of side effect. Our study aimed to determine the
effectiveness of Dexa+omeprazol versus Dexa+omeprazol+metoclopramide in the
prophylaxis of dealyed emesis after emetogenic chemotheray.
METHODS: Patients after treated with FAC regimen-adjuvant
chemotherapy for early stage breast cancer, receive dexamethasone 4mg oral,
twice time daily and omeprazol 20mg oral, twice time daily, all for five days
(Daxo) or dexamethoasone 4mg oral, twice time daily, omeprazol 20mg oral, twice
time daily and metoclopramide 20mg oral, thrice time daily, all for five days
(DexoPrim). Patient diary with nausea and vomiting module and toxicity criteria
were used to monitor and evaluate patient outcomes.
RESULTS: From Jan 2004 to Dec 2005, 122 (mean=45,7years)
outpatients were randomized with 60 Dexo and 62 DexoPrim confirmed eligible.
Patient characteristics were similar between the two groups. No drug related
serious adverse evetns were reported. During first cycle fo chemotherapy,
DexoPrim was complete protection against vomiting better Dexo(78vs.52%;p=0.05).
For the entire study period, there was better DexoPrim (69vs, 48%;p=0.02),
lower average nausea score (0.02 vs. 0.39, p=0.04) and no cases must entry
hospital for recuing anti eetic. Global QoL declined in both groups during
chemotherapy but DexoPrim was less than Dexo (p=0.03). Appetite was the same in
both groups. There were no significant differences in toxicity.
CONCLUSION: The use of combination DexoPrim oral daily for
five day after chemotherapy is simple, cheap cost, safe, and effective in
preventing vomiting, reducing nausea and preserving QoL.
YES THERE IS SUCH A THING AS CHEMOBRAIN!
[1094] Memory loss after adjuvant chemotherapy for breast
cancer: a preliminary analysis of mediating variables utilizing cross-sectional
correlations and multilevel longitudinal analysis.
Beadle G, Rolfe M, Vearncombe K, Andrew B, Mengersen K,
Wright M. Queensland Institute of Medical Research, Brisbane, Queensland,
Australia; Southern Cross University, Lismore, New South Wales, Australia;
University of Queensland, Brisbane, Queensland, Australia; Queensland
University of Technology, Brisbane, Queensland, Australia
BACKGROUND
Cognitive impairment is a well recognized complication of
adjuvant chemotherapy but further research is required to identify factors that
mediate cognitive change in breast cancer survivors.
METHODS
This study investigated cognitive change in verbal memory in
119 women aged less than 70 years before, at completion of, and 6 months after
adjuvant chemotherapy. Verbal memory was assessed with the auditory verbal
learning test trials 1-5 (AVLT1-5) and executive processing of immediate and
delayed recall with the AVLT7 and the AVLT8 respectively. Cross-sectional
correlations were performed with time invariant variables of age, years of
education and general cognitive ability utilizing the national adult reading
test (NART). Correlations with time varying variables included quality of life
measures (HADS, FACT-B and FACT-F) and changing hormonal phenotype (cessation
of hormone replacement therapy after diagnosis of breast cancer and changing
menstrual function after chemotherapy). Unconditional random intercept
quadratic regression models were fitted to AVLT1-5, AVLT7 and AVLT8, with
temporal and subject level variances estimated by restricted maximum
likelihood.
RESULTS
In this exploratory analysis, age, NART and years of
education were significantly correlated with AVLT1-5, AVLT7 and AVLT8 at all
time points (all p values <0.05). Quality of life correlates were
inconsistent at most time points but statistically significant when all time
points were combined (HADS depression <0.05 and FACT fatigue <0.05 for
AVLT8; FACT-B <0.05 for AVLT1-5, and <0.01 for AVLT7 and AVLT8). Age,
NART and years of education were significant predictors of these changes (p
<0.01). In particular, a high NART predicted a less steep decline of memory
over time. There was no evidence of a statistically significant association
between AVLT and self-report measures of quality of life or changing hormonal
phenotype after adjustment for age and NART.
CONCLUSION
A significant decline of the AVLT occurred during and after
treatment with adjuvant chemotherapy. Age, NART and years of education were
strongly associated with AVLT at all time points but not quality of life or
changing hormonal phenotype. Further investigation of memory and executive
functioning is currently underway in a larger sample of patients followed over a
longer time. Multilevel longitudinal analysis is a promising tool for
investigating longitudinal data that contain multiple changing covariates.
THE EFFECT OF BREAST CANCER ON COUPLES
[1097] Appraisals, coping and distress among couples dealing
with breast cancer.
Hernandez AM,
This study aimed to investigate the cognitive appraisals,
coping styles and levels of distress of couples dealing with breast cancer.
Cognitive appraisals are evaluations individuals make of stressful situations
in order to categorize them as benign/irrelevant, challenge, threat, or harm.
These cognitive appraisals predict coping mechanisms, which in turn impact
levels of distress. Studying couples, or dyads, is important because the coping
style of one individual in the dyad is associated with outcomes in the other.
One adaptive form of coping is emotional approach coping, which consists of
emotional processing and emotional expression. Breast cancer patients currently
undergoing chemotherapy treatment (n = 22) and their spouses (n = 22) were
recruited from a breast cancer clinic. Both the patient and spouse completed
surveys at home and returned them by mail. Stantons Emotional Approach Coping
Scale, Kesslers Cognitive Appraisal of Health Scale, and the Profile of Mood
States (POMS) were included in the questionnaire packages. Most of the patients
had stage IV breast cancer (68.2%). The average age for patients was 53.55 (SD
= 11.571) and for husbands was 54.49 (SD = 11.784). Participants were married
an average of 27.28 years (13.99). Most reported a yearly income above $70,000.
Husbands scored higher in the anxiety subscale of the POMS and were more likely
to appraise the cancer as a threat than the patients themselves. We grouped
couples into those who matched on appraisals and those who did not and examined
the groups level of distress and coping. We found no differences by group for
husbands on either variable, or for wives on the POMS. However, wives who did
not match on appraisals with their husbands engaged in more emotional approach
coping F(1,20)= 6.474, p=.019), and more specifically emotional expression
F(1,20) = 4.969, p = .037) and emotional processing coping F (1,20) = 6.089, p
= .023). These findings suggest that patients who have a different view of the
cancer than their partners may need to engage in more coping efforts than those
who have the same view. Possibly agreement, regardless of the appraisal agreed
upon, relieves the patient from reappraising. On the other hand disagreement
may require both processing and expression to determine whether the appraisal
is in fact correct or should be reconsidered. Because appraisals change
throughout the cancer experience, it may be that one impetus for reappraisals
is disagreement with a spouse and subsequent emotional work.
COQ10, RIBOFLAVIN AND NIACIN
INCREASES EFFECTIVENESS FOR DISEASE FREE SURVIVAL IN WOMEN WHO TAKE
TAMOXIFEN
[1104] Anti-angiogenic potential of coenzyme Q10, riboflavin
and niacin in breast cancer patients undergoing tamoxifen therapy.
Panchanatham S. DR. A.L.M.P-G.I.B.M.S.,
Background: To evaluate the anti-angiogenesis effect of
CoenzymeQ10, riboflavin and niacin (CoRN) in breast cancer patients undergoing
tamoxifen therapy. Efficacy of the combinatorial (CT) drug was correlated with
serum angiogenic marker levels.
Methods: Eighty four women with breast cancer undergoing
tamoxifen therapy were treated with 100 mg CoenzymeQ10, 10 mg Riboflavin and 30
mg Niacin for 90 days. Blood samples were collected at the start of the study,
at 45 days and 90 days of the treatment regimen. Circulating markers such as
Vascular endothelial growth factor (VEGF), Matrix metalloproteinase (MMP) - 2,
MMP-9, Tissue Inhibitor of metalloproteinase (TIMP) - 1, TIMP-2, Interleukin
(IL) -1, IL-6, IL-8, Tumour necrosis factor (TNF) -, Extracellular domain (ECD)
Her-2/neu, c-myc, Epidermal growth factor (EGFR), VCAM-1, E-selectin, Tumour
growth factor (TGF) , Angiogenin, Carcinoembryonic antigen (CEA) and
Carbohydrate antigen (CA) 15-3 were evaluated to determine the anti-angiogenic
of this CT drug.
Results and Discussion: We found a statistically significant
correlation between CoRN supplementation and reduction in angiogenesis markers.
There was a reduction in the levels of serum IL-1, IL-6, IL-8, TNF-, MMP-2,
MMP-9, Angiogenin, E-selectin, VCAM-1 EGFR, TGF- and VEGF levels, which are
stimulators of angiogenesis as well as factors for cancer cell proliferation
and growth. There was a significant reduction in tumour marker levels of CEA,
CA15-3, ECD Her-2/neu and c-myc. In conclusion, this study suggests that
supplementation of CoRN to tamoxifen therapy may provide good treatment
prognosis by reducing the risk of cancer recurrence and metastases by
decreasing the levels of angiogenic and tumour markers and importantly, the
relation between dietary supplementation and cancer treatment may also have
therapeutic implications in the future.
OSTEONECROSIS OF THE JAW CAN BE PREVENTED
[2056] Application of preventative measures minimizes the
occurence of the osteonecrosis of the jaw (ONJ) in solid tumors patients with
bone metastases treated with bisphosphonates
Ripamonti C, Maniezzo M, Cislaghi E, Campa T, Fagnoni E,
Saibene G, Bareggi C, Ascani L, Pigni A, Brunelli C. National Cancer Institute,
IRCCS Foundation, Milano, Italy
Background: ONJ is an uncommon side effect reported in
cancer patients receiving cancer treatment regimens including BPs. Dental
problems or mouth interventions were identified as the most important risk
factors to develop ONJ in these pts. As consequence, screening of the oral
cavity was suggested as preventive measure (Ruggiero J Oral Max Surg 2004). We
investigated the occurrence rate of ONJ in our Institution before and after the
implementation of dental preventive measures.
Material and Methods: Since April 2005, 153 consecutive pts
treated with BPs (group POST), underwent a baseline mouth assessment (dentists
visit panoramic jaw radiograph) to assess potential dental pathologies and
dental care when required. Regular dental examination was maintained along BPs
treatment. From Jan 1999 to Feb 2007, a retrospective review of 813 consecutive
cancer patients with bone metastases (group PRE) treated with BPs in our clinic
but not undergoing any preventive measure, has been conducted. Occurrence of
ONJ will be presented both as row percentages (n of cases by n pts at risk) and
as incidence rates (IR) (n of cases by person-time at risk). Differences
between the two groups (PRE and POST preventive measures) have been analyzed
through one-tailed Fishers exact test and will be presented as incidence rate
difference (IRD) and its 95% CI.
Results: In the overall pts population (966 pts;
M/F=255/711), 73% had breast cancer. The type of BP received was: Zoledronic
Acid (ZOL) administered to 244 pts, Pamidronate (PAM) to 600, PAM followed by
ZOL to 79, and Clodronate (CLO) or PAM/CLO to 43. Overall ONJ observed rate was
2.9% (ZOL/PAM+ZOL = 19 ONJ cases, PAM = 9). In group PRE and POST, ONJ cases
observed were 27 (3.3%) and 1 (0.6%), respectively (p =0.048). Considering pts
exposed to ZOL/PAM+ZOL, the application of dental assessment succeeded to a
consistent reduction of ONJ rate (Group PRE 8.7% vs group POST 0.9%, p =0.002).
The IR of ONJ in all 966 patients treated with BPs was 0.03/yr for group PRE
and 0.007/yr for group POST (IRD=0.023, 95% CI from 0.0045 to 0.041).
Conclusion: According to our experience the routinely
application of preventive measures before starting, and during the treatment
with BPs, lead to a reduction of 75% in the incidence of ONJ. This evidence
supports the relevance of applying prevention measures in all patients
receiving BPs treatment.
PRIOR HRT USE INCREASES JOINT PROBLEMS
ASSOCIATED WITH ENDOCRINE THERAPY
[2071] Risk factors for joint symptoms in the ATAC trial.
Sestak I, on Behalf of the ATAC Trialists' Group. Wolfson
Institute of Preventive Medicine,
Background: Joint symptoms are a well-known side effect of
aromatase inhibitors. Low oestrogen levels and postmenopausal status are
associated with the development of joint symptoms. Furthermore, it is known
that chemotherapy induces joint symptoms. Tamoxifen seems to have little impact
on the development of joint symptoms.
Methods: The two monotherapy arms of the ATAC trial
randomised 6,241 postmenopausal women to anastrozole (1mg/day) or tamoxifen
(20mg/day) in a double dummy double blind fashion. Here we investigate other
risk factors that might have an influence on the development of joint symptoms,
and examine if there was an interaction with either endocrine treatment.
Pre-existing joint symptoms will be examined in the final analysis.
Results: After a median of 68 months of follow-up, a total
of 2,011 joint symptoms were reported (1,100 (35.6%) anastrozole vs. 911
(29.4%) tamoxifen, OR=1.32 (1.19-1.47)). For women who used hormone replacement
therapy (HRT) before trial entry, 40.1% developed joint symptoms compared with
28.3% without previous HRT use (OR=1.70 (1.52-1.89)). Women who had
chemotherapy as part of their treatment developed significantly more joint
symptoms than those without chemotherapy (37.2% vs. 31.2%, OR=1.31
(1.15-1.48)). The Figure shows plots of joint symptoms in each treatment arm
according to prior HRT or prior chemotherapy use. It can be seen that the
factors were import in both arms of the trial and that their magnitude was
similar to the difference between tamoxifen and anastrozole. Women with hormone
receptor negative tumours developed significantly fewer joint symptoms than
those with hormone receptor positive tumours (25.8% vs. 34.0%, OR=0.67
(0.55-0.83)). Furthermore, women from
Conclusions: In this trial, the major risk factors for
developing joint symptoms were prior HRT use, treatment with anastrozole, prior
chemotherapy, and obesity, leading to significant increases of 11.8%, 6.1%,
6.0%, and 5.4% respectively. There was no clear indication of any interaction
between these factors.
PATIENTS WITH ADVERSE SIDE EFFECTS SHOULD TRY
DIFFERENT ENDOCRINE THERAPY FOR RELIEF
[2072] Comparison of joint problems as reported by patients
in a randomised adjuvant trial of anastrozole and letrozole.
Renshaw L, McHugh M, Williams L,
Background: Anastrozole (A) and letrozole (L) are well
tolerated potent non-steroidal aromatase inhibitors (AIs). Musculoskeletal
problems are reported frequently by patients on these drugs. This study aimed
specifically to compare reported side effects of L, A and tamoxifen (T).
Patients and Methods: 182 postmenopausal women with invasive
ER positive breast cancer were randomised as part of their adjuvant hormone
therapy to receive
12 weeks of L followed by 12 weeks of A or
12 weeks of A followed by 12 weeks of L.
106 had L or A after surgery and were then switched to T and
76 took L or A after 5 years of T.
Detailed side effect profiles were collected by a nurse from
patient interviews after 4, 8 and 12 weeks of each drug.
This analysis specifically relates to musculoskeletal side
effects. Data were available on 181 patients. 11 patients failed to complete at
least one month of each drug. This leaves an effective sample size of 170
patients. An analysis was performed to look specifically at side effects that
were reported on one drug that were not reported by the same patient on other
drugs. Statistical analysis was by McNemars test for matched data.
Results:
Letrozole vs. Anastrozole: Muscle pain was reported by only
3 patients. Joint pain was reported by 131 patients with no differences in
frequency between L and A. Joint stiffness was reported by only 10 patients but
was significantly more common with A compared with L (p=0.014). These two joint
symptoms have been combined as joint problems in subsequent analyses.
46 of 83 patients (56%) reporting joint problems on L did
not have the same problems on A and 46 of 83 (55%) patients with problems on A
did not report joint symptoms on L. The % improvement was similar whether or
not patients had taken prior T. Joint problems did increase over time irrespective
of drug sequence (p=0.0009).
Letrozole and Anastrozole vs. Tamoxifen: Joint problems
continued on T with 13/68 patients who did not get joint problems on L and
17/65 who did not get problems on A reporting these symptoms on T.
57% (13/23) with joint problems on T did not have these when
taking L and 74% (17/23) who had problems on T did not have these on A.
Conversely 74% (28/38) of patients with joint problems on L and 35/41 (85%) of
patients with joint problems on A did not have these on T.
Conclusions:
Over half of patients with joint symptoms on one non
steroidal AI did not have the same problems on the other AI.
Three quarters of patients who had joint symptoms on a non
steroidal AI did not have these problems on tamoxifen.
This study suggests that for women with significant joint
problems switching hormonal therapy to another agent is likely to improve their
symptoms.
AI THERAPY BETTER AS FIRST LINE TREATMENT
THAN TAMOXIFEN
[2083] Survival analysis of first-line tamoxifen versus
aromatase inhibitors for estrogen-positive metastatic breast cancer in
postmenopausal women a BC perspective.
Kyritsis V, De Lemos M, Walker B, Kennecke H, Nakashima L.
BC Cancer Agency, Vancouver, BC, Canada; Queens University Belfast, Belfast,
Belfast, Ireland
Background: Tamoxifen has been the gold standard of
treatment in postmenopausal women with estrogen receptor positive (ER+)
metastatic breast cancer (MBC). Over the past decade, new aromatase inhibitors
(AIs) anastrozole, letrozole, exemestane have emerged as equally efficacious
alternatives to tamoxifen. Recent data suggest that first-line AI therapy may
even confer a moderate increase ( 4months) in overall survival compared to
tamoxifen. We performed a population-based analysis of survival associated with
first-line tamoxifen versus AIs for ER+ MBC to examine whether the above
findings hold true for patients in BC.
Methods: This is a population-based retrospective analysis.
Patients were identified from the BC Cancer Agency Information System (CAIS),
systemic therapy drug database, and the provincial registry (Breast Cancer
Outcomes Unit). Data was analyzed for all postmenopausal women treated with
first-line tamoxifen and AIs (anastrozole, exemestane, letrozole) for ER+ MBC
(stage IV disease) from January 1998 through September 2004 in BC. Patients
treated with other first-line hormonal agents were excluded. The primary
outcome is overall survival, defined as the time to death by any cause from the
date of first-line tamoxifen or AI therapy. Overall survival was compared
between patients treated with tamoxifen versus AI.
Results: We found that there is an overall survival benefit
with the use of first line AI therapy in comparison to tamoxifen in our patient
population. Survival data will be presented as Kaplan-Meier curves and a
2-tailed log-rank test will be used to compare the hazard rates of the survival
curves.
Discussion: This analysis will provide pertinent information
regarding the survival benefit between the use of first-line treatment with
tamoxifen and AI. The preliminary data provided by this analysis will assist in
decision making regarding appropriate first-line hormonal therapy for ER+ MBC.
We hope to disseminate these findings to the rest of the communities oncology
network centers in BC.
BETTER THERAPY NEEDED FOR TRIPLE NEGATIVE DISEASE
[3070] T1N0 triple negative breast cancer: adjuvant
chemotherapy treatment and risk of recurrence.
Kaplan HG, Malmgren JA, Atwood MK. Swedish Cancer Institute,
Background: Triple negative (TN) breast cancer (BC) has a
high recurrence rate warranting more aggressive therapy at all stages.
Materials and methods: From a prospective cohort of registry
patients at our institution diagnosed with primary breast cancer between 1999
and 2004 we identified a subset of TNM Stage I (T1N0) BC. Estrogen (ER) and
progesterone receptor (PR)/her2-neu (her2) negative (TN) (N=91) patients were
compared to ER+/PR+/her2- (HR+/her2-) (N=770) patients. Patients with equivocal
her2 results unconfirmed by FISH testing were excluded (n=24). Clinical
variables including age, race, t stage, and surgical, radiation and adjuvant
chemotherapy treatment method were chart abstracted and vital and disease
status was updated annually. Length of follow up was at least 2 years with an
average follow up of 3.76 years. Pearson chi square and Fishers Exact testing
were used for bivariate analysis. Relapse free survival (RFS) was calculated
using the Kaplan-Meier procedure and hazard ratios using the Cox proportional
hazards model.
Results: Average patient age was 59 years, ranging from 23
to 88 years with no difference between the two groups. 5.6% of the TN patients
were black vs. .7% of the HR+/her2- patients (chi square =18.12, p<.001).
Distribution by t stage was 10% t1a (<.5 cm), 32% t1b (>.5 - <1 cm),
and 58% t1c (>1cm - <2 cm). 80% of the TN vs. 56% of the HR+/her2- were
t1c (chi square = 20.97, p<.001). Among all TNM Stage I patients 88% had
lumpectomy + radiation and 12% had mastectomies. Seventy percent of the TN
patients had adjuvant chemotherapy vs. 20% of the HR+/her2- patients (chi
square = 109.92, p<.001) with 86% of the HR+/her2- receiving hormone
therapy. In both groups women less than 60 years of age were more likely to
receive adjuvant chemotherapy. TN patients were more likely to receive
adriamycin/cytoxan/taxane combination adjuvant chemotherapy, 25% vs. 8% (chi
square = 20.97, p<.001). In total there were 3 local, 1 regional and 11
distant recurrence. The 4 local/regional all received radiation as part of
initial treatment and 3/4 were TN. The rate of any recurrence was 8.8% in the
TN group vs. .9% in the HR+/her2 group (chi square = 29.54, p<.001) and
distant recurrence was 5.5% vs. .8% (chi square = 33.13, p<.001). The rate
of recurrence was 0% in TN t1a (0/5), 7.7% in t1b (1/13), and highest in the TN
t1c group, 9.6% (7/73). Five year RFS was 99% in the HR+/her2- group and 91% in
the TN group (log rank test = 32.84, p<.001). In a Cox proportional hazards
model comparing TN to HR+/her2- patients, the hazard ratio of any recurrence
was 3.53 for TN patients (95% CI = 1.96, 6.33) adjusted for t stage (t1a/t1b
vs. t1c) and chemotherapy treatment (yes/no).
Conclusions: In early stage BC triple negative patients have
more than three times greater risk of recurrence in spite of more aggressive
treatment by number treated and type of adjuvant chemotherapy. Triple negative
specific treatment modalities and protocols need to be developed to reduce
recurrence in this high risk group.
ILC Shows Better Response to Endocrine Therapy
More Prone to Bone
Metastasis than Lung Metastasis
Compared with IDC
[3078] Do patients with infiltrating lobular carcinoma (ILC)
have an increased risk of contralateral, local, or distant recurrences compared
with patients with infiltrating ductal carcinoma (IDC)?
Pestalozzi BC, Zahrieh D, Mallon E, Gusterson B, Gelber R,
Price K, Castiglione-Gertsch M, Coates A, Goldhirsch A. International Breast
Cancer Study Group, Berne, Switzerland
Background: ILC differs from IDC in many respects including
increased frequency of multifocality and bilaterality, undefined margins,
metastatic pattern. Differences in prognosis are controversial.
Patients (pts) and methods: We analyzed data from 13,220
breast cancer (BC) pts who were entered onto IBCSG trials I through 15-95
between 1978 and 2002. Median follow-up is 13 years. Histology was based on
central pathology review for trials I through V, VIII through 15-95, and local
assessments for Trials VI and VII.
Results: 767 (6.2%) tumors were classified as ILC, 8,607
(70.5%) as IDC, 2,832 (23.2%) as other, and 1,014 (7.6%) unknown. This analysis
is based on the 9,374 patients categorized as IDC or ILC. Selected baseline
characteristics are shown in Table 1. Compared with IDC, ILC is associated with
older pts, larger, better differentiated and ER-positive tumors with less
vessel invasion.
Conclusion: Compared with IDC, ILC is associated with an
increased frequency of contralateral BC while local relapse is not increased.
In terms of distant recurrence, we observed a significant increase in bone
metastases and a significant decrease in lung metastases for pts with ILC.
These findings may be related to the higher level of endocrine responsiveness
of ILC.
Topical Estrogen Safe for Hormone Receptor Positive Patients
[3085] The effects of vaginal estrogens on plasma estradiol
levels in women taking aromatase inhibitors.
Howard G, Wills S, Kresge C, McConnell D, Balasubramaniam M,
Decker D. William Beaumont Hospital, Royal Oak, MI; School of Public Health,
University of Michigan, Ann Arbor, MI
Background: Absorption of vaginal estrogens (VE)s in breast
cancer survivors on an aromatase inhibitor (AI), has been reported in one small
series with short term follow-up 3 months (Ann Onc 17:584, 2006). We
hypothesized that over time, the initial absorption of VEs would decrease, as a
result of estrogen driven vaginal epithelial expansion. Methods: Twenty-four
postmenopausal women with estrogen receptor positive breast cancer (12 cases
taking AIs daily 180d as adjuvant therapy and VE (Vagifem) 2 x per week for
180d and 12 controls receiving an AIs daily >14d not on VE) were recruited
after informed consent. Blood was drawn in the morning prior to VE insertion
and the morning post insertion. Blood was drawn in controls >2 weeks after
beginning an AI. Serum samples were assayed for estrogen (E2) concentrations.
Patients on VEs were asked to rate their dyspareunia on a scale of 1-5 (1=good;
5=poor). Statistical analyses on the E2 levels were performed using the
Students t-test and the Wilcoxon signed rank test. Results: Table. The mean E2
levels in AI cases pre-insertion of VE was 14.8 pg/mL (standard deviation [SD]
6.5 95% confidence interval [CI] 10.9-18.7) and for controls on AI alone 12.01
pg/mL (SD 1.94, 95% CI 10.8-13.2) with a p-value of 0.1633. A comparison of the
median in pre-insertion and post-insertion E2 levels in cases yielded a p-value
of 0.0117. In five patients (42%) there was no difference (E2 change < 2
pg/mL) between the pre and post-insertion E2 levels. We found no correlation
between symptom relief, time to insertion, duration of VE and post-insertion E2
levels.
Conclusions: In this
small convenience sample, we found no statistical correlation between E2 levels
in controls and the pre-insertion E2 level of patients on an AI and using VE
180d. For patients receiving VEs there was a significant difference between the
pre-insertion E2 levels and the post-insertion levels. The clinical
significance with short term elevation is unknown. However, this elevation was
heterogeneous and was not observed in 5 of 12 receiving VEs. These data suggest
that a subset of women taking AIs might be able to use VEs safely to treat
vaginal atrophy.
WHY WE FIND BROKEN
RIBS?
[5092] Rib fractures: a complication of radiation therapy
and tissue expansion for breast reconstruction.
Huang AH, Wong MS, Whetzel TP,
Introduction: Tissue expansion remains a mainstay of breast
reconstruction. Despite increased complications associated with the use of
expanders in irradiated fields, tissue expansion for breast reconstruction
continues to be used in this setting. We present a previously unreported
complication of rib fractures caused by breast tissue expansion following
radiation therapy.
Materials Methods: A six-year retrospective review of tissue
expander use for breast reconstruction was conducted. Patients were categorized
by age, body mass index (BMI), indication for mastectomy, history of radiation
therapy, timing of tissue expander placement relative to mastectomy, minimum
and maximum expansion volumes in a single visit, and final tissue expander
volume prior to placing permanent saline implants.
Results: There were 144 tissue expanders placed in a total
of 91 patients, with an average age of 48 (range 22 to 78) years, and an
average BMI of 26.5 (range 17.4 to 42.1). Of the 53 (58%) patients who
underwent bilateral tissue expansion, nine patients had biopsy-proven breast
cancer or carcinoma-in-situ bilaterally and two patients underwent bilateral
prophylactic mastectomies. The remaining 42 patients requested prophylactic
contralateral mastectomies with bilateral tissue expander reconstruction after
the discovery of their unilateral breast cancer. Only fifteen (16%) patients
had a history of irradiation to their affected breast, though five additional
patients underwent radiation therapy immediately after tissue expansion was
completed, and two other patients had histories of irradiation for other
malignancies involving the thorax. Of the fifteen patients with breast tissue
expansion in an irradiated field, two patients eventually had evidence of rib
fractures discovered after both patients complained of pain at their follow-up
visits after tissue expansion. The first patient had a total of ten separate
tissue expansions with a mean single-volume expansion of 37 mL and a mean of
nineteen days between expansions.
Conclusion: Radiation is known to weaken the skeletal bony
matrix and stiffen overlying soft tissues. We present two cases of rib fracture
due to tissue expansion following chest wall radiation. We recommend any breast
reconstruction patient utilizing tissue expanders in an irradiated field be
cautioned about the possibility of rib fracture, which may change the course or
timeline of the patients future reconstruction.
PROOF WE NEED TO TAKE 10,000 STEPS A DAY!
[4050] A pilot study to increase physical activity in
sedentary women at risk for breast cancer.
Korde L, Venzon D, Smith AW, Nehrebecky M, Calhoun T,
Sebring N, Drinkard B, Smith M, Prindiville S, Zujewski J, Eng-Wong J. NCI; NIH
Clinical Center
Background: Epidemiologic data indicate that physical
activity (PA) is associated with a decreased incidence of breast cancer. One study
also suggested that physically active breast cancer survivors are at lower risk
of recurrence compared with inactive survivors. Thus, PA may be beneficial for
both the primary and secondary breast cancer prevention.
Methods: We designed a feasibility study to assess a 12 week
PA intervention in women at risk for breast cancer. Eligible women were those
at increased risk of breast cancer (by Gail model, family history, atypia on
biopsy, or history of Stage 0-III breast cancer). All participants completed a
one week baseline PA evaluation. Sedentary women (those with an average daily
pedometer step count of <6000 steps per day) were randomized to either PA
intervention or control. Intervention group participants received a pedometer,
a physician exercise prescription and a motivational/ educational booklet, and
were asked to incrementally increase their daily steps to a goal of 10,000
steps per day. Control participants received instruction on daily stretching
exercises. The primary objective of the study was to evaluate the feasibility
and success of the PA intervention in this population. Secondary objectives
included assessing the effect of short-term moderate activity on biomarkers and
quality of life. The study was powered to detect a mean increase of 3,000 steps
per day in intervention subjects. The Wilcoxon rank sum test was used to
evaluate the difference in mean change in step counts between intervention and
control participants.
Results: Ninety women were evaluated; of these 45 were at
high risk for breast cancer (HR) and 45 were breast cancer survivors (S). The
mean age of participants was 54.8 years. The mean baseline step count was 4578
steps per day (SD 2080, range 510 to 9983), and was not significantly different
in the two groups (S=4348, HR=4809, p=0.29). Of the 90 participants, 37 (20/45
HR, 17/45 S) were not sedentary and thus not eligible for randomization. The 53
randomized participants had a mean baseline step count of 3190 (SD 1226, range
510-5749). Follow-up step count data were available for 41 participants, (24
intervention, 17 control), of whom 36 completed the 12 week study. The mean
increase in step count was 3796 among intervention participants and 2149 among
controls (p=0.039). Three intervention participants achieved a final week step
count of > 10,000 steps per day.
Conclusion: This moderate intensity intervention was
effective in increasing PA in this selected population. Few participants
reached the final goal of 10,000 steps per day. Analysis of secondary endpoints
is underway. Additional research is needed to determine if this level of PA has
an effect on breast cancer related outcomes.