ML1
Breast cancer - a look to the future.
Veronesi U. European Institute of Oncology, Milan, Italy
In the last ten years a number of revolutions have occurred in our understanding of the biology of breast carcinoma and have deeply influenced our approaches to the disease in terms of prevention, detection and treatment.
1) The genetic studies have identified subgroups at high risk of developing the disease creating the premises for programs of targeted chemoprevention. 2) Endocrine modulators and other active principles have shown to be effective in reducing breast cancer incidence in specific subgroups of patients. 3) New developments in imaging procedures have made possible the detection of very early carcinomas greatly increasing the curability rates. 4) The analysis of the genetic profile of the cancer cells will be fundamental for prognostic evaluation. 5) Mastectomy is progressively abandoned in favor of breast conservative treatments. 6) Dissection of regional lymph nodes will be limited to patients with positive nodes. 7) Radiotherapy fields are being progressively reduced and partial breast irradiation is becoming a realistic perspective for the future. 8) Systemic treatments will be decided mainly according to the prediction of response to specific endocrine or chemical drugs. 9) New types of drugs built to meet specific biomolecular targets, expressed by mutated genes, will likely appear in the future as a result of the postgenomic research.
All these new facts are at the root of dramatic changes in paradigms for prevention, detection and treatment of breast cancer. The main shift refers to the progressive awareness of the importance of quality of life, which is changing the traditional approach based on the “maximum tolerated treatment” to the “minimum effective treatment”. This new trend has led to limited surgery (instead of mutilating operations), more targeted radiotherapy (instead of large field involving the regional nodes), less aggressive chemotherapy (instead of the high dose approach). This new trend will motivate more women to participate in early detection programmes, which in turn will reinforce the new paradigms.
P1
Stem cells in the normal and cancerous human breast. Wicha MS, Dontu G, Al-Hajj M, Clarke MF. University of Michigan, Ann Arbor, MI
It has been postulated that the epithelial components of the mammary gland arise from a common stem cell precursor that is capable of self-renewal, as well as lineage-specific differentiation. However, the isolation of these putative mammary stem cells has been hindered by the lack of suitable systems that maintain these cells in culture in an undifferentiated state, and by the lack of defined cell surface markers. We have developed an in-vitro culture system in which primary human mammary epithelial cells isolated from reduction mammoplasties, are cultured as “mammospheres” on non-adherent surfaces. We have demonstrated that mammospheres are highly enriched in undifferentiated cells capable of both self-renewal, as well as differentiation into the three lineages of the mammary gland: myoepithelial cells, ductal epithelial cells, and alveolar epithelial cells. Affymetrix-based gene arrays demonstrate a significant overlap between genes expressed in mammospheres to those previously described in hematopoietic, neuronal, and embryonic stem cells. Studies designed to determine factors that regulate cell fate determination indicate an important role for leukemia inhibitory factor (LIF), as well as NOTCH signaling in the regulation of self-renewal and lineage specific differentiation in this system.
We hypothesize that mammary stem cells or their immediate progeny are prime targets for transformation during carcinogenesis. Normal stem cells and carcinoma cells share many characteristics, including self-renewal capacity, ability to differentiate, resistance to apoptosis, and ability to home to specific sites. Disregulation of the self-renewal capacity of normal stem cells may represent a key event in transformation. This may involve disregulation of pathways that control normal stem cell self-renewal, such as the Wnt signaling pathway,
LMO4, PTEN, and BMI1. Furthermore, we find that the phenotypic heterogeneity found in human breast carcinoma best fits a stem cell model in which transformed stem or progenitor cells undergo aberrant differentiation. Utilizing flow cytometry, we have identified a small population of cells within primary or metastatic human breast carcinomas that bear the cell surface phenotype CD44+CD24-/lowESA+Lineage- that
have the property of tumor stem cells. As few as 200 of these cells are able to generate tumors in NOD-SCID mice, while the vast majority of cells in these tumors that lack this phenotype are incapable of tumor formation, even when tens of thousands of cells are injected. Consistent with a stem cells model, the CD44+CD24-/lowESA+Lineage- cells generate
tumors that recapitulate the phenotypic heterogeneity found in the original tumors. Current therapies that have been developed by virtue of their ability to induce tumor regression may selectively target more differentiated cells in tumors, while leaving the tumor stem cell population intact, accounting for treatment resistance and relapse. More effective therapies will require the targeting and elimination of the tumor stem cell population in breast cancer patients.
P2
Survival pathway and relationship to breast cancer therapy. Reed JC. The Burnham Institute, LaJolla, CA
Data Not Provided
P3
Breast MRI – where we are today. Daniel BL. Stanford University, Stanford, CA
Data Not Provided
P4
Breast reconstruction: the perforator flap technique. Allen R. New Orleans, LA
Data Not Provided
MS1-1
Control of cell cycle progression in breast cancer.
Pestell RG. Georgetown University Medical Center, Washington, DC
Orderly progression through the mammalian cell cycle is coordinated by the sequential activation and inactivation of cyclin-dependent holoenzymes. The cell cycle states include the initiation and completion of DNA replication (S phase) and cell division or mitosis (M). In between these are gaps (G). In current models of cell cycle control, the transition between cell cycle states are regarded as checkpoints at which the cellular environment is assessed for growth factors and DNA integrity. Passage through a restriction point in late G1 is coordinated by a group of serine threonine kinases. Cyclin D1 encodes a labile rate-limiting regulatory subunit of a G1S holoenzyme. Substrates for cyclin-dependent kinases in breast epithelial cells include the retinoblastoma susceptibility gene product [pRB protein] and the related p107 and p130 proteins. Activities of these holoenzymes are, in turn, regulated by post-translational modification by CDK-activating kinase and Cdc25 phosphatases. The RB protein, once phosphorylated by cyclin D-dependent kinases, is sequentially phosphorylated by cyclin E/CDK2 kinase. Negative regulators of the cyclin-dependent holoenzymes include the endogenous inhibitors of the p21 (p21CIP1, p27KIP1, p57KIP2 and INK4
family (p16INK4a, p15INK4b, p18INK4c, p19INK4d).
The vast majority of human cancers have abnormalities in one or more of the cell cycle components due to hyperactivation of Cdk and/or a decrease in negative regulation of Cdk function. A common feature in human breast cancer includes the overexpression of the cyclin D1 gene, initially cloned as a breakpoint rearrangement of the PTH gene in a parathyroid adenoma. The abundance of cyclin D1 is rate limiting in growth factor-induced DNA synthesis in MCF-7 human breast cancer cells. Homozygous deletion of the cyclin D1 gene resulted in mice that are resistant to oncogenesis by Ras or ErbB2. A variety of studies have identified the cyclin D1 gene as a downstream target of a broad array of
S2
Abstracts – Invited Speakers
oncogenic and growth factor signaling pathways. In addition, cyclin D1 protein is stabilized through activation of the AKT signal pathway. Recent studies have identified an important role for cyclin D1 in regulating cellular differentiation. Cyclin D1 forms physical interactions with histone acetyl transferases (P/CAF, p300, AIB1) and several transcription factors (ERα, AR, PPARγ) which, in turn, regulate breast cellular proliferation. The accumulating evidence that cyclin D1 and cyclin E either physically interact with, or regulate the activity of histone-modifying proteins, provides important evidence for cross talk between cell cycle control and acetylation. As histone acetylases regulate the activity of diverse proteins including histone transcription factors, coactivators, and structural proteins, the abundance of these regulatory subunits may play a role in coordinating diverse metabolic processes.
MS1-2
Tumor-specific low molecular weight forms of cycline E induce genomic instability and resistance to anti-estrogens, p21, and p27 in breast cancer.
Keyomarsi K, Akli S. University of Texas, MD Anderson Cancer Center, Houston, TX
Cyclin E, a positive regulator of the cell cycle, controls the transition of cells from G1 to S phase. Deregulation of the G1-S checkpoint contributes to uncontrolled cell division, a hallmark of cancer. We have previously reported that cyclin E is overexpressed in breast cancer and such overexpression is usually accompanied by the appearance of low molecular weight (LMW) isoforms of cyclin E protein, which are not present in normal cells. Furthermore, we have shown that the expression of cyclin E low molecular weight isoforms can be used as a reliable prognostic marker for breast cancer to predict patient outcome. The tumor-specific processing of cyclin E is generated by an elastase like serine protease that cleaves the full-length form at 2 distinct sites in the amino terminus. These LMW forms have higher CDK2 kinase activity and differ in substrate specificity from the full-length cyclin E. This hyperactivity is due to more effective binding of CDK2 to the LMW forms than the full length cyclin E. We also examined the role of cyclin dependent kinase inhibitors, p21 and p27 (CKIs) in the hyperactivity of the LMW forms of cyclin E. Our analysis revealed that the full length cyclin E/CDK2 complexes could be readily inhibited by both CKIs using either Histone H1 or GST-Rb as substrates. However, the LMW cyclin E/CDK2 complexes were significantly more resistant to inhibition by the CKIs, both in vitro using purified p21 and p27, and in vivo when the CKIs were co-infected with cyclin E and CDK2. To address the biological properties of LMW cyclin E isoforms in cultured cells, we stably transfected human mammary epithelial MCF7 cells with each of the forms of cyclin E. Our results revealed that overexpressing the LMW forms of cyclin E transformed MCF7 cells from an estrogen-responsive, antiestrogen sensitive state to one in which the cells are significantly resistant to antiestrogens. The LMW forms of cyclin E can also bind and sequester p21 and p27 without being inhibited. Such deregulation of the G1/S checkpoint as induced by the LMW cyclin E also leads to genomic instability. The genetic instability and the increased resistance to endocrine therapy and cyclin dependent kinase inhibitors, provide a molecular mechanism for poor clinical outcome of breast cancer patients with high levels of LMW forms of cyclin E in their tumor.
MS1-3
Clinical development of targeted cell cycle inhibitors. Swain S. National Cancer Institute, Bethesda, MD
Data Not Provided
MS2-1
Partial breast irradiation: current status. Vicini F. William Beaumont Hospital, Royal Oak, MI
Introduction: Multiple phase III trials have demonstrated equivalent long-term survival between breast conserving therapy (BCT) and mastectomy in patients with early-stage breast cancer but have provided
insufficient information on the optimal volume of breast tissue requiring post-lumpectomy radiation therapy (RT).
Materials and Methods: Since 1993, 199 cases of early stage breast cancer were prospectively treated with radiation therapy limited to the region of the tumor bed after conservative surgery (CS) at William Beaumont Hospital (WBH), Royal Oak, Michigan. Radiation therapy was administered using interstitial brachytherapy in all cases [120 cases with low dose rate (LDR) brachytherapy and 79 with high dose rate (HDR) brachytherapy]. The LDR brachytherapy dose was 5000 cGy delivered over 96 hours and the HDR dose was 3200 cGy in 8 fractions (twice per day over 4 days) or 3400 cGy in 10 fractions (twice per day over 5 days). The clinical target volume included the lumpectomy cavity plus a 1-2 cm margin. Local-regional control, disease-free and overall survival were analyzed. Median follow-up was 65 months. In order to compare potential differences in failure rates based upon the volume of breast tissue irradiated, results in a matched cohort of 199 patients treated with conventional whole breast RT at WBH were analyzed. Match criteria included tumor size, nodal status, patient age, margins of excision, estrogen receptor status and the use of tamoxifen.
Results: Five ipsilateral breast failures were observed in patients treated with partial breast irradiation (PBI). Two failures were classified as representing recurrences of the index lesion and 3 as new primaries in untreated breast tissue. The cumulative incidence of local recurrence was 1%. On matched-pair analysis, no significant differences in the rate of local recurrence were noted between patient groups based upon the volume of breast irradiated (1% in patients treated with PBI vs 1% in patients treated with whole breast RT, p=0.65). Cosmetic results were judged as good/excellent in 98% of all brachytherapy patients.
Conclusion: Results with brachytherapy limited to the region of the lumpectomy cavity after tumor excision provide comparable 5-year outcomes to whole breast treatment in selected patients. In recognition of the success of this work and data from other institutions, multiple other centers in the United States (US) and Europe have now started exploring this concept and several similar phase I and II studies have been initiated. In addition, other methods of delivering PBI are also being explored such as the use of the MammoSite balloon breast brachytherapy catheter approved by the US FDA in May of 2002 as well as single fraction, intra-operative radiation therapy delivered at the time of tumor excision. Currently, we are offering PBI to women as an option for the management of their breast cancer (on study) but are also exploring if the implant (which requires the temporary placement of needles or catheters in the breast) can be replaced with 3D conformal external beam RT delivered in only 5 days. Thirty-one patients have been treated and early results have been excellent.
MS2-2
Intra-operative breast radiation: the targeted intra-operative radiotherapy (Targit) trial.
Vaidya JS, Tobias JS, Houghton J, Joseph D, Wenz F, Hilaris BS, Massarut S, Keshtgar M, Sainsbury R, Taylor I, Corica T, Saunders C, Roncadin M, DSouza D, Baum M. University College London, London, United Kingdom; Middlesex Hospital, London, United Kingdom; Sir Charles Gairdner Hospital, Perth, Australia; University of Mannheim, Mannheim, Germany; Our Lady of Mercy Medical Center, New York Medical College, New York, NY; Centro di Riferimento Oncologico, Aviano, Italy
Early local recurrence usually occurs at the site of the primary tumour, suggesting that it may be unnecessary to irradiate the whole breast in all patients. In 1998, we pioneered the use of targeted intra-operative radiotherapy (Targit) with a portable device, Intrabeam , that delivers 50Kv x-rays from the surface of a spherical applicator, inserted in the tumour bed. The physical dose is 20Gy at the surface of the applicator and 5Gy at 1cm depth delivered over 25-30 minutes. The estimated biological effectivity is higher by a factor of 2 - 3 in clinical analogy to radiosurgery and IORT of other body parts.
We conducted pilot studies in the UK, USA, Germany, Italy and Australia. The traditional boost dose was substituted by a single dose with Intrabeam, with the aim of assessing the safety and overall feasibility of the approach. We have treated 185 patients. At the median follow up of 22
months, there have been 2 relapses. One recurrence in the UK cohort at 3.5 years was in a separate quadrant and the other in German cohort was diffuse at 2m. 22 patients did not have any further radiotherapy because of various reasons such as patient choice, older age, SLE, previous contralateral breast cancer. The cosmetic results are satisfactory and a formal analysis is being presented separately. We have thus found the technique to be feasible and safe.
Our ultimate aim is to test in a pragmatic randomised trial, whether Targit can effectively substitute the whole course of postoperative radiotherapy in patients with low risk of local recurrence and, by virtue of its excellent conformation (no geographical misses) improve upon the traditional boost dose in patients with high risk of local recurrence. A multi-centre randomised trial (TARGIT) is underway and is open for participation from interested centres. If found effective, Targit may be able to replace the usual 6-week course of postoperative radiotherapy and this would have significant implications for the patient and the healthcare system.
1. Vaidya JS, Baum M, Tobias JS; Ann Oncol 2001;12:1075-80
MS2-3
Intensity-modulated breast radiotherapy: the new standard of care?
Pierce LJ. University of Michigan, Ann Arbor, MI
Intense research in recent years has focused upon further technical improvements in radiotherapy (RT) planning and delivery in the treatment of breast cancer. In contrast to standard RT techniques where 2-dimensional planning only optimizes dose in a single plane of the breast, emphasis has now been placed upon development of techniques to improve conformal dose delivery and homogeneity throughout the entire target volume and to further reduce RT exposure to the heart, lung, and contralateral breast. Many studies have demonstrated the superiority of 3-dimensional planning over 2-dimensional techniques with respect to improved dose homogeneity throughout the target, the ability to deliver more conformal therapy, and the ability to use dose-volume data to predict normal tissue complication probabilities. Recent studies have suggested, however, the need for further dose optimization beyond that obtained with 3-dimensional planning alone.
Further dose optimization has been achieved using a new treatment delivery technique called Intensity-Modulated Radiation Therapy (IMRT). IMRT removes the usual reliance upon flat (or uniform internsity) radiation fields and instead uses a variable intensity pattern ususally determined with a computerized optimization algorithm. This algorithm, often called ‘inverse planning’ is used to determine the intensity pattern to be delivered since there are too many individual ‘beamlet’ intensities involved to interactively determine the correct beamlet weights using forward planning by a dosimetrist. The combination of IMRT delivery with inverse planning tools is expected to achieve better dosimetric results than standard or 3-dimensional techniques, resulting in either the improvement of local control due to improved coverage of the target or reduced normal tissue dose while achieving the same tumor coverage.
Many techniques to intensity modulate dose in the treatment of breast cancer have been proposed and, in some cases, utilized in the clinic. The benefits of many of these techniques will be discussed.
With the advantages in dose homogeneity observed using IMRT for breast cancer, IMRT may appear to be the future ‘gold standard’ of radiotherapy. While this technical advance is truly promising, many
issues will have to be resolved before IMRT is routinely applicable. Adjustment for motion and daily set-up variation will be necessary to minimize rapid dose fall-off due to shart dose gradients observed with IMRT. Improvements in dose homogeneity throughout the target and restriction of high dose to normal tissues may come at the expense of increased exposure of other tissues to low dose RT, the consequences of which are unknown. And finally, whether the dosimetric improvements obtained with IMRT will translate into improvement in clinical outcome is still unclear. These will be the challenges to be addressed in the next generation of clinical studies.
MS3-1
Estrogen signaling from the plasma membrane in breast cancer. Levin ER. Long Beach VAMC, Long Beach, CA; UC-Irvine, Irvine, CA
Rapid and more prolonged effects of estrogen result from steroid binding its receptor pools localized both in the plasma membrane and the nucleus. At the membrane of many target cells, estrogen binds classical ERα and ERβ, receptors that are G-protein coupled in membrane rafts (such as caveolae). However, ER also may tether to the cytoplasmic face of the membrane via binding to caveolin-1. Caveolin-1 facilitates ER transport to the membrane through direct binding, and may serve as a scaffold to co-localize G proteins, growth factor receptor tyrosine kinases, and non-receptor tyrosine kinases (e.g.Src) at defined membrane areas. Co-localization with other signaling molecules facilitates rapid signaling by membrane ER and underlies the important effects of estrogen to promote growth and survival. In breast cancer, an important cross-talk occurs from membrane ERα to transactivation of members of the EGF receptor family. The cross talk mainly requires the ligand binding domain of ERα inducing the autophosphorylation of EGFR or ErbB2.The cross talk requires Src, matrix metalloproteinases II and IX, and the secretion of HB-EGF. EGFR autophosphorylation triggers cascades leading to the activation of ERK MAP kinase and PI3 kinase, cell cycle progression, and the survival of breast cancer cells. Specific targets of this signaling include the upregulation of cyclins D1 and B1 production, cell cycle kinase activation (Cdk4 and Cdc2), and transition through G1/S and G2/M checkpoints. Intact BRCA1 opposes many of these key functions of estrogen, a novel action for this tumor suppressor protein that is lost when BRCA1 is mutated in human breast cancer. Intact BRCA1 also prevents EGF and IGF-I signaling through ERK to proliferation. When the E domain of ERα is targeted to the plasma membrane of ER negative breast cancer, E2 activation of ERK induces cell proliferation after 3-4 days of steroid exposure. This occurs despite the absence of the nuclear receptor. However, targeting the E domain to the nucleus also results in E2-induced proliferation, suggesting that both receptor pools are important. Intact BRCA1 inhibits proliferation in either model. Typical treatment for breast cancer includes taxol chemotherapy, radiation, or tamoxifen administration, and these modalities in part cause cancer cell apoptosis through inducing c-Jun N-terminal kinase upregulation, inactivating phosphorylation of Bcl-2 and Bclxl, and inhibition of the apoptosome. Estrogen serves as a survival factor in these situations, and prevents the mentioned apoptotic signaling by transactivating EGFR and inhibiting JNK. Estrogen-induced survival also is linked to activation of ERK. Estrogen promotes the survival and migration of endothelial cells and enacts blood vessel formation via signaling through p38 MAP kinase; this is potentially relevant to tumor angiogenesis.Thus, rapid but sustained signaling from membrane estrogen receptors to the post-translational modification of existing proteins, and the transcriptional transactivation of target genes importantly contributes to breast cancer biology
MS3-2
ER interaction with AP-1.
Kushner PJ. Metabolic Research Unit, San Francisco, CA
S4
Abstracts – Invited Speakers
MS3-3
BRCA1 and ER.
Rosen EM, Fan S, Ma Y. Lombardi Cancer Center, Georgetown University, Washington, DC
Mutations of the breast cancer susceptibility gene BRCA1 confer a high risk for breast cancer and ovarian cancers and a significantly increased risk for several other hormonally responsive tumor types, including cervical, endometrial, and prostate cancers. As is true of other tumor suppressors, BRCA1 functions in cell cycle regulation, DNA repair, and apoptosis pathways. However, these activities, by themselves, do not explain the specific association of BRCA1 mutations with hormone-responsive tumor types. We found that BRCA1 selectively inhibits the activity of the liganded estrogen receptor (ER)-alpha, in human mammary and prostate cancer cell lines. The ability of BRCA1 to transcriptionally repress ER-alpha is due, in part, to a direct interaction between the BRCA1 and ER-alpha proteins and, in part, to down-regulation of its transcriptional coactivator, p300. On the other hand, BRCA1 does not inhibit the activity of ER-beta or the progesterone receptors (PR-A and PR-B). BRCA1 inhibits the conserved carboxyl-terminal ligand-dependent ER-alpha activation function-2 (AF-2) but has no effect on the amino-terminal activation function-1 (AF-1). We have identified the contact points for BRCA1 on ER-alpha and vice versa, and we are in the process of designing full-length BRCA1 mutants that selectively disrupt its ability to repress ER-alpha activity but not its function in the DNA damage response. Interestingly, an ER-a mutation commonly observed in precancerous lesions and in invasive breast cancers (ER-K303R) renders the estrogen receptor resistant to repression by BRCA1. Over-expression of several oncogenes or oncogenic signaling pathways linked to breast cancer (eg., cyclin D1, c-Myc, and c-Akt) “rescued” (reversed) the BRCA1 inhibition of ER-alpha activity, suggesting that these pathways may functionally inactivate the BRCA1 protein in the absence of a BRCA1 mutation. The ability of indole-3-carbinol and genistein - two phytochemicals proposed as chemoprevention agents for hormone-responsive cancer types - to inhibit estrogen-inducible ER-alpha activity was due, in part, to up-regulation of the expression of BRCA1. Finally, alcohol (ethanol) - consumption of which contributes to breast cancer risk - increased the transcriptional activity of alpha, in part, by up-regulating ER-alpha protein levels and, in part, by down-regulating the expression of BRCA1. Taken together, these findings suggest that BRCA1 inhibition of ER-alpha activity contributes to its tumor suppressor activity for estrogen-dependent cancer types.
MS3-4
Molecular insights into endocrine resistance - implications for future therapies.
Johnston SRD. Royal Marsden Hospital, London, United Kingdom
For postmenopausal women with estrogen receptor (ER) positive advanced breast cancer, estrogen deprivation therapy with aromatase inhibitors (AIs) is now considered more effective first-line therapy than the antiestrogen tamoxifen. However, it is known that hormone-sensitive breast carcinomas successfully treated by AIs or tamoxifen will over time acquire endocrine resistance and start to re-grow. A number of potential mechanisms have been proposed to explain endocrine resistance including loss of functional ER, poor pharmacokinetics and/or inefficient deprivation of estrogen biosynthesis or blockade, or mutations in ER or the aromatase enzyme. Recent laboratory studies have shown gradual adaptation of breast cancer cells over time to the low levels of circulating oestrogens induced by AIs, and investigated the subsequent mechanisms of acquired resistance which allow cells use to bypass and escape from oestrogen deprivation. Hormone-sensitive wild-type MCF7 cells treated by long-term oestrogen deprivation (LTED) adapt, becoming hypersensitive to very low levels of estradiol. In part this is caused by an increase in ER expression and its associated transcriptional activity. In addition there is evidence for increased “ross-talk” between various growth factor receptor signalling pathways and ER at the time of relapse, with ER becoming activated and super-sensitised by a number of different intracellular kinases,
including mitogen-activated protein kinases (MAPKs) and the insulin-like growth factor (IGF) / AKT pathway. There is evidence that increased expression of HER2 / HER3, MAPK, and IGFR signalling in cells that become resistance to LTED or tamoxifen may phosphorylate and activate residual ER. This link has been confirmed by experiments in which ER-mediated gene transcription in endocrine resistant cells is abrogated by various approaches to interrupt up-stream signalling, including the EGFR tyrosine kinase inhibitor gefitinib, the MEK inhibitor UO126, and the ER downregulator fulvestrant which degrades ER receptor. Thus, ER remains an integral part of signalling even following failure of either aromatase inhibitors or tamoxifen, and strategies to target the enhanced expression and pathways which activate ER are worth exploring in the clinical setting.
MS4-1
Local-regional management issues in the elderly. Fentiman IS. Guy’s Hospital, London, United Kingdom
Evidence is now available to refute the many misconceptions concerning the nature of breast cancer in older women. This is an age group in which under-investigation and undertreatment has been common on both sides of the Atlantic. Many older women are being denied the benefits of screening. With age as the major risk factor and the median life expectancy of a 70-year old women being 15 years, mammographic screening can be cost-effective in women aged 50-79. Average sub-clinical sojourn time of tumours in 70 year olds is 3.6 years, so that biennial screening is reasonable. Frailty in older women has been overestimated: only 4% of breast cancer patients aged >65 in the SEER project had 3 grade 2 comorbidity. In the Guy’s trial comparing modified
radical mastectomy and wide excision plus tamoxifen for patients aged >70, over 50% were alive 10 years later.
There are subtle differences in the biology of the disease with increasing age and a tendency to better differentiated, slower growing ER positive tumors. Nevertheless one third of cases aged >70 have grade III lesions, many of which will be ER-ve so that treatment has to be tailored to the needs of the individual patient and her tumor. Several randomized trials have shown that tamoxifen alone leads to a high rate of local progression. EORTC 10850 demonstrated this local relapse be reduced substantially by wide excision prior to tamoxifen. In the subset of patients treated by wide excision plus tamoxifen at Guy’s Hospital the major risk factor for breast relapse was vascular invasion (p = 0.04), followed by tumor grade (p = 0.47). Neither ER status nor margin status were significant variable on multivariate analysis.
There is mounting evidence that older women are at reduced risk of axillary nodal relapse when treated with tamoxifen and a selective policy of avoidance of axillary surgery in patients with N0 and ER+ve cancers is reasonable. An alternative approach is the use of sentinel node biopsy if knowledge of nodal status will have an impact on management. The role of breast irradiation in the older age group is still controversial. In younger women the unacceptably high breast relapse rate when radiotherapy is not given as part of breast conservation therapy has mandated its use. Radiation is often withheld in older women for logistic reasons or because of fears of cardiac damage in those with left sided lesions. Hypofractionation of standard radiotherapy or the use of intraoperative brachytherapy may be useful alternatives. There remains a need for randomized trials to determine simpler but effective local treatments in older women with breast cancer.
MS4-2
Systemic breast cancer therapy in the elderly. Muss HB. University of Vermont, Burlington, VT
Breast cancer is a disease of aging and almost half of the new patients diagnosed with breast cancer in the U.S. are 65 years and older. The U.S. population continues to age; by the year 2025 about 20% of the population will be 65 years and older. Older women with breast cancer are less likely to have mammographic screening, less likely to be offered breast conserving surgery, and breast radiation, and less likely to be offered adjuvant systemic therapy. Although breast cancer tends to have more favorable biologic characteristics in older patients, age and
stage adjusted survival is similar for older and younger patients - the exception being the very young (>40 years) and the very old (85+ years). Breast cancers in older patients are more likely to be of lower tumor grade, ER positive, HER-2 (c-erbB-2) negative, and have lower tumor cell proliferation rates (low S-phase). In the adjuvant setting, the overview analysis of the Early Breast Cancer Trialists Collaborative Group (EBCTCG) has clearly shown that older patients (70 and older) with ER+, node-negative, and node-positive early breast cancer have significant improvements in both relapse-free and overall survival with tamoxifen. For those in whom tamoxifen is contraindicated, anastrozole represents an excellent option. Chemotherapy data are sparse in for those 70 and over; extrapolating from patients 50 to 69 years old in trials analyzed by the EBCTCG suggests that patients above 70 are likely to derive the same benefits as other postmenopausal women in reducing the annual risk of relapse and death. The challenge in caring for older breast cancer patients is factoring in the patients anticipated life span and the effect of comorbidity on treatment selection. Today, a healthy 65 year old women is estimated to live on average another 20 years; for a healthy 85 year old average life-expectancy is about 6 years. Co-existing illness however can have a dramatic effect in shortening survival and minimizing the benefit of adjuvant systemic therapy, especially chemotherapy, even in high risk patients. Older patients should be considered for chemotherapy if they have reasonable life-expectancy (5-10 years) and large, ER and PR-negative, node negative (N-) lesions or if they are node-positive (N+). The added value of chemotherapy in addition to endocrine therapy in older patients with ER+ lesions is minimal in most node-negative patients but may be substantial in N+ patients. Available literature shows that older patients with breast cancer who are in good general health tolerate standard chemotherapy regimens (for example CMF or AC) as well as younger patients. Older patients with metastatic disease who are ER or PR+ should be treated with endocrine therapy. Once metastases are refractory to endocrine treatment the use of sequential chemotherapeutic agents should be considered. Trastuzumab with or without chemotherapy is another option for those with HER-2+ tumors. Health care providers must overcome age bias and offer older patients the same treatment options as younger patients; taking into account life-expectancy, functional status and co-morbidity is essential in treatment recommendations.
MS4-3
Optimal care in minority populations.
Freeman HP. Ralph Laurent Center for Cancer Care and Prevention, New York, NY
S6
Abstracts – General Sessions
1
Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial.
Smith I , Dowsett M, on behalf of the IMPACT Trialists. Royal Marsden Hospital, London, United Kingdom
Background: The ATAC trial showed that anastrozole (‘Arimidex’; A) has superior efficacy to tamoxifen (T) as adjuvant therapy in early hormone receptor-positive breast cancer. The IMPACT trial compared the efficacy of A and T alone and in combination (C) as neoadjuvant therapy. In contrast to a previous randomized neoadjuvant trial1, IMPACT enrolled patients who were eligible for breast-conserving surgery (BCS) as well as those requiring mastectomy.
Materials and Methods: Postmenopausal women with core biopsy ER+ invasive, operable breast cancer (≥2cm diameter) were randomized double-blind to 3 months’ treatment prior to surgery with A, T or C. Core biopsies were repeated after 2 weeks’ treatment. After 3 months tissue samples were taken during surgery for biological studies; if surgery was not performed a core biopsy was taken. The primary objective was to compare between-treatment differences in objective clinical tumor response (OR) assessed by the product of the 2 maximum clinical diameters. Ultrasound assessments were also made. Secondary objectives included downstaging of surgery in patients initially deemed to require mastectomy, possible identification of surrogate markers for efficacy, and tolerability.
Results: 330 patients (mean age 72years) were randomized to treatment with A (n=113), T (n=108) or C (n=109). Of the 220 patients with surgeon’s preferred surgery recorded at baseline, 56% were deemed to need a mastectomy and 44% were eligible for BCS. The primary endpoint, OR by caliper, was achieved in 37.2%, 36.1% and 39.4% of patients in the A, T and C groups, respectively. The relative risks (RR) of OR for A and C vs T are 1.03 (95%CI:0.73, 1.46) and 1.09 (0.78, 1.54), respectively. Results were similar with ultrasound: 23.9%, 20.4% and 27.5% of patients, respectively, achieved an OR. Differences between treatment groups were not significant for either method of assessment. Of the 124 patients considered by the surgeon to require a mastectomy at baseline, an OR was achieved in 39.1% (18/46), 27.8% (10/36) and 35.7% (15/42) of patients in the A, T and C groups, respectively; RR for A and C vs T are 1.41 (0.74, 2.67) and 1.29 (0.66, 2.50). In these 124 patients, 45.7%, 22.2% and 26.2% in the A, T and C groups, respectively, became eligible for BCS after 3 months’ treatment (A vs T p=0.03; RR 2.05 [1.03, 4.09]). Outcome relating to HER2 will be presented, and biological data reported separately. All treatments were well tolerated and only 1.8%, 2.8% and 3.7% of patients in the A, T and C groups, respectively, withdrew due to a drug-related adverse event. Total cholesterol was unchanged vs baseline in the A group and was reduced in the T and C groups.
Discussion: In the overall population A and T were similarly effective as neoadjuvant therapy in ER+ operable breast cancer in postmenopausal women. In patients recorded as requiring a mastectomy at baseline, twice as many became eligible for BCS in the A group as in the T group.
1. Ann Oncol 2001;12:1527-32
2
Greater Ki67 response after 2 weeks neoadjuvant treatment with anastrozole (A) than with tamoxifen (T) or anastrozole plus tamoxifen (C) in the IMPACT trial: a potential predictor of relapse-free survival.
Dowsett M, Smith I, on behalf of the IMPACT Trialists. Royal Marsden Hospital, London, United Kingdom
Background: Comparative trials of adjuvant therapy in early breast cancer require large numbers of patients (pts) and many years of follow-up to detect differences between treatments. For example, the ATAC trial randomized 9366 pts and acquired sufficient events after 33 months median follow-up to reveal that A was more effective than T or C. Intermediate markers that accurately predict long-term outcome could radically decrease the numbers of patients and time needed for therapeutic comparisons. We therefore explored whether biological response (change in the proliferation marker Ki67) during neoadjuvant therapy with A, T or C would have predicted the outcome of the ATAC trial.
Materials and Methods: Postmenopausal women with core biopsy
estrogen receptor (ER)-positive, invasive operable breast cancer (≥2cm diam) were randomized to 12 wks treatment prior to surgery with A, T or C. Core biopsies were repeated after 2 wks of treatment, and after 12 wks tissue samples were taken from the surgical specimen; if surgery was not performed a core biopsy was taken. Objective response (OR) was measured by caliper. Ki67 and ER were assessed in all biopsy specimens. Progesterone receptor (PgR), HER2 and EGFR were measured on the pre-treatment samples.
Results: 330 pts (mean age 72 years) were randomized to A (n=113), T (n=108) or C (n=109). OR was achieved in 37.2%, 36.1% and 39.4% of pts on A, T or C, respectively; greater advantages for A vs T were seen in the subgroup of pts considered to require a mastectomy at presentation (39.1% vs 27.8%; see separate abstract). Biopsies were performed in 292 pts; after excluding protocol violators and deviators (including 8 pts confirmed after central review to be ER-ve at baseline and 4 with high plasma estradiol levels) 259 pts contributed to the biological analyses. Ki67 expression was significantly reduced by all 3 treatments after 2 and 12 wks: geometric mean reductions (expressed as % change from baseline) after 2 wks (12 wks) were 76% (82%), 59% (62%) and 64% (61%) in the A, T and C groups, respectively. Reductions in Ki67 were virtually maximal at 2 wks with only marginal changes between 2 and 12 wks. The decrease with A was greater than that with T at both time-points (p<0.01), but there were no differences between T and C. There was a weak but significant relationship between change in Ki67 at 2 wks and response to T (p=0.01) but not to A or C. T and C slightly reduced ER levels after 12 wks but there was no change with A (A vs T p<0.01). Comparison of the change in Ki67 according to HER2 and EGFR status will be shown.
Conclusion: A had a greater antiproliferative effect than T or C at both 2 and 12 wks. These results are parallel to the better relapse free survival with A than with T or C in ATAC, suggesting that Ki67 might be used as a marker for long-term outcome in the adjuvant setting. If confirmed by other studies the measurement of short-term changes in Ki67 could radically alter our approach to the comparison of new therapeutic agents in early breast cancer.
3
Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant tamoxifen treatment.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Massobrio M, Porpiglia M, Rinaldini M, Paladini G, Distante V, Franchi R, Failla G, Bordonaro R, Sismondi P, on Behalf of the Italian Tamoxifen Arimidex (ITA) Trial. NCRI and University of Genoa, Italy; University of Messina, Italy; University of Turin, Italy; General Hospital, Arezzo, Italy; Policlinico S. Orsola-Malpighi, Italy; University of Florence, Italy; General Hospital, Casalpusterlengo, Italy; San Luigi Hospital, Catania, Italy; Mauriziano Hospital, Turin, Italy
Background: Tamoxifen (T) represents a common therapy for most estrogen receptor (ER) +ve patients. However, a substantial proportion of women relapse and die in spite of antiestrogenic treatment. Though T is usually regarded as a safe drug, concern has been raised regarding its carcinogenic and cardiovascular effects. The results of a previous trial based on switching patients from T to aminoglutethimide (AG) (JCO
2001;19[22]:4209–15) provided us with the rationale for investigating switching women receiving adjuvant T to anastrozole (A), a new-generation non-steroidal aromatase inhibitor, expected to be less toxic and more effective than AG.
Patients and Methods: Postmenopausal ER +ve women on existing adjuvant treatment with T (20 mg/day) for 2 or more years were randomly assigned to continue with T up to a total of 5 years or to be switched to A (1 mg/day) for a comparable period of time. Women were regularly followed until they reached a major trial endpoint which included any of the following: disease recurrence, second primary tumor (including a second breast tumor) and death (from any cause).
Results: 426 patients were enrolled between March 1998 and October 2002 (median follow-up time: 24 months). All patients were node +ve and ER +ve, and groups were well balanced with respect to age, tumor size, tumor grade, treatment of primary tumors (including adjuvant chemotherapy) and median time on T before randomization. A total of 218 and 208 patients were assigned to continue on T or receive A, respectively. There were 26 events in the T group (19 disease recurrences, 5 second primaries, 2 deaths in absence of progression) and 10 events in the A group (8 disease recurrences, 2 second primaries). After adjusting for age, number of involved nodes, tumor grade and treatment of primary
tumors, the results were in favor of A. The hazard ratio of relapse for the women switched to A was 0.36 (0.17–0.75; p=0.006). Hazard ratio of death was 0.18 (0.02–1.57; p=0.07). Serious adverse events were more common in the women continued on T (29 vs 14).
Conclusions: These findings confirm the role of A in the treatment of early breast cancer. Furthermore, the findings show that switching patients on adjuvant T to treatment with adjuvant A appears to decrease their risk of relapse and death. A was found to be more effective and induce less serious adverse effects than T in women already on treatment with this antiestrogen.
4
Analysis of time to recurrence in the ATAC (arimidex, tamoxifen, alone or in combination) trial according to estrogen receptor and progesterone receptor status.
Dowsett M, on Behalf of the ATAC Trialists’ Group. Royal Marsden Hospital, London, United Kingdom
Background: The ATAC trial randomized 9366 postmenopausal women with early breast cancer to 5 years of treatment with anastrozole (A) or tamoxifen (T) or the combination (C) of A+T. After 47 months median follow-up the hazard ratio (HR) for disease-free survival was 0.86 (0.76–0.99, p=0.03) in the overall population and 0.82 (0.70– 0.96, p=0.014) in the estrogen receptor (ER) and/or progesterone receptor (PgR) positive group, in favor of A when compared with T. The corresponding figures for time to recurrence (breast cancer events) were 0.83 (0.71–0.96, p=0.015) and 0.78 (0.65–0.93, p=0.007) in the overall population and receptor-positive group, respectively.
Methods:The status of both ER and PgR was known in 7993 patients and retrospective exploratory analyses were conducted in these patients to compare time to recurrence in the four receptor sub-groups: ER+/-PgR+/-. ER and PgR analyses were carried out in local laboratories.
Results:The results are shown in the table below:
These results are in line with the overall results: there were fewer events in the A arm for all the sub-groups except ER-PgR-, which is now generally accepted as insensitive to hormonal therapy. There were similar numbers of events in the T and C arms for all subgroups. Comparison of the ER+PgR+ with the ER+PgR- groups indicated a marginally significant difference (p=0.05), but this was not a preplanned comparison and was not a full test of interaction. Adjustment for nodal status, tumor size, tumor grade or prior adjuvant chemotherapy did not affect this result.
Discussion:These exploratory results create the hypothesis that there is a greater differential efficacy between A and T in ER+PgR- than ER+PgR+ tumors. This hypothesis requires prospective confirmation and should not lead to change of therapy in patients currently receiving T. The difference might depend on a greater efficacy of A than T in breast carcinomas expressing growth factor receptors such as HER2 that co-segregate with PgR- status in ER+ tumors. This possibility is being assessed in further translational research in the ATAC trial.
N A T C A vs T*
ER+PgR+ 5704 129(7%) 154(8%) 152(8%) 0.82 (0.65-1.03)
ER+PgR- 1370 39(9%) 73(17%) 91(19%) 0.48 (0.33-0.71)
ER-PgR+ 220 14(22%) 20(26%) 19(23%) 0.79 (0.40-1.50)
ER-PgR- 699 62(27%) 66(27%) 63(29%) 1.04 (0.73-1.47)
*Hazard ratios less than one indicate values in favor of anastrozole
5
Ten-year outcome of breast-conserving surgery (BCS) and radiotherapy (RT) in women with breast cancer (BC) and germline BRCA 1/2 mutations: results from an international collaboration.
Pierce L, Levin A, Rebbeck T, Kardia S, BenDavid M, Harris E, Solin L, Haffty B, Wynen E, Gaffney D, Narod S, Metcalfe K, Dawson L, Eisen A, Whelan T, Olivotto I, Galinsky D, Meirovitz A, Olopade O, Garber J, Nixon A, Merajver S, Isaacs C, Weber B. U Michigan, Ann Arbor, MI; U Pennsylvania, Philadelphia, PA; Sheba Medical Ctr, Ramat-Gan, Israel; Yale U, New Haven, CT; U Utah, Salt Lake City, UT; U Toronto, Toronto, Canada; Hamilton Regional Cancer Ctr, ON, Canada; BC Cancer Agency, BC, Canada; Hadassah Medical Ctr, Jerusalem, Israel; U Chicago, Chicago, IL; Dana-Farber, Boston, MA; Georgetown U, Wash, DC
Background: BCS+RT is accepted treatment for Stage I/II BC, but previous studies with limited patient numbers and/or F/U have suggested increased
rates of in-breast tumor recurrence (IBTR) in BRCA 1/2 carriers compared to historical controls. Some have postulated increased risk of chronic RT complications in BRCA 1/2 carriers due to possible alterations in DNA repair. Thus, the purpose of this study was to report the outcome of BCS+RT in a large collaborative series of BRCA1/2 carriers compared to a matched sporadic cohort (SC).
Materials and Methods: Following IRB approval, the charts of 170 BRCA1/2 carriers and 469 patients with sporadic BC diagnosed with Stage I/II disease and treated with BCS+RT from 12 medical centers were reviewed. Patients in the genetic cohort (GC) were matched by age and date of diagnosis with the SC. Conditional logistic regression models were used to analyze rates of recurrence and treatment-related complications by cohort.
Results: GC and SC were comparable except for more medullary (p=.0006), grade 3 (p=1.7 E-05), ER neg (p=1.2 E-10) and PR neg (p=8.5 E-10) cancers in GC. With 8.3-year median F/U in GC and 6.3 yrs. in the SC, 10-yr IBTR as isolated first recurrence was 12.5% for GC and 8.6% for SC (p=.55). Significantly more IBTR occurred in a different quadrant from the primary lesion in GC vs.SC (60% vs. 26%, p=.02). When IBTR was analyzed by age (≤40, 41-50, 51-65,>65 years), nodal status and stage, IBTR was not significantly increased in GC vs. SC in any subset. In the patients with an isolated IBTR, freedom from subsequent relapse was 100% for GC vs. 58% in SC (p=.02). Contralateral breast cancers were significantly greater in GC (25% versus 4% at 10 yrs. p<.0001;HR 8.0). Cause- specific, relapse-free, and overall survivals did not significantly differ by cohort. Using RTOG/EORTC grading, rates of RT-associated complications were similar by cohort. Discussion: Using a large collaborative database, 10-year resulst of BCS+RT do not suggest significantly increased rates of IBTR or RT-associated complications in BRCA1/2 cariers compared to sporadic controls even when analyzed by age and stage of disease. Rate of contralateral breast cancers, however, was significantly higher in carriers. Our results suggest an even greater need for risk reduction strategies for the contralateral breast compared to the irradiated affected breast at 10 years.
6
Breast-conserving therapy after neoadjuvant chemotherapy: the M. D. Anderson Cancer Center experience.
Chen AM, Meric F, Hunt KK, Thames HD, Outlaw ED, Strom EA, McNeese MD, Kuerer HM, Ross MI, Singletary SE, Ames FC, Feig B, Hortobagyi GN, Sahin AA, Perkins GH, Schechter NR, Buchholz TA. The University of Texas M.D. Anderson Cancer Center, Houston, TX
Background: The purpose of this research was to determine patterns of locoregional recurrence (LRR) after neoadjuvant chemotherapy and breast-conserving therapy (BCT) in order to refine eligibility guidelines for this treatment strategy.
Material and Methods: 362 breast cancer patients were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy between 1987 and 2000. Clinical stage (AJCC 2003) at diagnosis was I in 4%, IIA in 24%, IIB in 33%, IIIA in 25%, IIIB in 8%, and IIIC in 7%. Only 4% had positive surgical margins. Rates of LRR, ipsilateral breast tumor recurrence (IBTR), and distant metastasis-free survival were calculated by Kaplan-Meier analysis. Patient and tumor characteristics were then analyzed in an attempt to identify predictors of clinical outcome.
Results: With a median follow-up period of 65 months (range 10-180 months), 34 patients developed a LRR, 21 of which were classified as IBTRs. Five-year actuarial rates of LRR-free, IBTR-free, and distant metastasis-free survival were 91%, 94%, and 86%, respectively. Pretreatment and pathological parameters that positively correlated with IBTR were clinical N2 or N3 stage (p=0.009), pathological tumor size greater than 2 cm (p=0.009), multifocal pattern of residual disease (p=0.005), and lymphovascular space invasion (LVSI) in the specimen (p=0.002). The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 86-88% and 74-82%, respectively. Initial T stage (T1-2 versus T3-4) did not correlate with IBTR (5-year IBTR-free rate: 94% versus 93%, p=0.28). In a Cox logistic regression analysis, clinical N2 or N3 stage, pathological tumor size greater than 2 cm, multifocal residual disease, and LVSI independently predicted for both LRR and IBTR.
Discussion: BCT results in acceptably low rates of IBTR and LRR in appropriately selected patients treated after neoadjuvant chemotherapy.
S8
Abstracts – General Sessions
Advanced nodal involvement at diagnosis, residual tumor size greater than 2 cm, multifocal pattern of residual disease and LVSI predict for relatively higher rates of LRR and IBTR..
7
Pooled analysis of prognostic impact of bone marrow micrometastasis: 10-year survival of 4199 breast cancer patients. Braun S, Vogl FD, Schlimok G, Diel IJ, Janni W, Gerber B, Gebauer G, Coombes RC, Pierga J-Y, Naume B, Pantel K, Collaborative Group Bone Marrow Micrometastasis. Dept. Ob/Gyn, Innsbruck, Austria; Bozen, Italy; Dept. Hem/Oncol, Augsburg, Germany; Dept. Ob/Gyn, Heidelberg, Germany; Dept. Ob/Gyn, Munich, Germany; Dept. Ob/ Gyn, Rostock, Germany; Dept. Ob/Gyn, Nuernberg-Erlangen, Germany; Div. Med., London, United Kingdom; Dept. Hem/Oncol, Paris, France; Dept. Hem/Oncol, Oslo, Norway; Inst. Tumorbiology, Hamburg, Germany
Background: The level of evidence of the prognostic impact of occult metastatic cells (OMC) in the bone marrow (BM) of breast cancer patients is considered rather low because of variations of methods and limited statistical power of single studies.
Design and Methods: We performed a pooled analysis of individual patient data from 8 recently published studies addressing long-term outcome of patients with and without OMC. Data of 4199 patients (stratified by center in order to account for variation due to different immunoassays) were analyzed using univariate and multivariable Cox regression. Primary study end point was overall survival (OS). Events that occurred after 10 years of follow-up were censored. All patients were free of distant metastases at primary surgery. Patients were staged T1 / T2 in 90%, and node-negative in 58%. Adjuvant therapy was administered in 70% patients.
Results: OMC were detected in BM of 1277 patients (30%). The proportion of patients with OMC increased significantly (P<0.001) across strata of tumor size, nodal status and grading. During a 10-year follow-up (median follow-up of survivors, 58 months) 763 patients (18%) died. OMC-positive patients had a significantly higher risk of death from any cause (HR 2.33, 95%CI 2.02-2.70, P<0.001) in univariate analysis. Increased tumor size, axillary lymph node metastases, low grading, and negative estrogen receptor expression were further significant negative prognostic factors (each P<0.001). In the subgroup of OMC-positive patients without adjuvant therapy (285 of 1244; 23%), mortality was significantly increased (HR 1.87; CI 1.32-2.65; P<0.001) as compared with OMC-negative patients. In the multivariable model, presence of OMC in BM remained a significant risk factor for reduced OS for all patients (HR 1.83; CI 1.55-2.15; P<0.001) and those node-negative patients without adjuvant therapy (HR 1.72; CI 1.18-2.51; P=0.004).
Discussion: This pooled analysis provides a high level of evidence for the independent prognostic value of OMC in primary breast cancer. Thus, testing for OMC should be the subject of controlled clinical trials investigating both improved treatment strategies in OMC-positive patients and the necessity of adjuvant therapy in OMC-negative patients.
8
The presence of isolated tumor cells in bone marrow three years after diagnosis in disease free breast cancer patients predicts an unfavourable outcome.
Wiedswang G, Borgen E, Karensen R, Qvist H, Naume B. Ullevaal University Hospital, Oslo; The Norwegian Radium Hospital, Oslo
The aim of this study was to explore the value of analysing for the presence of isolated tumor cells (ITC) in bone marrow (BM) in good prognosis breast cancer patients three years after the diagnosis. Isolated tumor cells in BM was found to be an independent prognostic factor of both distant disease free survival (DDFS) and breast cancer specific survival (BCSS) in 817 breast cancer patients analysed at the of operation (Wiedswang et al 2003). Among these patients, 356 disease-free patient patients were analysed with a second BM at 3 years follow up. BM was aspirated from posterior iliac crest bilaterally, followed by immunocytochemical analysis for ITC by use of anti-cytokeratin mAbs (AE1/AE3) and alkaline phosphatase/anti-alkaline phosphatase reaction. Based on criteria from the European Working Group for Standardisation of Tumor Cell Detection, detection of ≥ 1 cell compatible with a tumor cell was scored as positive.
Results:
The patient population consisted of 70 % T1- and 72 % node negative patients. The detection of ITC in BM was associated with nodal status and the use of adjuvant systemic therapy. After median 25.3 months follow up after the second BM aspiration (65.8 months since diagnosis), 32 patients developed relapse, 12 local and 20 systemic. Of the patients with ITC in BM, 20.8% (11/53) experienced a relapse, as compared to 6.9% (21/303) of those with negative BM analysis (p=0.001). Ten patients died of breast cancer during the observation period. Survival analyses revealed that ITC in BM predicted reduced DDFS and BCSS (p<0.001). In addition to the BM analysis, N-, T-, ER/PgR-status, grade, vascular invasion, p53-, c-erbB2- and cathepsinD-expression were analysed in uni- and multivariate analyses. The presence of ITC in BM was found to be an independent prognostic factor for both DDFS and BCSS, whereas c-erbB2-expression and N-status only for BCSS. Including in the analysis the results from the BM analysis at the time of operation showed that patients with a positive BM both at diagnosis and after 3 years had an especially poor prognosis.
Conclusion:
The presence of ITC in BM 3 years after diagnosis in disease-free breast cancer patients is an independent prognostic factor for both DDFS and BCSS. BM-analysis can be used in the follow up of patients for early disseminating disease monitoring.
9
Micrometastases in sentinel lymph nodes of patients with ductal carcinoma in situ of the breast have no clinical relevance. Wijsman JH, Broekhuizen LN, Peterse HL, Rutgers EJT. Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, Netherlands
Background:(Micro-)metastases may be detected in sentinel axillary lymph nodes of patients with in situ carcinoma or small invasive carcinomas of the breast. For some surgeons this is a reason to routinely perform a sentinel node procedure in situations otherwise known to have an excellent prognosis without axillary staging. The incidence and predictive value of these positive nodes is uncertain.
Methods: Retrospectively a consecutive series of patients was identified with ductal carcinoma in situ (DCIS) or with invasive ductal or lobular carcinoma (IDC/ILC) ≤ 5 mm who had undergone axillary lymph node dissection (ALND) as part of their treatment. All patients had primary tumors, treated in the Netherlands Cancer Institute between 1989 and 1998. The incidence of lymph node metastases after routine examination was compared with that after re-evaluation of new sections of all archived lymph nodes immunostained with CAM 5.2, an epithelial marker. The presence of macro- or micrometastases or solitary cells (i.e. clusters of 10-20 cells) was scored and related to survival.
Results: Routine examination showed one macrometastasis in 71 patients with pure DCIS, no metastases in 12 patients with DCIS with microinvasion (MI) and 1 macrometastasis in 18 patients with IDC/ ILC≤ 5 mm. Immunostaining of all retrieved lymph nodes (mean: 14 per patient) showed:
Patients with Type of lymph node
CAM 5.2 metastasis
positive nodes
n= % solitary cells micro macro
DCIS 7 / 66 11 6 1 0
DCIS+MI 3 / 11 27 2 0 1
IDC/ILC≤ 5 mm 2 / 17 12 0 2 0
None of these patients showed metastases in more than two lymph nodes. All of the node-positive patients remained free of disease with a median follow-up of 102 months (range 36-126), without adjuvant systemic therapy.
Discussion:In these low-risk tumors a relatively high incidence of lymph node metastasis was identified by immunostaining. However, it concerned mainly solitary cells or micrometastases. Because 1) no more than two nodes were affected and survival was excellent and 2) literature has shown excellent prognosis without ALND in these low-risk tumors, we advise not to perform an ALND when a micrometastasis is found in the SN of DCIS. ALND may also be omitted in T1a tumors in the absence of other negative prognostic factors.
10
Randomized trial comparing docetaxel and paclitaxel in patients with metastatic breast cancer.
Jones S, Erban J, Overmoyer B, Budd GT, Hutchins XL, Lower E, Laufman L, Sundaram S, Urba W, Olsen S, Meyers ML, Ravdin PM. US Oncology, Houston, TX; Tufts-New England Med Ctr, MA, Boston, MA; Ireland Cancer Center, Cleveland, OH; Cleveland Clinic, Cleveland, OH; Univ Arkansas Med Ctr, Little Rock, AR; Univ of Cincinnati Med Ctr, Cincinnati, OH; Hem/Onc Consultants Inc, Columbus, OH; Sharp Rees-Stealy Medical Grp, San Diego, CA; Providence Med Ctr, Portland, OR; Aventis Pharmaceuticals Inc, Bridgewater, NJ; Univ Texas Health Science Ctr, San Antonio, TX
Docetaxel and paclitaxel are widely used agents for the treatment of patients (pts) with MBC. In randomized studies, the reported response rates for D have ranged from 30-48% and for P (3-hour infusion) from 16-29%, but such indirect comparisons need to be viewed with caution. We report a randomized trial directly comparing D to P in pts with MBC after failure of anthracyclines. Methods: 449 women were randomized to either D 100 mg/m2 (1-hour infusion) q 3 wks or P 175 mg/m2 (3-hour infusion) q 3 wks. Patients were entered between 1994 and 2001. Eligibility criteria included: bi-dimensionally measurable MBC; and, either 1 prior anthracycline-based regimen as first-line therapy for MBC or disease progression during or within 12 months of completing anthracycline-based adjuvant or neoadjuvant chemotherapy. Results:
The arms were well balanced for (D vs P): median age (56 vs 54); median KPS (90% vs 90%); hormone receptor positivity (56% vs 50%). Intent-to-treat (ITT) analysis was performed for the major efficacy endpoints.
ITT D(n=225) P(n=224) p-value
ORR (CR + PR) 32.0% 25.0% 0.10
SD 38.2% 39.7%
P D 16.9% 29.0%
Med TTP 5.7mos 3.6mos 0.0001
Med OS 15.4mos 12.7mos 0.03
In the analysis of 388 eligible pts evaluable for response, the ORR for D was 37.4% vs 26.4% for P (p=0.02), and D maintained its statistical superiority in TTP and OS. These results were further confirmed in multivariate analyses. Median number of cycles administered was 6 for D and 4 for P. 444 pts received drug and were evaluable for safety, 222 pts on each arm. Grade 3/4 toxicities were more common for D than P: neutropenia 93.3% vs 54.5%; asthenia 23.9% vs 6.8%; infection 14.0% vs 5.0%; edema 11.3% vs 4.5%; stomatitis 10.4% vs 0.5%; neuromotor 9.0% vs 4.5%; neurosensory 8.6% vs 4.5%. Conclusion: The ORR was higher for D than for P, with this difference approaching statistical significance in the ITT analysis. TTP and OS were statistically superior for D. Treatment with D was associated with an increased incidence of grade 3/4 toxicities. Quality of life analyses will be presented.
11
Docetaxel primary chemotherapy in breast cancer: a five year update of the Aberdeen trial.
Hutcheon AW, Heys SD, Sarkar TK, Ogston KN, Eremin O, Walker LG, Miller ID. University of Aberdeen, Scotland, United Kingdom
Background: Primary chemotherapy has been increasingly used in the treatment of operable breast cancer. Clinical response rates of more than 80% occur, although complete pathological responses (cPR), a surrogate marker for survival, occur in less than 20% . The Aberdeen trial and the NSABP B27 trials have demonstrated that the addition of docetaxel to primary chemotherapy results in an increased cPR. We now report survival in the Aberdeen trial.
Patients and Methods: Patients with large or locally advanced (T3, T4, or N2) breast cancers received 4 X CVAP (cyclophosphamide 1000mg/m², doxorubicin 50mg/m², vincristine 1.5mg/m², prednisolone 40mg for 5 days). Those who had responded (CR or PR) were randomised to receive either further 4 X CVAP or 4 X DOC (docetaxel 100mg/m²). All patients who failed to respond, received 4 X DOC (100mg/m²). Clinical and pathological responses were obtained and patients followed for a median of 65 months.
Results: 162 patients were enrolled. 145 patients completed 8 cycles of chemotherapy. The breast cancers in 102 patients (66%) achieved a clinical response (PR or CR) following 4 X CVAP. Following randomisation 50 patients received 4 X CVAP and 47 patients received 4 X DOC. In patients who received 8 cycles of chemotherapy the cCR
& cPR (94% vs 66%) and pCR (34% vs 16%) response rates were higher (p = 0.001 and p = 0.04) in those who received further DOC. Intention to treat analysis demonstrated cCR & cPR ( 85% vs 64%, p = 0.03 ) and pCR ( 31% vs 15%, p = 0.06).
A median follow up of 65 months has now been reached. At this time survival are 93% in those randomised to DOC versus 78% in the CVAP group (p=0.04), with 12 deaths in the CVAP arm and 4 in the DOC arm.
Discussion: This study had previously demonstrated that docetaxel would increase pathological response rates to primary chemotherapy (subsequently confirmed by NSABP B27). This is the first study to demonstrate that primary chemotherapy with docetaxel significantly increases 5-year survival.
12
Phase III adjuvant trial comparing standard versus accelerated FEC regimen in early breast cancer patients. Results from GONO – MIG1 study.
Venturini M, Aitini E, Del Mastro L, Sertoli MR, Conte P, Olmeo N, Mammoliti S, Cavazzini G, Pastorino S, Bruzzi P, Rosso R. National Cancer Research Institute, Genova, Italy; AO Poma, Mantova, Italy; AO Santa Chiara, Pisa, Italy; AO 1 Sassari, Sassari, Italy; Ospedale Galliera, Genova, Italy
Between 1992 and 1997, 1214 patients (pts) with operable breast cancer (node positive and high-risk node negative) were randomly assigned to receive either 6 courses of FEC21 (5-fluororacil 600mg/ m2, epirubicin 60 mg/m2, and cyclophosphamide 600 mg/m2 on day 1, repeated every 21 days) or 6 courses of FEC14 (the same drugs at the same doses of FEC21, q. 14 days, with the support of filgrastim). The distribution of main characteristics was similar in the two arms. Median age was 53 (25-70) years; 43% were premenopausal; 64% node positive; 33% ER and PgR negative.
Nearly 94% of patients completed 6 cycles of chemotherapy (CT), without any substantial difference between the two treatment arms. Eighteen pts never begun CT, and for 9 pts no data were available. About 4% of pts discontinued CT, with no difference between the two treatment arms. Main toxicities leading to treatment discontinuation were: hematological (10 pts), gastrointestinal (5 pts), chemical phlebitis (4 pts), and fever (3 pts). The median dose-intensity actually given was 94% and 93% of that planned, in FEC21 and FEC14 respectively. No toxic death was reported. Grade 4 toxicity was seldom reported and overall accounted for 2.3% in FEC21, and 0.5% in FEC14 arm. The most common grade 3 toxicity was nausea and vomiting observed in 11% and 12% of pts, in FEC21 and FEC14 respectively. Anemia (38%, any grade) and bone pain (33%, any grade) were more common in FEC14 arm, and leukopenia in FEC21 arm (45%, any grade). No case of acute leukemia was reported.
At a median follow-up of 6.7 years, 294 events were recorded. In multivariate analysis, a statistically non-significant 18% reduction in the hazard of death was observed (HR= 0.82, 95% C.L.=0.6-1.12, p=0.22), in favor of FEC 14 arm; while the effect on event free survival was less marked (HR=0.92, 95%C.L.0.73-1.17, p=0.5). When the effect of the experimental treatment on survival was assessed in the strata of the prognostic factors by including in the multivariate model the appropriate interaction terms, only age was associated with a statistically significant variation in treatment effect (p=0.049). The Hazard Ratio associated with the experimental treatment was 0.51 (95% CL 0.27-0.94) in pts <50 yrs, while it was 0.71 (95%CL 0.40-1.25) and 1.48 (95% CL 0.80-2.75) in pts 50-59 years and in patients 60+, respectively. Accelerated FEC is a safe and effective regimen in the treatment of early breast cancer. Despite numbers of events preclude drawing any definitive conclusion, in the whole group of patients accelerated FEC seems to be associated with a favorable improvement in survival compared to standard FEC. Particularly in patients aged less than 50 years, in terms of survival a statistically significant advantage of accelerated FEC was observed.
