- Email: [email protected]
S39 Treatment of postmenopausal women with hormone responsive breast cancer
S16
Session 10. Adjuvant systemic treatment choice for the individual patient II
1970s established the role of adjuvant chemotherapy, with both showing statistically significant and clinically important reductions in recurrence and, ultimately, mortality. Since these reports, a multitude of investigations from around the world have addressed the three questions raised above. Early subgroup analyses of both the NSABP and Milano studies suggested that premenopausal women were more likely to benefit than older women, although subsequent single study results and meta-analysis have demonstrated that older women do, indeed, benefit. Adjuvant chemotherapy was initially felt to be indicated only in women with positive lymph nodes, but with increasing sophistication, the field has refined our understanding of prognosis and prediction. Increasingly we are able to identify both those patients most likely to need adjuvant chemotherapy (prognosis) and, perhaps, those most likely to benefit from it (prediction). In this regard, web-based, multifactorial calculators, best exemplified by Adjuvant!, permit a patient and her caregiver to estimate her absolute odds of benefit from chemotherapy, thus better informing women in their assessment of benefits and risks (http://www.adjuvantonline.com/index.jsp). The next question is whether there is an optimal regimen, dose, and schedule of adjuvant chemotherapy. The answer is, frankly, “no”. However, clinical research over the last four decades has strongly suggested the following principles: • Combination chemotherapy is superior to single agent. However, ongoing clinical trials, such as CALGB 40101, are re-addressing this issue in women with relatively favorable prognoses using modern chemotherapy, such as paclitaxel. • “Modern” chemotherapy including an anthracycline (doxorubicin [A] or epirubicin [E]) and a taxane appears to be superior to the CMF regimen. However, there may be biologic subgroups of patients for whom either anthracyclines or taxanes are less beneficial, or even inactive. Furthermore, the “best” combination has not been proven. AC appears to be similar to CMF, CEF appears superior to CMF, and AC-T(paclitaxel) or T(docetaxel)AC appears to be superior to AC or CAF, respectively. AC and AT(docetaxel) appear to be quite similar, although T(docetaxel)C appears to be superior to AC. AC-paclitaxel and AC-docetaxel also appear nearly identical. • Multiple cycles of chemotherapy are superior to a single peri-operative course. Furthermore, there appears to be an optimal duration of therapy, although this has not been well-defined. Older studies suggest that 12 is no better than 6 months of CMF, 6 may be slightly better than 3 cycles of CMF, and that 10 cycles of a doxorubicin-based regimen is no better than 5. • For most, if not all, chemotherapy agents there is a dose response curve with increasing benefit up to an optimal dose level, but this curve appears to plateau. Further dose escalation, at least for cyclophosphamide, anthracyclines, and the taxanes, or very high doses of combination therapies which require bone marrow stem cell transplantation, is of little benefit. • Dose-dense chemotherapy (every one or two weeks) may be superior to less frequent scheduling (every three weeks), although this strategy may be class or even agent specific. In summary, it is clear that adjuvant chemotherapy is beneficial for women with early stage breast cancer, and it is clear that selected regimens, based on specific agents, cumulative and cycle-specific dose, and schedule may affect the relative efficacy. It is not clear which patients are most likely to benefit from any adjuvant chemotherapy at all, or from specific strategies. Thus, at this time there is no single standard type or duration of adjuvant chemotherapy, and physicians should choose from regimens that have proven benefit as demonstrated in randomized Phase III trials. The choice of regimen in an individual patient should be based on differential toxicity and patient clinical factors, and arbitrary dose reductions or modification of the regimen should be avoided. Finally, it is also clear that many women will suffer recurrence and death in spite of these enormous advances and that new strategies are needed to further reduce the burden of breast cancer on our patients.
S38
Friday, 13 March 2009 Late effects of systemic adjuvant therapies in women diagnosed with breast cancer at a young age
H.J. Burstein1 . 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Adjuvant systemic therapies have particular, long-term side effects in young women, principally related to the anti-estrogen consequences of adjuvant endocrine and chemotherapy treatments. Adjuvant chemotherapy can be toxic to the ovary, contributing to premature menopause and impaired fertility. Endocrine treatments including tamoxifen and ovarian suppression also contribute to menopausal symptoms and are contraindications to pregnancy, and may be associated with other stigmata of menopause including accelerated osteopenia / osteoporosis, sexual dysfunction, weight gain and climacteric symptoms such as hot flashes and night sweats. Clinical experience suggests that young women who experience abrupt changes in hormonal status are at greater jeopardy for more intense menopausal symptoms. Other consequences of cancer diagnosis and treatment, including fatigue, psychosocial distress, cognitive changes, and impaired body image, also appear more prevalent in women diagnosed at younger ages. Younger women may also have unique concerns about fertility preservation and options for child-bearing after breast cancer. Limited data suggest that pregnancy per se does not increase the risk of cancer recurrence, but patients must factor into account that possibility as well as the possible interruption of effective endocrine therapy when weighing such a choice. Very young women are more likely to have hereditary predisposition to breast cancer, and warrant consideration of genetic testing and, when appropriate, prophylactic surgery to reduce the risk of ovarian cancer and second breast cancers. Historically, age has been considered an adverse prognostic factor in breast cancer outcomes. It now seems likely that much if not all of this can be accounted for by the different distributions of breast cancer subsets in younger women, who bear a higher burden of hormone-receptor negative and/or HER2 positive cancers, lack of ovarian suppression with chemotherapy in very young women, and in the past, limited use of adjuvant endocrine therapy in these patients. Thus, there are no differences in surveillance or other follow-up guidelines for women based on age. However, as younger women have fewer more comorbid conditions, and longer life expectancy overall, the long-term consequences of breast cancer loom larger than for many women diagnosed at later ages. Clinicians need to be aware of the special survivorship needs of younger women with early stage breast cancer.
Friday, 13 March 2009
16.00–17.30
Session 10. Adjuvant systemic treatment choice for the individual patient II S39
Treatment of postmenopausal women with hormone responsive breast cancer
E. Winer1 . 1 Dana-Farber − Brigham and Women’s Cancer Center, Harvard Medical School, Boston, USA Over half of all women diagnosed with breast cancer are postmenopausal and have hormone receptor positive disease. Almost all of these women are potential candidates for adjuvant endocrine therapy, and the majority have an excellent overall prognosis. A decade ago, the only treatment available was tamoxifen, which was typically administered for a period of 5 years. Over the course of the past decade, well over 10 randomized trials have addressed the role of the aromatase inhibitors in the treatment of postmenopausal hormonally sensitive breast cancer. These trials have used a variety of distinct strategies including: 1. direct comparison of 5 years of tamoxifen with 5 years of an aromatase inhibitor; 2. cross-over or sequential approaches in which women receive either a 5 year course of tamoxifen or 2−3 years of tamoxifen followed by 2−3 years of an aromatase inhibitor, with randomization occurring either after 2−3 years of tamoxifen or at the time of diagnosis;
Friday, 13 March 2009
Session 10. Adjuvant systemic treatment choice for the individual patient II
3. sequential treatment with 2 years of an aromatase inhibitor followed by 3 years of tamoxifen versus 5 years of an aromatase inhibitor; and 4. extended therapy with a direct comparison of aromatase inhibitor treatment versus placebo after a 5 year course of tamoxifen. In total, these studies have included over 30,000 patients and have provided a detailed view of the role of aromatase inhibition as adjuvant therapy in postmenopausal women. Overall, there is no question that the use of an aromatase inhibitor, either initially or after a course of tamoxifen, adds to the benefits seen with a 5 year course of tamoxifen alone. To date, improvements in diseasefree survival have been seen in virtually all studies, with very studies demonstrating a survival advantage. The optimal therapeutic approach for many patients remains uncertain. The most commonly used treatment regimens include a 5 year course of an aromatase inhibitor or a 2−3 year course of tamoxifen followed by an aromatase inhibitor. To date, no study has documented that more than a 5 year course of an aromatase inhibitor is either safe or effective, though longer duration therapy can be administered if both tamoxifen and an aromastase inhibitor are included in the treatment regimen. There are a large number of unresolved questions regarding the use of endocrine therapy in postmenopausal women. These questions include: 1. should all patients receive an aromatase inhibitor as initial therapy, or are some patients better served with an initial course of tamoxifen? 2. To what extent should tumor characteristics, both anatomic and biologic features, influence initial treatment choice? 3. Are individual differences in the metabolism of tamoxifen of clinical relevance? 4. How do the side effects of tamoxifen and the aromatase inhibitors differ, and to what extent can these side effects be treated? 5. How long should therapy be administered, and can we identify a population of women who are at particularly high risk of late recurrence and would derive even greater benefit from prolonged treatment? 6. Can we identify groups of patients who can forego hormonal therapy and its associated side effects? and 7. How can we maximize adherence to these oral agents that have moderate side effects for some patients? The lecture will address each of these controversies and provide treatment recommendations for specific patient subgroups.
S40
S17
Duration of treatment: All the major trials have empirically used one year of adjuvant trastuzumab. The HERA trial is also comparing 2 v.1 year and results are awaited. A much smaller trial (FinHER) has shown similar efficacy gains with a mere 9 weeks of trastuzumab given concurrently with chemotherapy, suggesting that much shorter treatment may be as effective. The role of anthracyclines: Adjuvant trastuzumab after anthracyclines is associated with a small but significant increase in the risk of cardiotoxicity. Results from the BCIRG 006 trial suggest that a non-anthracycline regimen of docetaxel and carboplatin with trastuzumab achieves similar efficacy to anthracycline-containing regimens but without an increase in cardiotoxicity. Standardised measurement of HER2: ASCO and the College of American Pathologists recently convened an expert panel which concluded that around 20% of current HER2 testing may be inaccurate and proposed recommendations for standardised central testing in accredited laboratories with defined proficiency testing requirements. A positive HER2 result should be defined as IHC staining of 3+ (uniform intense membrane staining of greater than 30% of invasive tumour cells) or a fluorescent in situ hybridisation (FISH) result of more than 6 HER2 gene copies per nucleus or a FISH ratio of more than 2.2. ‘Low-risk’ HER2: So called low-risk T1, N0 HER2+ve breast cancers were largely excluded from the major adjuvant trastuzumab trials but data are accumulating that these have significant risk of relapse, even including <1 cm tumours. It is likely that trastuzumab with chemotherapy would also be of benefit in these circumstances; the role of adjuvant trastuzumab alone is plausible here but no direct data are available. New anti-HER2 targeted therapies: These are rapidly becoming available including lapatinib, an oral small molecule dual HER1/HER2tyrosine kinase inhibitor with significant clinical activity in metastatic breast cancer after trastuzumab. Adjuvant single agent lapatinib is being assessed in patients with trastuzumab-naive HER2 positive breast cancer in continuing remission following adjuvant chemotherapy in the TEACH trial. In addition, adjuvant lapatinib and chemotherapy is being compared directly with trastuzumab, or the 2 agents sequentially, or in combination, in the ALTTO trial.
S42
Adjuvant therapy of triple negative breast cancer
E.A. Perez. Jacksonville, USA Should genomic profiles be used to determine who should receive adjuvant chemotherapy?
K.S. Albain. Maywood, IL, USA
Abstract not received.
S43
Review of new targeted drugs: Crawling towards the adjuvant setting
Abstract not received.
S41
Targeting HER2 in the adjuvant setting: Dealing with new standards and open questions
I.E. Smith1 . 1 Medicine, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom The HER2 gene is amplified and the receptor overexpressed in around 20% of women with early breast cancer, and this is associated with an adverse prognosis. Trastuzumab (Herceptin), a humanised monoclonal antibody targeted against the external domain of the HER2 receptor, has been shown to have major clinical benefit in all stages of HER2 positive breast cancer including in particular as adjuvant therapy for early disease. The 2007 St Gallen guidelines recommended that trastuzumab should be considered as standard treatment concurrently with or sequentially after chemotherapy in patients with HER2 positive disease which is IHC (immunohistochemistry) 3+ or FISH positive except in those with a primary tumour less than 1 cm and no axillary node involvement. Important unanswered questions remain however. Concurrent or sequential therapy: Three major trials (NSABPB-31; NCCTG N9831 and BCIRG006) have shown significant survival benefit with concurrent trastuzumab given with a taxane chemotherapy following anthracycline treatment. A further major trial (HERA) has shown similar survival benefit with sequential trastuzumab given after standard adjuvant chemotherapy, but another smaller trial of sequential trastuzumab (PACS004) also given after chemotherapy has failed to show benefit. Results from the N9831 trial comparing concurrent with sequential treatment are awaited.
J. Baselga1 . 1 Vall Hebron Institute of Oncology, Vall Hebron University Hospital, Barcelona, Spain The cellular and molecular processes that lead to cancer, the already classical “hallmarks of malignancy”, include self-sufficiency in growth signals, insensivity to anti-growth factor signals, evasion of apoptosis, lack of senescence, invasion and metastasis, and sustained angiogenesis. All these processes can be potentially targeted in breast cancer. Among the most promising agents: 1. Inhibitors of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway. Uncontrolled activation of the PI3K/Akt/mTOR pathway, achieved via numerous genetic and epigenetic alterations, contributes to the development and progression of breast cancer. These genetic alterations include PTEN deletions and ‘hot-spots’ mutations of the PI3K gene. Further, these alterations may result in resistance to upstream anti-receptor agents. Clinical trials are currently underway with mTOR, PI3K, and Akt inhibitors. Based on the cross talk between the estrogen receptor and the PI3K/Akt/mTOR pathways, clinical trials with mTOR inhibitors have explored the combination of rapamycin analogues and aromatase inhibitors. Other potentially active combinations with mTOR inhibitors include in combination with trastuzumab in patients with trastuzumab-refractory disease. In terms of PI3K inhibitors they are currently being studied in early clinical trials. Among them, NVP-BEZ235 is a potent dual PI3K/mTOR inhibitor that is highly active in breast cancer cells harboring activating PI3K mutations. Other agents under study include XL765, also a dual PI3K/mTOR inhibitor and XL147, a more pure PI3K inhibitor. 2. Insulin-like growth factor-I receptor (IGF-IR) inhibitors. The IGF-IR is a transmembrane tyrosine kinase receptor that stimulates different
Session 10. Adjuvant systemic treatment choice for the individual patient II
1970s established the role of adjuvant chemotherapy, with both showing statistically significant and clinically important reductions in recurrence and, ultimately, mortality. Since these reports, a multitude of investigations from around the world have addressed the three questions raised above. Early subgroup analyses of both the NSABP and Milano studies suggested that premenopausal women were more likely to benefit than older women, although subsequent single study results and meta-analysis have demonstrated that older women do, indeed, benefit. Adjuvant chemotherapy was initially felt to be indicated only in women with positive lymph nodes, but with increasing sophistication, the field has refined our understanding of prognosis and prediction. Increasingly we are able to identify both those patients most likely to need adjuvant chemotherapy (prognosis) and, perhaps, those most likely to benefit from it (prediction). In this regard, web-based, multifactorial calculators, best exemplified by Adjuvant!, permit a patient and her caregiver to estimate her absolute odds of benefit from chemotherapy, thus better informing women in their assessment of benefits and risks (http://www.adjuvantonline.com/index.jsp). The next question is whether there is an optimal regimen, dose, and schedule of adjuvant chemotherapy. The answer is, frankly, “no”. However, clinical research over the last four decades has strongly suggested the following principles: • Combination chemotherapy is superior to single agent. However, ongoing clinical trials, such as CALGB 40101, are re-addressing this issue in women with relatively favorable prognoses using modern chemotherapy, such as paclitaxel. • “Modern” chemotherapy including an anthracycline (doxorubicin [A] or epirubicin [E]) and a taxane appears to be superior to the CMF regimen. However, there may be biologic subgroups of patients for whom either anthracyclines or taxanes are less beneficial, or even inactive. Furthermore, the “best” combination has not been proven. AC appears to be similar to CMF, CEF appears superior to CMF, and AC-T(paclitaxel) or T(docetaxel)AC appears to be superior to AC or CAF, respectively. AC and AT(docetaxel) appear to be quite similar, although T(docetaxel)C appears to be superior to AC. AC-paclitaxel and AC-docetaxel also appear nearly identical. • Multiple cycles of chemotherapy are superior to a single peri-operative course. Furthermore, there appears to be an optimal duration of therapy, although this has not been well-defined. Older studies suggest that 12 is no better than 6 months of CMF, 6 may be slightly better than 3 cycles of CMF, and that 10 cycles of a doxorubicin-based regimen is no better than 5. • For most, if not all, chemotherapy agents there is a dose response curve with increasing benefit up to an optimal dose level, but this curve appears to plateau. Further dose escalation, at least for cyclophosphamide, anthracyclines, and the taxanes, or very high doses of combination therapies which require bone marrow stem cell transplantation, is of little benefit. • Dose-dense chemotherapy (every one or two weeks) may be superior to less frequent scheduling (every three weeks), although this strategy may be class or even agent specific. In summary, it is clear that adjuvant chemotherapy is beneficial for women with early stage breast cancer, and it is clear that selected regimens, based on specific agents, cumulative and cycle-specific dose, and schedule may affect the relative efficacy. It is not clear which patients are most likely to benefit from any adjuvant chemotherapy at all, or from specific strategies. Thus, at this time there is no single standard type or duration of adjuvant chemotherapy, and physicians should choose from regimens that have proven benefit as demonstrated in randomized Phase III trials. The choice of regimen in an individual patient should be based on differential toxicity and patient clinical factors, and arbitrary dose reductions or modification of the regimen should be avoided. Finally, it is also clear that many women will suffer recurrence and death in spite of these enormous advances and that new strategies are needed to further reduce the burden of breast cancer on our patients.
S38
Friday, 13 March 2009 Late effects of systemic adjuvant therapies in women diagnosed with breast cancer at a young age
H.J. Burstein1 . 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Adjuvant systemic therapies have particular, long-term side effects in young women, principally related to the anti-estrogen consequences of adjuvant endocrine and chemotherapy treatments. Adjuvant chemotherapy can be toxic to the ovary, contributing to premature menopause and impaired fertility. Endocrine treatments including tamoxifen and ovarian suppression also contribute to menopausal symptoms and are contraindications to pregnancy, and may be associated with other stigmata of menopause including accelerated osteopenia / osteoporosis, sexual dysfunction, weight gain and climacteric symptoms such as hot flashes and night sweats. Clinical experience suggests that young women who experience abrupt changes in hormonal status are at greater jeopardy for more intense menopausal symptoms. Other consequences of cancer diagnosis and treatment, including fatigue, psychosocial distress, cognitive changes, and impaired body image, also appear more prevalent in women diagnosed at younger ages. Younger women may also have unique concerns about fertility preservation and options for child-bearing after breast cancer. Limited data suggest that pregnancy per se does not increase the risk of cancer recurrence, but patients must factor into account that possibility as well as the possible interruption of effective endocrine therapy when weighing such a choice. Very young women are more likely to have hereditary predisposition to breast cancer, and warrant consideration of genetic testing and, when appropriate, prophylactic surgery to reduce the risk of ovarian cancer and second breast cancers. Historically, age has been considered an adverse prognostic factor in breast cancer outcomes. It now seems likely that much if not all of this can be accounted for by the different distributions of breast cancer subsets in younger women, who bear a higher burden of hormone-receptor negative and/or HER2 positive cancers, lack of ovarian suppression with chemotherapy in very young women, and in the past, limited use of adjuvant endocrine therapy in these patients. Thus, there are no differences in surveillance or other follow-up guidelines for women based on age. However, as younger women have fewer more comorbid conditions, and longer life expectancy overall, the long-term consequences of breast cancer loom larger than for many women diagnosed at later ages. Clinicians need to be aware of the special survivorship needs of younger women with early stage breast cancer.
Friday, 13 March 2009
16.00–17.30
Session 10. Adjuvant systemic treatment choice for the individual patient II S39
Treatment of postmenopausal women with hormone responsive breast cancer
E. Winer1 . 1 Dana-Farber − Brigham and Women’s Cancer Center, Harvard Medical School, Boston, USA Over half of all women diagnosed with breast cancer are postmenopausal and have hormone receptor positive disease. Almost all of these women are potential candidates for adjuvant endocrine therapy, and the majority have an excellent overall prognosis. A decade ago, the only treatment available was tamoxifen, which was typically administered for a period of 5 years. Over the course of the past decade, well over 10 randomized trials have addressed the role of the aromatase inhibitors in the treatment of postmenopausal hormonally sensitive breast cancer. These trials have used a variety of distinct strategies including: 1. direct comparison of 5 years of tamoxifen with 5 years of an aromatase inhibitor; 2. cross-over or sequential approaches in which women receive either a 5 year course of tamoxifen or 2−3 years of tamoxifen followed by 2−3 years of an aromatase inhibitor, with randomization occurring either after 2−3 years of tamoxifen or at the time of diagnosis;
Friday, 13 March 2009
Session 10. Adjuvant systemic treatment choice for the individual patient II
3. sequential treatment with 2 years of an aromatase inhibitor followed by 3 years of tamoxifen versus 5 years of an aromatase inhibitor; and 4. extended therapy with a direct comparison of aromatase inhibitor treatment versus placebo after a 5 year course of tamoxifen. In total, these studies have included over 30,000 patients and have provided a detailed view of the role of aromatase inhibition as adjuvant therapy in postmenopausal women. Overall, there is no question that the use of an aromatase inhibitor, either initially or after a course of tamoxifen, adds to the benefits seen with a 5 year course of tamoxifen alone. To date, improvements in diseasefree survival have been seen in virtually all studies, with very studies demonstrating a survival advantage. The optimal therapeutic approach for many patients remains uncertain. The most commonly used treatment regimens include a 5 year course of an aromatase inhibitor or a 2−3 year course of tamoxifen followed by an aromatase inhibitor. To date, no study has documented that more than a 5 year course of an aromatase inhibitor is either safe or effective, though longer duration therapy can be administered if both tamoxifen and an aromastase inhibitor are included in the treatment regimen. There are a large number of unresolved questions regarding the use of endocrine therapy in postmenopausal women. These questions include: 1. should all patients receive an aromatase inhibitor as initial therapy, or are some patients better served with an initial course of tamoxifen? 2. To what extent should tumor characteristics, both anatomic and biologic features, influence initial treatment choice? 3. Are individual differences in the metabolism of tamoxifen of clinical relevance? 4. How do the side effects of tamoxifen and the aromatase inhibitors differ, and to what extent can these side effects be treated? 5. How long should therapy be administered, and can we identify a population of women who are at particularly high risk of late recurrence and would derive even greater benefit from prolonged treatment? 6. Can we identify groups of patients who can forego hormonal therapy and its associated side effects? and 7. How can we maximize adherence to these oral agents that have moderate side effects for some patients? The lecture will address each of these controversies and provide treatment recommendations for specific patient subgroups.
S40
S17
Duration of treatment: All the major trials have empirically used one year of adjuvant trastuzumab. The HERA trial is also comparing 2 v.1 year and results are awaited. A much smaller trial (FinHER) has shown similar efficacy gains with a mere 9 weeks of trastuzumab given concurrently with chemotherapy, suggesting that much shorter treatment may be as effective. The role of anthracyclines: Adjuvant trastuzumab after anthracyclines is associated with a small but significant increase in the risk of cardiotoxicity. Results from the BCIRG 006 trial suggest that a non-anthracycline regimen of docetaxel and carboplatin with trastuzumab achieves similar efficacy to anthracycline-containing regimens but without an increase in cardiotoxicity. Standardised measurement of HER2: ASCO and the College of American Pathologists recently convened an expert panel which concluded that around 20% of current HER2 testing may be inaccurate and proposed recommendations for standardised central testing in accredited laboratories with defined proficiency testing requirements. A positive HER2 result should be defined as IHC staining of 3+ (uniform intense membrane staining of greater than 30% of invasive tumour cells) or a fluorescent in situ hybridisation (FISH) result of more than 6 HER2 gene copies per nucleus or a FISH ratio of more than 2.2. ‘Low-risk’ HER2: So called low-risk T1, N0 HER2+ve breast cancers were largely excluded from the major adjuvant trastuzumab trials but data are accumulating that these have significant risk of relapse, even including <1 cm tumours. It is likely that trastuzumab with chemotherapy would also be of benefit in these circumstances; the role of adjuvant trastuzumab alone is plausible here but no direct data are available. New anti-HER2 targeted therapies: These are rapidly becoming available including lapatinib, an oral small molecule dual HER1/HER2tyrosine kinase inhibitor with significant clinical activity in metastatic breast cancer after trastuzumab. Adjuvant single agent lapatinib is being assessed in patients with trastuzumab-naive HER2 positive breast cancer in continuing remission following adjuvant chemotherapy in the TEACH trial. In addition, adjuvant lapatinib and chemotherapy is being compared directly with trastuzumab, or the 2 agents sequentially, or in combination, in the ALTTO trial.
S42
Adjuvant therapy of triple negative breast cancer
E.A. Perez. Jacksonville, USA Should genomic profiles be used to determine who should receive adjuvant chemotherapy?
K.S. Albain. Maywood, IL, USA
Abstract not received.
S43
Review of new targeted drugs: Crawling towards the adjuvant setting
Abstract not received.
S41
Targeting HER2 in the adjuvant setting: Dealing with new standards and open questions
I.E. Smith1 . 1 Medicine, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom The HER2 gene is amplified and the receptor overexpressed in around 20% of women with early breast cancer, and this is associated with an adverse prognosis. Trastuzumab (Herceptin), a humanised monoclonal antibody targeted against the external domain of the HER2 receptor, has been shown to have major clinical benefit in all stages of HER2 positive breast cancer including in particular as adjuvant therapy for early disease. The 2007 St Gallen guidelines recommended that trastuzumab should be considered as standard treatment concurrently with or sequentially after chemotherapy in patients with HER2 positive disease which is IHC (immunohistochemistry) 3+ or FISH positive except in those with a primary tumour less than 1 cm and no axillary node involvement. Important unanswered questions remain however. Concurrent or sequential therapy: Three major trials (NSABPB-31; NCCTG N9831 and BCIRG006) have shown significant survival benefit with concurrent trastuzumab given with a taxane chemotherapy following anthracycline treatment. A further major trial (HERA) has shown similar survival benefit with sequential trastuzumab given after standard adjuvant chemotherapy, but another smaller trial of sequential trastuzumab (PACS004) also given after chemotherapy has failed to show benefit. Results from the N9831 trial comparing concurrent with sequential treatment are awaited.
J. Baselga1 . 1 Vall Hebron Institute of Oncology, Vall Hebron University Hospital, Barcelona, Spain The cellular and molecular processes that lead to cancer, the already classical “hallmarks of malignancy”, include self-sufficiency in growth signals, insensivity to anti-growth factor signals, evasion of apoptosis, lack of senescence, invasion and metastasis, and sustained angiogenesis. All these processes can be potentially targeted in breast cancer. Among the most promising agents: 1. Inhibitors of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway. Uncontrolled activation of the PI3K/Akt/mTOR pathway, achieved via numerous genetic and epigenetic alterations, contributes to the development and progression of breast cancer. These genetic alterations include PTEN deletions and ‘hot-spots’ mutations of the PI3K gene. Further, these alterations may result in resistance to upstream anti-receptor agents. Clinical trials are currently underway with mTOR, PI3K, and Akt inhibitors. Based on the cross talk between the estrogen receptor and the PI3K/Akt/mTOR pathways, clinical trials with mTOR inhibitors have explored the combination of rapamycin analogues and aromatase inhibitors. Other potentially active combinations with mTOR inhibitors include in combination with trastuzumab in patients with trastuzumab-refractory disease. In terms of PI3K inhibitors they are currently being studied in early clinical trials. Among them, NVP-BEZ235 is a potent dual PI3K/mTOR inhibitor that is highly active in breast cancer cells harboring activating PI3K mutations. Other agents under study include XL765, also a dual PI3K/mTOR inhibitor and XL147, a more pure PI3K inhibitor. 2. Insulin-like growth factor-I receptor (IGF-IR) inhibitors. The IGF-IR is a transmembrane tyrosine kinase receptor that stimulates different