- Email: [email protected]
S34 Acceptance of Adjuvant Endocrine Therapies and Quality of Life Issues
Friday, 28 January 2005
Session 9. Back to the Future: What Will it Be Like in 2007?
comorbidity, functional status, and assessment of prognostic and predictive markers, are part of this trial. Older patients with hormone receptor positive tumors should be considered for adjuvant endocrine therapy. The use of chemotherapy in such patients must be tempered by its potential added value to endocrine therapy in reducing recurrence and breast cancer related mortality. Chemotherapy has greater rationale in hormone receptor negative older women where endocrine therapy is ineffective. Factoring comorbidity and life expectancy into these treatment decisions is critical. More adjuvant trials focused on older patients are needed.
I•41
Acceptance of Adjuvant Endocrine Therapies and Quality of Life Issues
L. Fallowfield. Cancer Research, UK Psychosocial Oncology Group,
Brighton & Sussex Medical School, Brighton, United Kingdom Until recently tamoxifen was the primary adjuvant endocrine therapy used in post-menopausal women with early stage, hormone receptor-positive breast cancer (EBCTCG,1998). Despite its efficacy in reducing the risk of recurrence and development of contralateral breast cancer it is associated with serious adverse events including thromboembolic events, stroke and endometrial cancer making it unsuitable for some patients and limiting its use in chemoprevention. Tamoxifen also has many non life-threatening but unpleasant vasomotor, gynaecologic and sexual side-effects that have a deleterious impact on QoL. Some of these influence compliance with more than 40% of patients failing to adhere to prescribed regimens (Fallowfield 2001, Partridge 2002). The aim of the third generation aromatase inhibitors(AIs) is to enhance the efficacy of endocrine treatment without the associated sideeffect profile. Early QoL results from 3 large international trials compared letrozole versus placebo (MA-17), and tamoxifen versus anastrozole (ATAC) and exemestane (IES). MA-17 and IES were sequencing trials in which patients had already received either 5 or 2-3 years respectively of tamoxifen whereas ATAC patients were not pre-treated. All trials showed improved efficacy of the AIs and early results from the QoL sub-protocols provide useful indications of their acceptability and impact on patient QoL. In general the superior efficacy benefits of AIs over tamoxifen are achieved without compromising overall QoL in the short term, although some important questions still remain about their effect in the longer term especially on bone and thus fracture rate. There are also concerns about the putative impact AIs may have on cognition though few published data are available (Shilling, 2004). Even though overall QoL appears to be reasonably good, significant numbers of patients do experience troublesome side-effects. The primary symptoms that patients report include arthralgia, vaginal dryness, dysparunia and lowered libido (Fallowfield, 2004). Although clinicians report that hot flushes are fewer in those treated with AIs compared with tamoxifen, vasomotor problems of hot flushes, cold and night sweats affect between 25-30% women throughout 5 years of treatment. In this talk I will review some of the latest QoL life data emerging from adjuvant endocrine trials and consider further research needed on the interventions that might ameliorate some of the most bothersome symptoms.
FRIDAY, 28 JANUARY 2005
16.00-17.30
Session 9, Back to the Future: What Will it Be Like in 2007? [-~
When Will More Useful Predictive Factors Be Ready for Use?
L. Mauriac, M. Debled, G. MacGrogan. Institut Bergonie, Bordeaux, France In the last two decades, therapeutic strategies have been constructed on the results of randomised clinical trials in the light of classical clinical and pathological prognostic factors. Concurrently, retrospective prognostic factor studies have enabled identification of primary prognostic and predictive factors such as hormonal receptors, HER 2 neu... The combined results of these 2 approaches have enabled definition of breast cancer patient subgroups materialised in the conclusions of the EBCTCG meta-analysis, the Consensus Conference of NIH and the international panel of experts on adjuvant treatment of St. Gallen. However this approach has shown its limits because a therapeutic attitude based on a large series of patients is difficult to apply to an individual patient. Whatever the precision of prognostic categorisation, there still remain 2 subgroups of patients who do not get any benefit from adjuvant chemotherapy: the first one comprises patients who are already cured by Ioco-regional treatment alone and the second one pa-
S 13
tients who do not profit by adjuvant chemotherapy because of resistance to the employed regimens. If we want to improve the cost/benefit of this treatment strategy, we have two means: - one is to improve the sensitivity of prognostic factors to be able to select a specific group with a good signature, which do not need adjuvant treatment - the second is to identify predictive factors that may help us to select the optimal therapeutic strategy or the optimal regimen or drug for individual patients. If we attain this goal, we could obtain a substantial increase in the absolute benefit derived from adjuvant chemotherapy. For example, the increasing use of taxanes in our therapeutical weapons induces us to focus our efforts towards this therapeutic class. Due to their toxicity, their financial price and the small but significant benefit obtained in comparison with anthracycline containing regimens, it is important to detect patients who will not get any benefit from this class of drug. Biological tissue factors have not brought the proof of a predictive value of a sensitivity to docetaxel. But, with the obtention of new technologies to analyse genomics, several studies have been run since 2003 to improve this approach in neoadjuvant setting. All of them were focused on taxanes which are presently the optimal drug in (neo) adjuvant setting. These studies individualised several groups of genes which could be predictive of an histological complete response to taxane. At ASCO 2004, a study from Amsterdam compared two groups of patients whose tumours responded to AC or AD (docetaxel) regimens. Microarray analysis was carried out on 62 patients and 49 samples were available for RNA analysis from biopsy performed before neoadjuvant chemotherapy. Fifteen tumours were analysed post surgery: 45 genes were modified in case of response to AC and 17 in case of response to AD whereas only two genes were common to this good signature. A study from Houston individualised 92 genes which correlated with docetaxel response; positive and negative predictive value of these genes were 92% and 83%. Nevertheless, comparison of two different technologies have been done at MDACC, Affymetrix GeneChip (U133A) and Millenium cDNA arrays. Reproducibilty results from one or the other technics is poor and improvement of technology is warranted. Beside these technical methodology problems, new designs of clinical trials are developing to validate usefulness of these expensive technology. This is the concern of p53 trial conducted by the Breast Group of EORTC which has to verify that p-53 mutated tumours might be less sensitive to anthracyclines, while retaining sensitivity to taxanes. A genomic analysis is performed on all the biopsied tumours of this trial in order to give information on anthracycline (TGF I study) and taxane sensitivity (TGF II study). Another example is the future large trial of BIG which will compare the prognosis of node negative patients depending on the process of decision for adjuvant chemotherapy: St. Gallen criteria or microarray. Even if microarray technology is not today a ready to use, safe, reproducible laboratory method, its main quality is to clear the forest of biological mechanisms behind breast cancer and to pinpoint new specific agents in order to develop target therapy.
~-~
Antibodies and Vaccines: Hope or Illusion?
A. Knuth, D. J&ger. Universit~tsSpital ZOrich, Klinik u. Poliklinik for
Onkologie, ZOrich, Switzerland The search for target molecules on tumor cells eliciting strong immune responses in cancer patients has been pursued over decades. Growth factors and their respective receptors were discovered as suitable targets for passive or active immunotherapy approaches. Monoclonal antibodies directed against some of these targets like the proto-oncogene HER2/neu have become an accepted standard of therapy in the clinical management of subgroups of HER2/neu overexpressing breast cancer patients and in other malignancies. Antibodies against multiple other target molecules like EGFR, VEGF etc. are explored in ongoing clinical trials to enter clinical practice in the near future. More recently, potent techniques were developed to identify cancer antigens eliciting spontaneous immune responses in cancer patients. Cancer vaccination strategies targeting some of these cancer antigens are developed, maturing for clinical application. With reliable immunomonitoring techniques in place it was shown that vaccination with some of these cancer antigens may induce strong integrated (humoral and cellular) immune responses in antigen positive cancer patients. A prominent example is the cancer testis (CT-) antigen NY-ESO-1 which is expressed in 30% of all breast cancers. NY-ESO-1 is one of the most immunogenic human cancer antigens known to date. The aim of ongoing clinical trials is to induce or augment preexisting immune responses in cancer patients with NY-ESO-1 positive disease. There is preliminary evidence that patients with strong NY-ESO1 specific immune responses have more favourable courses of disease. In several clinical phase-I trials targeting Her2/neu it was shown that antigen specific T cell responses could be induced. Another new cancer antigen explored for cancer vaccination is the breast differentiation antigen NY-BR-1, expressed in 70% of all tested primary breast cancers. Although this cancer antigen is still in preclinical testing, its strong and restricted pattern of expression in breast cancer makes it a promising target for clinical devel-
Session 9. Back to the Future: What Will it Be Like in 2007?
comorbidity, functional status, and assessment of prognostic and predictive markers, are part of this trial. Older patients with hormone receptor positive tumors should be considered for adjuvant endocrine therapy. The use of chemotherapy in such patients must be tempered by its potential added value to endocrine therapy in reducing recurrence and breast cancer related mortality. Chemotherapy has greater rationale in hormone receptor negative older women where endocrine therapy is ineffective. Factoring comorbidity and life expectancy into these treatment decisions is critical. More adjuvant trials focused on older patients are needed.
I•41
Acceptance of Adjuvant Endocrine Therapies and Quality of Life Issues
L. Fallowfield. Cancer Research, UK Psychosocial Oncology Group,
Brighton & Sussex Medical School, Brighton, United Kingdom Until recently tamoxifen was the primary adjuvant endocrine therapy used in post-menopausal women with early stage, hormone receptor-positive breast cancer (EBCTCG,1998). Despite its efficacy in reducing the risk of recurrence and development of contralateral breast cancer it is associated with serious adverse events including thromboembolic events, stroke and endometrial cancer making it unsuitable for some patients and limiting its use in chemoprevention. Tamoxifen also has many non life-threatening but unpleasant vasomotor, gynaecologic and sexual side-effects that have a deleterious impact on QoL. Some of these influence compliance with more than 40% of patients failing to adhere to prescribed regimens (Fallowfield 2001, Partridge 2002). The aim of the third generation aromatase inhibitors(AIs) is to enhance the efficacy of endocrine treatment without the associated sideeffect profile. Early QoL results from 3 large international trials compared letrozole versus placebo (MA-17), and tamoxifen versus anastrozole (ATAC) and exemestane (IES). MA-17 and IES were sequencing trials in which patients had already received either 5 or 2-3 years respectively of tamoxifen whereas ATAC patients were not pre-treated. All trials showed improved efficacy of the AIs and early results from the QoL sub-protocols provide useful indications of their acceptability and impact on patient QoL. In general the superior efficacy benefits of AIs over tamoxifen are achieved without compromising overall QoL in the short term, although some important questions still remain about their effect in the longer term especially on bone and thus fracture rate. There are also concerns about the putative impact AIs may have on cognition though few published data are available (Shilling, 2004). Even though overall QoL appears to be reasonably good, significant numbers of patients do experience troublesome side-effects. The primary symptoms that patients report include arthralgia, vaginal dryness, dysparunia and lowered libido (Fallowfield, 2004). Although clinicians report that hot flushes are fewer in those treated with AIs compared with tamoxifen, vasomotor problems of hot flushes, cold and night sweats affect between 25-30% women throughout 5 years of treatment. In this talk I will review some of the latest QoL life data emerging from adjuvant endocrine trials and consider further research needed on the interventions that might ameliorate some of the most bothersome symptoms.
FRIDAY, 28 JANUARY 2005
16.00-17.30
Session 9, Back to the Future: What Will it Be Like in 2007? [-~
When Will More Useful Predictive Factors Be Ready for Use?
L. Mauriac, M. Debled, G. MacGrogan. Institut Bergonie, Bordeaux, France In the last two decades, therapeutic strategies have been constructed on the results of randomised clinical trials in the light of classical clinical and pathological prognostic factors. Concurrently, retrospective prognostic factor studies have enabled identification of primary prognostic and predictive factors such as hormonal receptors, HER 2 neu... The combined results of these 2 approaches have enabled definition of breast cancer patient subgroups materialised in the conclusions of the EBCTCG meta-analysis, the Consensus Conference of NIH and the international panel of experts on adjuvant treatment of St. Gallen. However this approach has shown its limits because a therapeutic attitude based on a large series of patients is difficult to apply to an individual patient. Whatever the precision of prognostic categorisation, there still remain 2 subgroups of patients who do not get any benefit from adjuvant chemotherapy: the first one comprises patients who are already cured by Ioco-regional treatment alone and the second one pa-
S 13
tients who do not profit by adjuvant chemotherapy because of resistance to the employed regimens. If we want to improve the cost/benefit of this treatment strategy, we have two means: - one is to improve the sensitivity of prognostic factors to be able to select a specific group with a good signature, which do not need adjuvant treatment - the second is to identify predictive factors that may help us to select the optimal therapeutic strategy or the optimal regimen or drug for individual patients. If we attain this goal, we could obtain a substantial increase in the absolute benefit derived from adjuvant chemotherapy. For example, the increasing use of taxanes in our therapeutical weapons induces us to focus our efforts towards this therapeutic class. Due to their toxicity, their financial price and the small but significant benefit obtained in comparison with anthracycline containing regimens, it is important to detect patients who will not get any benefit from this class of drug. Biological tissue factors have not brought the proof of a predictive value of a sensitivity to docetaxel. But, with the obtention of new technologies to analyse genomics, several studies have been run since 2003 to improve this approach in neoadjuvant setting. All of them were focused on taxanes which are presently the optimal drug in (neo) adjuvant setting. These studies individualised several groups of genes which could be predictive of an histological complete response to taxane. At ASCO 2004, a study from Amsterdam compared two groups of patients whose tumours responded to AC or AD (docetaxel) regimens. Microarray analysis was carried out on 62 patients and 49 samples were available for RNA analysis from biopsy performed before neoadjuvant chemotherapy. Fifteen tumours were analysed post surgery: 45 genes were modified in case of response to AC and 17 in case of response to AD whereas only two genes were common to this good signature. A study from Houston individualised 92 genes which correlated with docetaxel response; positive and negative predictive value of these genes were 92% and 83%. Nevertheless, comparison of two different technologies have been done at MDACC, Affymetrix GeneChip (U133A) and Millenium cDNA arrays. Reproducibilty results from one or the other technics is poor and improvement of technology is warranted. Beside these technical methodology problems, new designs of clinical trials are developing to validate usefulness of these expensive technology. This is the concern of p53 trial conducted by the Breast Group of EORTC which has to verify that p-53 mutated tumours might be less sensitive to anthracyclines, while retaining sensitivity to taxanes. A genomic analysis is performed on all the biopsied tumours of this trial in order to give information on anthracycline (TGF I study) and taxane sensitivity (TGF II study). Another example is the future large trial of BIG which will compare the prognosis of node negative patients depending on the process of decision for adjuvant chemotherapy: St. Gallen criteria or microarray. Even if microarray technology is not today a ready to use, safe, reproducible laboratory method, its main quality is to clear the forest of biological mechanisms behind breast cancer and to pinpoint new specific agents in order to develop target therapy.
~-~
Antibodies and Vaccines: Hope or Illusion?
A. Knuth, D. J&ger. Universit~tsSpital ZOrich, Klinik u. Poliklinik for
Onkologie, ZOrich, Switzerland The search for target molecules on tumor cells eliciting strong immune responses in cancer patients has been pursued over decades. Growth factors and their respective receptors were discovered as suitable targets for passive or active immunotherapy approaches. Monoclonal antibodies directed against some of these targets like the proto-oncogene HER2/neu have become an accepted standard of therapy in the clinical management of subgroups of HER2/neu overexpressing breast cancer patients and in other malignancies. Antibodies against multiple other target molecules like EGFR, VEGF etc. are explored in ongoing clinical trials to enter clinical practice in the near future. More recently, potent techniques were developed to identify cancer antigens eliciting spontaneous immune responses in cancer patients. Cancer vaccination strategies targeting some of these cancer antigens are developed, maturing for clinical application. With reliable immunomonitoring techniques in place it was shown that vaccination with some of these cancer antigens may induce strong integrated (humoral and cellular) immune responses in antigen positive cancer patients. A prominent example is the cancer testis (CT-) antigen NY-ESO-1 which is expressed in 30% of all breast cancers. NY-ESO-1 is one of the most immunogenic human cancer antigens known to date. The aim of ongoing clinical trials is to induce or augment preexisting immune responses in cancer patients with NY-ESO-1 positive disease. There is preliminary evidence that patients with strong NY-ESO1 specific immune responses have more favourable courses of disease. In several clinical phase-I trials targeting Her2/neu it was shown that antigen specific T cell responses could be induced. Another new cancer antigen explored for cancer vaccination is the breast differentiation antigen NY-BR-1, expressed in 70% of all tested primary breast cancers. Although this cancer antigen is still in preclinical testing, its strong and restricted pattern of expression in breast cancer makes it a promising target for clinical devel-