Friday, 28 January 2005 Session 7. Best Use of Adjuvant Systemic Therapies II; Chemotherapy Aspects S 11

to find gene profiles with predictive value in relation to the presently used drugs and the upcoming new drugs with a more targeted profile. In conclu- sion, one fit for all is a poor reflection of the complex breast cancer biology and individual drug handling, not compensated by BSA based dosage. We have to make best use of present knowledge regarding regimens, dose in- tensity, dose-density, low-dose and long exposure concepts, tailoring based on inter-individual variations in pharmacokinetics & tolerance, together with a willingness to explore more targeted therapy strategies based on the in- dividual tumour biological characteristics, aiming at more effective therapies with less over- under treatment.

[ • T h e Best Use of Adjuvant Chemotherapy: New Drugs and New Use of "Old" Drugs

C. Hudis. MemoriaI-Sloan Kettering Cancer Center, Box # 206, New York, United States of America

The Best Use Of Adjuvant Chemotherapy: New Drugs And New Uses Of Old Drugs Clifford Hudis, M.D. Chief, Breast Cancer Medicine Service Associate Attending Physician MSKCC Part of the explanation for the falling breast cancer death rate in many parts of the world over the past 15 years, despite increased disease incidence, is certainly the broadened use of chemother- apy in patients with invasive breast cancer. Standard regimens have evolved from brief courses of modestly active single agents to somewhat longer courses of combinations of drugs with greater efficacy. Usual toxicities have been addressed through the use of widely available and effective supportive care interventions. Standard chemotherapy regimens generally include two or more drugs given over a period of 12 to 24 weeks or bit longer. In gen- eral, anthracycline-containing regimens are superior to those without these agents but with increased toxicities, treatments longer than six months are not advantageous, and very high dose-regimens - meaning those that re- quire autologous stem cell support - have not proven significantly or con- sistently superior. Further improvements can come from many directions, including more and better targeted therapies and better selection of pa- tients with sensitive tumors. Building upon classical CMF, anthracyclines were added (and are still tested in comparison) adding a modest improve- ment in disease-free and overall survival partially counterbalanced by in- creased risks of congestive heart failure and other less frequent toxicities. Later, the taxanes were tested as adjuvant therapy and several of the largest randomized chemotherapy trials ever conducted demonstrate advantages in both disease-free and overall survival. A second generation of trials involv- ing taxanes focuses on their optimal use by comparing agents and sched- ules as well as newer combinations. All else being equal, more frequent ad- ministration of a standard AC followed by paclitaxel regimen is superior but the relative contribution of this specific schedule for each of the component agents can not be determined. Accruing studies add again to the standard regimens with new active chemotherapy agents, such as capecitabine and gemcitabine, as well as targeted agents. Appropriate modern chemother- apy options for routine use, as well as the background and justification for selected studies testing new agents, will be reviewed.

[• Preoperative (Neoadjuvant) Systemic Treatment of Breast Cancer

M. Kaufmann. J.W. Goethe University, Dept. of Obstetrics and Gynecology, Frankfurt~Main, Germany

A paradigm shift took place from post- to preoperative systemic treatment of primary operable breast cancer (BC) during the last two decades. Pre- operative (neoadjuvant) systemic therapy (PST) is standard care of locally advanced primary non operable BC and is now considered to be a choice of standard treatment for primary BC. All patients who are expected to be candidates for postoperative (adjuvant) chemotherapy or endocrine therapy are also candidates for PST. Aims of PST are: To obtain freedom of disease, to improve surgical options and to achieve information on response and biol- ogy of the disease. The presentation addresses the opportunities and future aspects within the multidisciplinary care of BC provided by PST. Overview data clearly show that PST results in improvement of surgery with higher rates of breast conserving surgery. PST as an in vivo sensitivity test can vi- sualise the therapeutic effect for the patient and physician. Early elimination of micrometastases prior to development of resistance is the major objec- tive. However, surgical techniques are difficult and uncertain e.g. extent of primary tumor, Iocalisation of residual tumor after clinical and pathological complete response. Patients' fear may be that there is no immediate surgi- cal tumor removal after diagnosis. Anthracyclin/Taxane - based chemothera- pies are the most frequently prescribed treatment type and have been exten- sively studied. The sequential chemotherapy treatment is promising, which may be due to prolonged duration of treatment. At least 4 cycles of PST should be applied. Endocrine tumors demonstrate the best responses in

most trails. Endocrine PST was given primarly in postmenopausal women with hormone receptor positive tumors. On average aromatase inhibitors re- sult in a longer proportion of local response and breast conservation than tamoxifen in direct and indirect comparisons with at last 3- 4 months of treat- ment. Concurrent chemotherapy and tamoxifen should not be given. For pa- tients with endocrine unresponsive tumors treatment should be based on cytotoxic chemotherapy. For patients with tumors overexpressing Her2 anti- Her2 based therapy is under investigation. It is unclear whether treatment should be given until maximum response is reached. Postoperative adjuvant treatment can improve the outcome of patients by using biological charac- teristics of the disease. PST can achieve individualised (tailored) treatment. However, many questions remain to be solved. Imaging determination of margins status, and timing of sentinel lymph node biopsies (SLNB) needs further clarification. Besides clinical monitoring ultrasound is currently the most leasable and reliable apporach. Functional imaging by e.g. contrast - enhanced high resolution MRT-spectroscopy or measuring apoptosis are challenging tools. SLNB in experienced hands after PST is a reasonable ap- proach. Future aspects have to focus on the identification of predictive and decision markers. PST should be offered to every patient with locally ad- vanced as well as to medium and high risk operable primary BC. General recommendations have been made recently by the 2nd International Expert Panel in Biedenkopf/Germany (9/2004).

~ - ~ Predicting Response to Systemic Treatments: Learning from the Past to Plan for the Future

R.D. Gelber, A. Goldhirsch. Dana-Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, United States of America

Tailoring treatment approaches for subpopulations of patients requires the identification of predictive factors. In contrast to prognostic factors, which serve to characterize the background level of risk of relapse against which the benefits and burdens of adjuvant therapies are weighed, predictive fac- tors are inextricably linked to the specific treatment for which responsiveness is defined. Better use of predictive factors is essential both to define future clinical investigations, as well as to improve the patient-oriented informa- tion obtained from existing databases. As chemotherapy, tamoxifen, ovarian function suppression, and radiation therapy have all been demonstrated to be effective treatments in overview analyses, a current acute challenge is to determine how best to utilize these available treatments. Unfortunately, "across the board" overview analyses have been slow to adapt to the growing body of evidence that estrogen receptor (ER) status of the primary influences the magnitude of chemotherapy response as well as endocrine therapy re- sponse. Evaluation of polychemotherapy overview results focused primarily on ER-status and tamoxifen use according to age group reveals striking dif- ferences in chemotherapy effectiveness on the risk of recurrence. For pa- tients with ER-poor tumors, chemotherapy without tamoxifen provides sub- stantial benefit (approximately 37% relative risk (RR) reduction) compared with no adjuvant therapy irrespective of age. For patients with ER-positive tumors, chemotherapy with tamoxifen provides substantial benefit compared with tamoxifen alone for women < 50 years old (approximately 35% RR reduction), but not for women>50 (approximately 15% RR reduction). By contrast, tamoxifen compared with no tamoxifen provides about a 40% RR reduction for the ER-positive cohort and about a 4% RR increase for the ER- negative cohort, without evidence of an influence of age. The role of ovarian function suppression as a side effect of chemotherapy for younger women with ER-positive disease remains controversial and is the subject of an on- going randomised clinical trial (PERCHE). It is clear, however, that ER status alone does not completely define "endocrine responsiveness" because the proper cut-off values of ER are uncertain, the role of progesterone recep- tor (PgR) is not well studied, and the potential for endocrine non-responsive cohorts within the ER-positive population [e.g., tumors with HER-2/neu over- expression] requires further investigation. For example, aromatase inhibitors may prove most effective compared with tamoxifen for patients with an ER- positive, PgR-negative tumor. Given the widespread use of endocrine ther- apies for patients with steroid hormone receptor-positive disease, it is es- sential to revisit questions concerning the effectiveness of chemotherapy within separate cohorts defined by receptor status, patient age (surrogate marker of ovarian function) and use of endocrine therapy. Presenting risk ra- tio plots with confidence intervals estimating treatment effects for biologically and clinically relevant subgroups is critical to understand better the separate contributions to the overall trial results. The STEPP (Subpopulation Treat- ment Effect Pattern Plots) method can assist in determining whether the estimated magnitude of treatment effect changes as a function of increas- ing or decreasing values of a covariate of interest. Investigating the patterns of treatment effects within randomized clinical trials or using datasets from meta-analyses will help to identify features that predict responsiveness to the treatments under study.