- Email: [email protected]
S32 Taxing the taxanes in adjuvant therapy
Friday, 16 March 2007
Session 8. Adjuvant systemic therapies II: Targeting cytotoxics and biologicals
benefit for the addition of ovary-targeted therapy to chemotherapy. This may reflect the fact that chemotherapy frequently induces menopause, especially in women >40 years of age. Retrospective subset analyses from some of these trials suggest that OA/OS may be useful in those women who remain premenopausal after chemotherapy. Most of these trials did not use tamoxifen in an optimal fashion as they began at a time when tamoxifen was felt to be ineffective therapy for premenopausal women. Another question is how to integrate aromatase inhibitors into management of premenopausal breast cancer. These drugs are contraindicated as monotherapy for premenopausal women but interest in their use with ovarian suppression is high. Caution about their use in women with chemotherapy-induced amenorrhea has been raised. Together these results support current large randomized trials that are comparing tamoxifen, OA/OS plus tamoxifen, and OS/OS plus aromatase inhibitor as potential adjuvant strategies (e.g. SOFT, TEXT, ABCSG). Ongoing work to refine estimation of prognosis, predict response to endocrine therapy, select endocrine approaches, optimize duration of therapy, and identify long term side effects in premenopausal women is critical.
S29 Optimizing treatment and prevention of breast cancer: Time for a change? V.C. Jordan. Fox Chase Cancer Center, Medical Sciences, Philadelphia, PA 19111, USA The clinical application of the treatment strategy of long term antihormonal adjuvant therapy [1] is reaching its zenith with the integration of aromatase inhibitors into the treatment plan. Similarly, chemoprevention trials are providing important options for clinicians to reduce the incidence of breast cancer [2]. The challenge is to apply the knowledge acquired effectively both to reduce breast cancer risk in the general population and to apply emerging knowledge about antihormonal drug resistance [3] to extend the effectiveness of antihormonal therapy for patient care. Evidence now suggests that stopping hormone replacement therapy (HRT) or using the selective oestrogen receptor modulators (SERMs) tamoxifen and raloxifene for pre and postmenopausal women selectively will reduce breast cancer risk [4]. Physicians need to implement knowledge from clinical trials to improve public health. Remarkably, exhaustive antihormonal therapy for breast cancer has exposed a vulnerability of resistant advanced breast cancer cells. Oestrogen, at low doses, can kill antihormonal resistant breast cancer cells and restore the effectiveness of antihormone agents [5]. The goal of current laboratory studies is to expand responsiveness of antihormone resistant breast cancer to oestrogen by blocking survival pathways. Clinical implementation of the new oestrogen purging strategy will aid control of disease and allow the principle to be applied to long term adjuvant therapy with antihormones. A timely change in global clinical practice will enhance patient survival by harnessing the cidal action of oestrogen for breast cancer treatment and block the growth enhancing action of oestrogen in women at risk of developing breast cancer. References [1] [2] [3] [4] [5]
1. 2. 3. 4. 5.
Jordan Jordan Jordan Jordan Jordan
VC. VC. VC. VC. VC,
Breast Cancer Res Treat 1990; 15(3): 125−36. Nat Rev Cancer 2007, in press. Cancer Cell 2004; 5: 207−13. Eur J Cancer 2006; 42: 2909−13. Lewis JS, Osipo C, Cheng D. Breast 2005; 14: 624−30.
Friday, 16 March 2007
11.00–12.30
Session 8. Adjuvant systemic therapies II: Targeting cytotoxics and biologicals S30 Chemotherapy for endocrine responsive disease: An evolving story K. Albain. USA Abstract not received.
S9
S31 Using specific cytotoxics with a targeted mind A. Di Leo, W.M. Claudino, M. Pestrin, L. Biganzoli. Hospital of Prato “Sandro Pitigliani” Medical Oncology Unit, Department of Oncology, Prato, Italy It is largely known that the clinical activity of a given cytotoxic agent may vary between different patients. This suggests that breast cancer sub-types can be identified, each of them with its own sensitivity profile to different cytotoxic drugs. Pre-clinical and early clinical data suggest that in the future some molecular markers might have practical value in predicting cytotoxics activity in the clinical setting. The most relevant evidence is summarized below according to the type of cytotoxic agent. (a) Anthracyclines: Topoisomerase II alpha (topo II) gene aberrations (amplification or deletion) and/or topo II protein overexpression seem to predict response to topo II inhibitors such as anthracyclines. Of note, HER-2 amplified tumors have a concomitant topo II gene aberration in approximately 50% of cases. Moreover, the majority of hyper-proliferating tumors carry topo II protein overexpression. Early clinical data suggest the existence of a direct correlation between anthracyclines activity and the presence of topo II gene aberration or topo II protein overexpression. (b) Taxanes: Microtubule-associated parameters (MTAP) such as the TAU protein, HER-2 gene amplification, and p-53 gene mutations, have been suggested as potential predictive markers for taxanes. Although early clinical data support pre-clinical experiments, the lack of large prospectively designed clinical studies makes it difficult to draw conclusions on the predictive value of these molecular markers. (c) DNA-damaging agents: The BRCA 1 protein seems to play a major role in activating DNA repair mechanisms. Loss-of-function BRCA 1 mutations might lead to a substantial deficit in DNA repair mechanisms. This could ultimately translate into increased tumor sensitivity to DNAdamaging agents such as alkylating compounds and platinum-derivates. Pre-clinical and early clinical data seem to suggest that some BRCA 1 gene mutations might render the tumor more sensitive to DNA-damaging agents and clinical studies have recently been activated to investigate properly this hypothesis. A new generation of ongoing clinical studies and a “focused” use of the gene micro-array technology will hopefully clarify the complex interaction existing between molecular targets and cytotoxic drug activity. This “targeted” approach to chemotherapy might ultimately lead to a more effective strategy in breast cancer medical treatment.
S32 Taxing the taxanes in adjuvant therapy C. Hudis. USA Abstract not received.
S33 Benefit with adjuvant taxanes and endocrine responsiveness in breast cancer (BC) ´ M. Martin. Hospital Clinico San Carlos, Servicio de Oncologia Medica, Madrid, Spain The results of nine pure adjuvant trials comparing anthracycline-containing combinations with taxane-containing combinations (the so-called first generation taxane trials) have been reported so far. Six of them were clearly positive in terms of disease-free survival (DFS) in favour of the taxane arm, one was negative and two found a difference in favour of the taxane arms of borderline significance in the main endpoint. Overall, these trials provide level I evidence of the efficacy of taxanes in the adjuvant treatment of node-positive BC. However, the absolute 5-year DFS gain obtained with the taxane-containing regimens in the positive studies ranged from 5 to 7% and these regimens are more toxic than the conventional anthracylinecontaining combinations. Therefore, the identification of the population of patients who benefit most from taxanes is of the upmost importance. Several attempts have been made to identify the biological peculiarities of this subset of BC patients. Hormone receptor (HR) status has been suggested to be a factor conditioning response to adjuvant chemotherapy in general and taxanes in particular. Unfortunatelly, none of the nine first generation taxane adjuvant trials has included among their endpoints a prospectively planned and powered analysis of HR-based subsets of patients. Moreover, only one of the nine has used HR status as a stratification factor and none of them has reported results based on central determination and quantification of HR. These three problems make the analysis of the
Session 8. Adjuvant systemic therapies II: Targeting cytotoxics and biologicals
benefit for the addition of ovary-targeted therapy to chemotherapy. This may reflect the fact that chemotherapy frequently induces menopause, especially in women >40 years of age. Retrospective subset analyses from some of these trials suggest that OA/OS may be useful in those women who remain premenopausal after chemotherapy. Most of these trials did not use tamoxifen in an optimal fashion as they began at a time when tamoxifen was felt to be ineffective therapy for premenopausal women. Another question is how to integrate aromatase inhibitors into management of premenopausal breast cancer. These drugs are contraindicated as monotherapy for premenopausal women but interest in their use with ovarian suppression is high. Caution about their use in women with chemotherapy-induced amenorrhea has been raised. Together these results support current large randomized trials that are comparing tamoxifen, OA/OS plus tamoxifen, and OS/OS plus aromatase inhibitor as potential adjuvant strategies (e.g. SOFT, TEXT, ABCSG). Ongoing work to refine estimation of prognosis, predict response to endocrine therapy, select endocrine approaches, optimize duration of therapy, and identify long term side effects in premenopausal women is critical.
S29 Optimizing treatment and prevention of breast cancer: Time for a change? V.C. Jordan. Fox Chase Cancer Center, Medical Sciences, Philadelphia, PA 19111, USA The clinical application of the treatment strategy of long term antihormonal adjuvant therapy [1] is reaching its zenith with the integration of aromatase inhibitors into the treatment plan. Similarly, chemoprevention trials are providing important options for clinicians to reduce the incidence of breast cancer [2]. The challenge is to apply the knowledge acquired effectively both to reduce breast cancer risk in the general population and to apply emerging knowledge about antihormonal drug resistance [3] to extend the effectiveness of antihormonal therapy for patient care. Evidence now suggests that stopping hormone replacement therapy (HRT) or using the selective oestrogen receptor modulators (SERMs) tamoxifen and raloxifene for pre and postmenopausal women selectively will reduce breast cancer risk [4]. Physicians need to implement knowledge from clinical trials to improve public health. Remarkably, exhaustive antihormonal therapy for breast cancer has exposed a vulnerability of resistant advanced breast cancer cells. Oestrogen, at low doses, can kill antihormonal resistant breast cancer cells and restore the effectiveness of antihormone agents [5]. The goal of current laboratory studies is to expand responsiveness of antihormone resistant breast cancer to oestrogen by blocking survival pathways. Clinical implementation of the new oestrogen purging strategy will aid control of disease and allow the principle to be applied to long term adjuvant therapy with antihormones. A timely change in global clinical practice will enhance patient survival by harnessing the cidal action of oestrogen for breast cancer treatment and block the growth enhancing action of oestrogen in women at risk of developing breast cancer. References [1] [2] [3] [4] [5]
1. 2. 3. 4. 5.
Jordan Jordan Jordan Jordan Jordan
VC. VC. VC. VC. VC,
Breast Cancer Res Treat 1990; 15(3): 125−36. Nat Rev Cancer 2007, in press. Cancer Cell 2004; 5: 207−13. Eur J Cancer 2006; 42: 2909−13. Lewis JS, Osipo C, Cheng D. Breast 2005; 14: 624−30.
Friday, 16 March 2007
11.00–12.30
Session 8. Adjuvant systemic therapies II: Targeting cytotoxics and biologicals S30 Chemotherapy for endocrine responsive disease: An evolving story K. Albain. USA Abstract not received.
S9
S31 Using specific cytotoxics with a targeted mind A. Di Leo, W.M. Claudino, M. Pestrin, L. Biganzoli. Hospital of Prato “Sandro Pitigliani” Medical Oncology Unit, Department of Oncology, Prato, Italy It is largely known that the clinical activity of a given cytotoxic agent may vary between different patients. This suggests that breast cancer sub-types can be identified, each of them with its own sensitivity profile to different cytotoxic drugs. Pre-clinical and early clinical data suggest that in the future some molecular markers might have practical value in predicting cytotoxics activity in the clinical setting. The most relevant evidence is summarized below according to the type of cytotoxic agent. (a) Anthracyclines: Topoisomerase II alpha (topo II) gene aberrations (amplification or deletion) and/or topo II protein overexpression seem to predict response to topo II inhibitors such as anthracyclines. Of note, HER-2 amplified tumors have a concomitant topo II gene aberration in approximately 50% of cases. Moreover, the majority of hyper-proliferating tumors carry topo II protein overexpression. Early clinical data suggest the existence of a direct correlation between anthracyclines activity and the presence of topo II gene aberration or topo II protein overexpression. (b) Taxanes: Microtubule-associated parameters (MTAP) such as the TAU protein, HER-2 gene amplification, and p-53 gene mutations, have been suggested as potential predictive markers for taxanes. Although early clinical data support pre-clinical experiments, the lack of large prospectively designed clinical studies makes it difficult to draw conclusions on the predictive value of these molecular markers. (c) DNA-damaging agents: The BRCA 1 protein seems to play a major role in activating DNA repair mechanisms. Loss-of-function BRCA 1 mutations might lead to a substantial deficit in DNA repair mechanisms. This could ultimately translate into increased tumor sensitivity to DNAdamaging agents such as alkylating compounds and platinum-derivates. Pre-clinical and early clinical data seem to suggest that some BRCA 1 gene mutations might render the tumor more sensitive to DNA-damaging agents and clinical studies have recently been activated to investigate properly this hypothesis. A new generation of ongoing clinical studies and a “focused” use of the gene micro-array technology will hopefully clarify the complex interaction existing between molecular targets and cytotoxic drug activity. This “targeted” approach to chemotherapy might ultimately lead to a more effective strategy in breast cancer medical treatment.
S32 Taxing the taxanes in adjuvant therapy C. Hudis. USA Abstract not received.
S33 Benefit with adjuvant taxanes and endocrine responsiveness in breast cancer (BC) ´ M. Martin. Hospital Clinico San Carlos, Servicio de Oncologia Medica, Madrid, Spain The results of nine pure adjuvant trials comparing anthracycline-containing combinations with taxane-containing combinations (the so-called first generation taxane trials) have been reported so far. Six of them were clearly positive in terms of disease-free survival (DFS) in favour of the taxane arm, one was negative and two found a difference in favour of the taxane arms of borderline significance in the main endpoint. Overall, these trials provide level I evidence of the efficacy of taxanes in the adjuvant treatment of node-positive BC. However, the absolute 5-year DFS gain obtained with the taxane-containing regimens in the positive studies ranged from 5 to 7% and these regimens are more toxic than the conventional anthracylinecontaining combinations. Therefore, the identification of the population of patients who benefit most from taxanes is of the upmost importance. Several attempts have been made to identify the biological peculiarities of this subset of BC patients. Hormone receptor (HR) status has been suggested to be a factor conditioning response to adjuvant chemotherapy in general and taxanes in particular. Unfortunatelly, none of the nine first generation taxane adjuvant trials has included among their endpoints a prospectively planned and powered analysis of HR-based subsets of patients. Moreover, only one of the nine has used HR status as a stratification factor and none of them has reported results based on central determination and quantification of HR. These three problems make the analysis of the