Overview of the impact of conventional systemic therapies on breast cancer
http://www.100md.com
《肿瘤与内分泌》
CRUK Department of Medical Oncology, University of Manchester, Christie Hospital, 550 Wilmslow Road, Manchester M20 4BX, UK
This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.
Abstract
Survival in women with breast cancer is improving in the western world, in part related to improved surgery, radiotherapy and adjuvant systemic therapy. Aromatase inhibitors are superior to tamoxifen in this clinical situation and several studies indicate that taxane-based chemotherapy is superior to non-taxane-based regimens. Herceptin is active alone in HER-2/neu +ve advanced breast cancer and four clinical trials are testing this agent in the adjuvant situation. It seems likely that herceptin will add to conventional therapies and thus will be the paradigm for the introduction of other biological therapies to improve cure rates.
Introduction
In the UK, deaths from breast cancer have declined by 20–30% since the inexorable rise in the death rate began to be reversed in the late 1980s. During this time, however, the incidence of the disease has increased by about 25% to an all time high of over 40 000 cases per year. The increased incidence is presumed to be related to the ageing population and changes in lifestyle. The precise reasons for the improvement in mortality are not clear but may be related to earlier tumour detection and to the more widespread use of, and improvements in, systemic adjuvant therapy.
The aims of systemic therapy are to increase the cure rates associated with the removal of the primary tumour and to palliate advanced disease by inducing tumour regression or stabilisation. In this article we will review recent advances in the treatment of breast cancer by conventional therapies and indicate the current limitations of treatment, where improvements in efficacy of current approaches can be made, and where the addition of new treatments such as anti-growth factor therapies would be potentially advantageous.
Endocrine therapy
Endocrine therapy is effective because it deprives the tumour cell of oestrogen either by reducing local and systemic oestrogen concentrations or by blocking the oestrogen receptor. Beatson was the first to demonstrate that reduction of oestradiol concentrations by oophorectomy caused regression of advanced disease in premenopausal women. Later, adrenalectomy was used but was soon replaced by inhibitors of oestrogen synthesis. The introduction of the three modern aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, for treatment of postmenopausal breast cancer is clearly a major advance. Tamoxifen has been the major oestrogen receptor (ER) blocking agent for many years and more recently, fulvestrant, an ER down-regulator, has been introduced. Because of its relative lack of toxicity, endocrine therapy is widely used to treat advanced disease as adjuvant and preoperative therapy and is now being assessed for disease prevention.
The modern AIs were shown to be superior to megestrol acetate as second line therapy (Buzdar et al. 1996, 2001, Dombernowsky et al. 1998, Kaufmann et al. 2000) and to tamoxifen as first line therapy for advanced disease (Bonneterre et al. 2000, Milla-Santos et al. 2003, Mouridsen et al. 2003, Paridaens et al. 2003). This success led to the beginning of trials with the modern AIs as adjuvant therapy in 1996. AIs are superior to tamoxifen if AI treatment is initiated soon after surgery or if treatment is switched after 2–3 years of tamoxifen (Boccardo et al. 2003, Coombes et al. 2004, Jakesz et al. 2004, Howell et al. 2005, Thurliman 2005) (Fig. 1). There are significant reductions in relapse compared with tamoxifen in all five trials which have reported results to date (three using anastrozole, and one each using exemestane and letrozole). Another study (MA-17) which compared the use of letrozole with placebo after completion of five years of tamoxifen also showed a disease-free advantage and a survival advantage of letrozole in the axillary node-positive subgroup (Goss et al. 2003) (Fig. 1). These trials have also shown that the incidence of contralateral breast cancer is reduced by approximately 50%. Tamoxifen is known to reduce contralateral breast cancer by 50% compared with placebo. Since AIs are compared with tamoxifen it is possible that AIs may reduce new breast cancer by approximately 70–75% —an hypothesis which is being tested in two prevention trials where anastrozole and exemestane are being compared with placebo as preventive agents in high risk women. The AIs also have a better side effect profile compared with tamoxifen. There are fewer withdrawals due to serious adverse events and fewer gynaecological and cardiovascular side effects (Howell et al. 2005) (Table 1). However, the three AIs are associated with increased bone loss and fracture and a small increase in the incidence of aches in the joints and morning stiffness. Thus, the introduction of AIs has advanced the adjuvant treatment of breast cancer producing an enhanced therapeutic ratio compared with tamoxifen.
The standard adjuvant endocrine therapy for premenopausal women is tamoxifen. Trials are underway to assess the benefit of ovarian ablation (OA) in addition to tamoxifen and whether treatment with OA and tamoxifen is superior to treatment with OA and anastrozole or exemestane. The first of these studies was initiated by the Austrian Breast Group and has an additional randomisation to treatment with the bisphosphonate, zoledronate (4 mg i.v. every six months) in order to test its effectiveness for reducing bone loss. Recently presented results of this study indicate that, at three years of follow-up, OA and anastrozole was associated with 14.4% bone loss over three years which was completely abrogated by the use of zoledronate (Gnant et al. 2004).
The AIs are also superior to tamoxifen for treatment of advanced breast cancer. However, since they are being used increasingly as adjuvant treatment, additional endocrine therapies for advanced disease are required. The ER downregulator, fulvestrant, has proven to be a useful additional treatment for advanced breast cancer. Trials have shown that it is equivalent in efficacy to anastrozole as second line therapy after failure on tamoxifen, and equivalent to tamoxifen as first line therapy for advanced disease (Howell et al. 2002, Osborne et al. 2002). At present there are no other new endocrine therapies for advanced disease so that the introduction of fulvestrant is timely. For premenopausal patients, an overview study of four trials demonstrated that OA and tamoxifen treatment was better than either treatment used alone for advanced breast cancer and is thus the standard for this group of women (Klijn et al. 2001). Trials are in progress to determine whether treatment with OA and an AI will be superior to OA and tamoxifen.
The relative lack of toxicity of tamoxifen and the reduction in contralateral cancers in the adjuvant trials led to the initiation of several prevention trials in high risk women in the 1980s and 1990s. An overview of the four tamoxifen trials indicated that 38% of cancers were prevented (Cuzick et al. 2003). However, gynaecological and cardiovascular side effects have meant that tamoxifen is not widely used for prevention. A prevention trial using the selective estrogen receptor modulator (SERM), raloxifene, in women with osteoporosis also showed a reduction in breast cancers (Multiple Outcomes of RaloxifenE Trial (MORE)). The trial has been extended for up to seven years and shows a 59% relative risk reduction compared with placebo (Martino et al. 2004). Other prevention trials are in progress. Raloxifene is being compared with placebo in 10 000 women at risk of and with heart disease (Raloxifene Use and The Heart—the RUTH trial) and is also being compared with tamoxifen in 19 000 women at increased risk (the STAR trial). Anastrozole is being compared with placebo in 6000 high-risk women (IBISII) and exemestane with placebo in North America. All these studies will help define the value of endocrine prevention and set the scene for the possible additional use of growth factor inhibitors for prevention in the future.
Chemotherapy
Combination chemotherapy was first used to induce responses in advanced breast cancer and subsequently it has been shown to improve the cure rate when given after surgery in women at risk of relapse. In the sixties and seventies regimens based on cyclophosphamide, fluorouracil and methotrexate were introduced (Early Breast Cancer Trialists’ Collaborative Group 2005). Later, the anthracyclines were shown to be an improvement and more recently (1990 to the present) the taxanes, taxotere and taxol, have been associated with further improvement.
Adjuvant chemotherapy was initially employed in axillary node-positive breast cancer especially in younger women, but is increasingly being used in nodenegative breast cancer particularly steroid hormone receptor-negative tumours, and in older women. It improves both disease-free survival (DFS) and overall survival (OS). The meta-analysis published by the Early Breast Cancer Trialists’ Collaborative Group shows a clear benefit of some months of adjuvant polychemotherapy (e.g. with cyclophosphamide, methotrexate and fluorouracil (CMF)) typically producing an absolute improvement of about 7–11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2–3% for those aged 50–69 (unless their prognosis is likely to be extremely good even without such treatment) (Early Breast Cancer Trialists’ Collaborative Group 2005). Early anthracycline-based chemotherapy improved on CMF-type chemotherapy by an average of 3%. Modern anthracycline regimens appear to offer greater improvement (~30% reduction in hazard ratio) over CMF (Poole et al. 2003). There remains some controversy about the optimal anthracycline regimen particularly the dose of epirubicin. The dose of doxorubicin is less controversial mainly as a result of the work of the Cancer and Leukemia Group B trial (CALGB 8541 and 9344) (Budman et al. 1998, Henderson et al. 2003) and the NSABP (B-22 trial) (Fisher et al. 1997). The French Adjuvant Study Group (FASG) has demonstrated that epirubicin 100 mg.m–2 (when administered with fluorouracil 500 mg.m–2 and cyclophosphamide 500 mg.m–2 every 21 days (FEC 100) for six cycles) is superior to epirubicin 50 mg.m–2 (6 FEC 50) (French Adjuvant Study Group 2001). They previously demonstrated that the 6 FEC 50 regimen is superior to 3 FEC 50 and 3 FEC 75 (Fumoleau et al. 2003). Although the optimal dose of epirubicin remains uncertain, particularly in view of the results of the Jules Bordet trial (Piccart et al. 2001), it is generally accepted that 90–100 mg.m–2 represents an acceptable standard for epirubicin if administered in a q21day schedule.
The 1990s saw the initiation of many large randomised controlled trials of taxanes in the adjuvant therapy of breast cancer. First generation taxane trials compared taxane-based chemotherapy with the standard of care anthracycline-based chemotherapy and second generation taxane trials are comparing different taxane regimens. Results from four first generation taxane trials are available and have resulted in licensing of taxanes for the adjuvant treatment of node-positive breast cancer.
The addition of 4 cycles of paclitaxel after 4 cycles of doxorubicin and cyclophosphamide reduces the risk of recurrence by 17%, with manageable toxicity (Henderson et al. 2003, Mamounas et al. 2003). The effect on OS is conflicting with no benefit to 18% improvement (Henderson et al. 2003, Mamounas et al. 2003), which may be partially accounted for by differences in the patient populations (including patient, tumour size, number of lymph nodes involved, starting dose of paclitaxel, difference in dose administered and the use of tamoxifen (concurrent with chemotherapy or sequential)). The Intergroup 01-00 trial, most recently updated by Dr Albain at SABCS 2004, showed that concurrent administration of tamoxifen with cyclophosphamide, adriamycin and fluorouracil (CAF) chemotherapy resulted in a significant reduction in both DFS and OS compared with sequential tamoxifen deferred until completion of CAF chemotherapy (Albain et al. 2004). Two large randomised controlled trials comparing docetaxel/anthracycline chemotherapy to non-taxane containing anthracycline combination chemotherapy showed a risk reduction of 17–30% for DFS and 23–32% for OS (Martin et al. 2003, Roche et al. 2004). Exploratory analyses show no difference according to numbers of nodes involved or steroid hormone receptor status. Toxicity was greater for the triplet docetaxel containing regimen, with, in particular, a high rate of febrile neutropaenia (Martin et al. 2003), mucosal toxicity and asthenia. Toxicity was much more manageable with the sequential use of docetaxel after anthracycline (Roche et al. 2004).
Whether a combination or sequential taxane regimen will prove optimal in the adjuvant setting remains uncertain, as does the question of which taxane is better. The answers to these questions and many others will have to await the results of the many trials involving more than ten thousand women addressing some of the questions. Some of these results, including the comparison of taxanes and weekly vs 3-weekly regimens (ECOG 1199) can be anticipated in the coming months. In the meantime, an absolute gain of 4–7% DFS and 3–6% OS offered by taxanes represents an important advancement in adjuvant chemotherapy for breast cancer. It represents the potential of thousands of patients with prolonged DFS (and possibly cure). This can be achieved without considerably prolonging the duration of adjuvant chemotherapy. It is potentially an equivalent gain to that obtained by the addition of anthracyclines. Translational research associated with the many ongoing trials of docetaxel, such as in the National Cancer Research Institute Breast Cancer Studies Group (UK) TACT Trial and tAnGo trials in the UK may help to answer the question of whether certain breast cancers benefit more than others from the addition of taxanes.
Biological therapy
What may be achieved by biological therapy into breast cancer treatment is exemplified by the introduction of herceptin. First, the target of overexpression of HER/neu was identified and an antibody to the receptor was introduced into treatment of advanced disease in addition to chemotherapy. These studies demonstrated that herceptin was effective only in the target population of tumours with amplification or overexpression of genes for the growth factor receptor and that the response rate, duration of response and survival was increased when herceptin was added to chemotherapy compared with chemotherapy alone in women with this tumour sub-type (Tripathy 2005). Now herceptin is being tested in the appropriate population as adjuvant therapy in addition to chemotherapy in four large clinical trials. Three of these reported preliminary results at the recent ASCO meeting showing an approximate 50% reduction in relapse. All have completed recruitment and the eagerly awaited results will be available in the near future. If these trials are positive, other adjuvant studies will almost certainly be initiated with other inhibitors such as lapatinib which have the potential advantage of being orally bioavailable.
Just as overexpression of Erb B2 is vital for selecting tumours likely to respond to herceptin, measurement of steroid hormone receptors is vital for selecting tumours for the use of endocrine therapy. Multiple studies have now demonstrated that hormone receptor negative tumours do not respond to endocrine therapies. However, just as with herceptin, not all tumours with the target protein respond. The reasons for this are not clear but are an important subject for further study (Bardou 2003, Konecny et al. 2003, Osborne et al. 2003). Tumours with low levels of ER or ER in the absence of progesterone receptor (PR) have a worse prognosis than tumours with high levels of ER or ER+PR+ tumours. The presence of at least two groups of tumours based on ER has been shown by the 70 gene expression profiles reported by Sorlie et al. (2003). These investigators reported that a group with greater expression of ER and associated genes (group A) had a much better prognosis than a group with lower ER and their associated gene profiles (group B). It is thought that in tumours with lower ER, proliferation may be driven through the steroid receptor by growth factor signalling. Endocrine therapies such as tamoxifen which act by causing translocation of the ER to appropriate oestrogen response elements (EREs) could allow agonist action by growth factor signalling through phosphorylation of serines in the AF1 part of the molecule. AIs, by depriving the cell of oestrogen, prevent ER translocation to EREs. Thus we would expect a better response in this tumour type from AIs rather than from tamoxifen. In a preoperative study, Ellis et al. (2003) demonstrated that letrozole was more effective in low ER tumours, and in adjuvant trials where the AI used was anastrozole, patients with tumours which were ER+PR– fared better on the AI than on tamoxifen (Dowsett et al. 2003, Jakesz et al. 2004, Howell et al. 2005). Paradoxically, no difference in outcome was seen between ER+PR+ and ER+ PR– tumours with the adjuvant use of exemestane and letrozole (Coombes et al. 2004, Thurliman 2005). The reasons for these contrasting results are not clear and are the subject of active investigation. However, there is great potential for the use of signal transduction inhibitors to increase responsiveness in low ER tumours and to prevent resistance in the high ER group.
The ER may also be an indicator of response to chemotherapy. There is no doubt that chemotherapy is maximally active in tumours without measurable ER whereas endocrine therapy is completely inactive in this group. Chemotherapy appears less active in ER+ve tumours. In some studies there is no activity at all in this group whereas in others there is some. There is some evidence for the hypothesis that chemotherapy may be more active in ER-poor than in ER-rich tumours. This may be the mechanism of the effect seen using the 21 gene profile reported by Paik et al. (2004). They assessed the profile in the tumours of patients entered in the NSABP B20 study. In this study all patients had ER+ve, node-negative tumours and were treated with tamoxifen with a randomisation to chemotherapy or no chemotherapy. The 21 gene profile divided patients into three prognostic subgroups. In the best prognostic subgroups there was no additional benefit from chemotherapy compared with that assumed to have occurred with tamoxifen. In the third group with the poorest prognosis on tamoxifen, which could be assumed to have low or relatively inactive ER, chemotherapy was superior to no chemotherapy (Paik et al. 2004). The recent St Gallen Consensus Conference recommendations now divide tumours into three strata as suggested above recognising that the ER-poor group may be more responsive to chemotherapy and less responsive to endocrine therapy whereas the working hypothesis that ER-rich tumours gain minimal benefit from chemotherapy is reasonable but requires further test.
the results of the Oxford overview and subsequent studies many patients given adjuvant chemotherapy and endocrine therapy are cured by treatment (Early Breast Cancer Trialists’ Collaborative Group 2005). However, other tumours where we expect an effect of treatment are resistant or they may respond for a period (subclinically) but later recur and cause patient death. Few patients are cured after relapse. This makes it imperative that combinations of standard therapy with growth factor therapy are moved into the adjuvant setting as soon as reasonable results are seen in advanced disease. Treatment with herceptin is a model for what might be achievable using additional growth factor treatment in the future. Herceptin added to the effect of chemotherapy in advanced disease and has now shown to be highly effective as adjuvant therapy. It is possible, given that endocrine resistance may be mediated by increased surface receptor signalling, that herceptin may abrogate this resistance in studies under way in advanced disease and may be used in the adjuvant situation with endocrine therapy (Kurokawa & Arteaga 2003). The herceptin story exemplifies the importance of defining the target for therapy and ensuring that the tumours treated express or have overactivity of the target molecule. Thus, in the future, we may have a series of tailored therapies for women with early breast cancer. Early results from such studies are outlined in subsequent chapters in this issue. These studies must go hand in hand with studies to define, more precisely, women with micrometastases at surgery. With advances in early detection, more and more women have small, good prognosis tumours which do not require adjuvant therapy. Because our prognostic methods are imperfect women are treated unnecessarily and on the basis that they could possibly have metastases. Gene arrays and other methods show promise in defining prognosis more precisely.
References
Albain K, Barlow W, O’Malley F & Siziopikou K Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Conference 2004. Breast Cancer Research and Treatment Abstract 37.
Bardou VJ, Arpino G, Elledge RM, Osborne CK & Clark GM 2003 Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. Journal of Clinical Oncology 21 1973–1979.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Massobrio M, Porpiglia M, Rinaldi M, Paladini G, Distante V, Franchi R, Failla G, Bordernaro R, Sismondi P on behalf of the Italian Tamoxifen Arimidex (ITA) Trial 2003 Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant treatment. Breast Cancer Research and Treatment 82 (Suppl 1) S6.
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M & von Euler M 2000 Anastrozole versus tamoxifen as first line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. Journal of Clinical Oncology 18 3748–3757.
Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Moss HB, Green MR, Norton L & Frei E 3rd 1998 Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. Journal of the National Cancer Institute 90 1205–1211.
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eirmann W, Wolter JM, Azab M, Webster A & Plourde PV 1996 Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. Journal of Clinical Oncology 14 2000–2011.
Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X & Brady C 2001 Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. Journal of Clinical Oncology 19 3357–3366.
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Anderson J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpenterie M, Massimini G & Bliss JM; Intergroup Exemestane Study 2004 A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New England Journal of Medicine 350 1081–1092.
Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S & Boyle P 2003 Overview of the main outcomes in breast cancer prevention trials. Lancet 361 296–300.
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U & Trunet PF 1998 Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. Journal of Clinical Oncology 16 453–461.
Dowsett M on behalf of the ATAC Trialists Group 2003 Analysis of time to recurrence in the ATAC trial according to estrogen receptor and progesterone receptor status. Breast Cancer Research and Treatment 83 (Suppl 1) S27.
Early Breast Cancer Trialists’ Collaborative Group 2005 Effects of chemotherapy and hormonal therapy for early breast cancer on recurrance and 15-year survival: an overview of the randomised trials. Lancet 365 1687–1717.
Ellis MJ, Coop A, Singh B, Tao Y, Liombart-Cussac A, Janicke F, Mauriac L, Quebe-Fehling E, Chaudri-Ross HA, Evans DB & Miller WR 2003 Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Research 63 6523–6231.
Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P & Deckers P 1997 Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-22. Journal of Clinical Oncology 15 1858–1869.
French Adjuvant Study Group (2001). Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 Randomized Trial. Journal of Clinical Oncology 19 602–611.
Fumoleau P, Kerbrat P, Romestaing P, Fargect P, Bremond A, Namer M, Schraub S, Goudier MJ, Mihura J, Mannier A, Clavere P, Serin D, Seffert P, Pourney C, Facchini T, Jacguin JP, Sztermer JF, Datchary J, Ramos R & Luporsi E 2003 Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 Trial. Journal of Clinical Oncology 21 298–305.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ & Pater JL 2003 A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New England Journal of Medicine 349 1793–1802.
Gnant M, Jakesz R, Mlineritsch B, Luschin-Ebengreuth G, Schmid M, Menzel C, Kubista E, Samonigg H, Hausmaninger H, the ABCSG Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria 2004 Zoledronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) on premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen — bone density subprotocol results of a randomised multicenter trial (ABCSG-12). Breast Cancer Research and Treatment 88 (Suppl 1) S8.
Henderson IC, Berry DA & Demetri GD 2003 Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology 21 976–983.
Howell A, Robertson JFR, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A & Morris C 2002 Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. Journal of Clinical Oncology 20 3396–3403.
Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY & Tobias JS 2005 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 2131–2139.
Jakesz R, Kaufmann M, Gnant M, Jonat W, Mittleboek M, Greil R, Tausch C, Hilfrich J, Kwasny W, Samonigg H, on behalf of the ABCSG 2004 Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results from 3123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Breast Cancer Research and Treatment 88 (Suppl 1) S7.
Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL & Massimini G 2000 Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. Journal of Clinical Oncology 18 1399–1411.
Klijn JG, Blamey RW, Boccardo F, Tominaga T & Duchateau L 2001 Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. Journal of Clinical Oncology 19 343–353.
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H & Slamon DJ 2003 Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. Journal of the National Cancer Institute 95 142–153.
Kurokawa H & Arteaga CL 2003 ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clinical Cancer Research 9 (Suppl) 511–515.
Mamounas EP, Bryant J, Lembersky BC, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DC, Yothers G, Soran A & Wolmark N 2003 Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Proceedings of the American Society of Clinical Oncology 22 4 (Abstract 12).
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla J-P, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A & Vogel C for the Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. New England Journal of Medicine 352 2302–2313.
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR; CORE Investigators 2004 Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomised trial of raloxifene. Journal of the National Cancer Institute 96 1751–1761.
Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, Casanovas J & Puig-Gali M 2003 Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer. American Journal of Clinical Oncology 26 317–322.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleebom HP, Joenicke F, Pluzanska A, Dank M, Becquart D, Bopsy PB, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P & Bhatnagar A 2003 Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Journal of Clinical Oncology 21 2101–2109.
Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R & Buzdar A 2002 Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. Journal of Clinical Oncology 20 3386–3395.
Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM & Schiff R 2003 Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. Journal of the National Cancer Institute 95 353–361.
Paik S, Shak S, Tang G, Kim C, Joo H, Baker J, Cronin M, Watson D, Braynt J, Costantino J & Wolmark N 2004 Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NASBP study B-14 and chemotherapy in NASBP study B-20. Breast Cancer Research and Treatment 88 (Suppl 1) S24.
Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP & Piccart M 2003 Mature results of a randomised phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annals of Oncology 14 1391–1398.
Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M & Nogaret JM 2001 Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. Journal of Clinical Oncology 19 3103–3110.
Poole CJ, Earl HM, Dunn JA, Hiller L, Bathers S, Spooner D, Grieve R, Agrawall RK, Foster E & Twelves C for the NEAT and SCTBG 2003 NEAT (National Epirubicin Adjuvant Trial) and SCTBG BR9601 (Scottish Cancer Trials Breast Group) phase III adjuvant breast trials show a significant relapse-free and overall survival advantage for sequential ECMF. Proceedings of the American Society of Clinical Oncology 22 4 (Abstract 13).
Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Kerbrat P, Serin D, Lortholary A, de Ghislain C & Viens P 2004 Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Breast Cancer Research and Treatment 88 (Suppl 1) S16.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Dementer J, Perou CM, Lonning PE, Brown PO, Borreson-Dale AL & Botsein D 2003 Repeated observation of breast tumour subtypes in independent gene expression data sets. PNAS 100 8418–8423.
Thurliman B 2005 BIG 1-98: a prospective randomised double-blind double dummy phase III study. Letrozole versus tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. St Gallen 2005. The Breast 14 (Suppl 1) S3.
Tripathy D 2005 Targeted therapies in breast cancer. Breast Journal 11 (Suppl 1) S30–S35.(Anthony Howell and Andrew)
This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.
Abstract
Survival in women with breast cancer is improving in the western world, in part related to improved surgery, radiotherapy and adjuvant systemic therapy. Aromatase inhibitors are superior to tamoxifen in this clinical situation and several studies indicate that taxane-based chemotherapy is superior to non-taxane-based regimens. Herceptin is active alone in HER-2/neu +ve advanced breast cancer and four clinical trials are testing this agent in the adjuvant situation. It seems likely that herceptin will add to conventional therapies and thus will be the paradigm for the introduction of other biological therapies to improve cure rates.
Introduction
In the UK, deaths from breast cancer have declined by 20–30% since the inexorable rise in the death rate began to be reversed in the late 1980s. During this time, however, the incidence of the disease has increased by about 25% to an all time high of over 40 000 cases per year. The increased incidence is presumed to be related to the ageing population and changes in lifestyle. The precise reasons for the improvement in mortality are not clear but may be related to earlier tumour detection and to the more widespread use of, and improvements in, systemic adjuvant therapy.
The aims of systemic therapy are to increase the cure rates associated with the removal of the primary tumour and to palliate advanced disease by inducing tumour regression or stabilisation. In this article we will review recent advances in the treatment of breast cancer by conventional therapies and indicate the current limitations of treatment, where improvements in efficacy of current approaches can be made, and where the addition of new treatments such as anti-growth factor therapies would be potentially advantageous.
Endocrine therapy
Endocrine therapy is effective because it deprives the tumour cell of oestrogen either by reducing local and systemic oestrogen concentrations or by blocking the oestrogen receptor. Beatson was the first to demonstrate that reduction of oestradiol concentrations by oophorectomy caused regression of advanced disease in premenopausal women. Later, adrenalectomy was used but was soon replaced by inhibitors of oestrogen synthesis. The introduction of the three modern aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, for treatment of postmenopausal breast cancer is clearly a major advance. Tamoxifen has been the major oestrogen receptor (ER) blocking agent for many years and more recently, fulvestrant, an ER down-regulator, has been introduced. Because of its relative lack of toxicity, endocrine therapy is widely used to treat advanced disease as adjuvant and preoperative therapy and is now being assessed for disease prevention.
The modern AIs were shown to be superior to megestrol acetate as second line therapy (Buzdar et al. 1996, 2001, Dombernowsky et al. 1998, Kaufmann et al. 2000) and to tamoxifen as first line therapy for advanced disease (Bonneterre et al. 2000, Milla-Santos et al. 2003, Mouridsen et al. 2003, Paridaens et al. 2003). This success led to the beginning of trials with the modern AIs as adjuvant therapy in 1996. AIs are superior to tamoxifen if AI treatment is initiated soon after surgery or if treatment is switched after 2–3 years of tamoxifen (Boccardo et al. 2003, Coombes et al. 2004, Jakesz et al. 2004, Howell et al. 2005, Thurliman 2005) (Fig. 1). There are significant reductions in relapse compared with tamoxifen in all five trials which have reported results to date (three using anastrozole, and one each using exemestane and letrozole). Another study (MA-17) which compared the use of letrozole with placebo after completion of five years of tamoxifen also showed a disease-free advantage and a survival advantage of letrozole in the axillary node-positive subgroup (Goss et al. 2003) (Fig. 1). These trials have also shown that the incidence of contralateral breast cancer is reduced by approximately 50%. Tamoxifen is known to reduce contralateral breast cancer by 50% compared with placebo. Since AIs are compared with tamoxifen it is possible that AIs may reduce new breast cancer by approximately 70–75% —an hypothesis which is being tested in two prevention trials where anastrozole and exemestane are being compared with placebo as preventive agents in high risk women. The AIs also have a better side effect profile compared with tamoxifen. There are fewer withdrawals due to serious adverse events and fewer gynaecological and cardiovascular side effects (Howell et al. 2005) (Table 1). However, the three AIs are associated with increased bone loss and fracture and a small increase in the incidence of aches in the joints and morning stiffness. Thus, the introduction of AIs has advanced the adjuvant treatment of breast cancer producing an enhanced therapeutic ratio compared with tamoxifen.
The standard adjuvant endocrine therapy for premenopausal women is tamoxifen. Trials are underway to assess the benefit of ovarian ablation (OA) in addition to tamoxifen and whether treatment with OA and tamoxifen is superior to treatment with OA and anastrozole or exemestane. The first of these studies was initiated by the Austrian Breast Group and has an additional randomisation to treatment with the bisphosphonate, zoledronate (4 mg i.v. every six months) in order to test its effectiveness for reducing bone loss. Recently presented results of this study indicate that, at three years of follow-up, OA and anastrozole was associated with 14.4% bone loss over three years which was completely abrogated by the use of zoledronate (Gnant et al. 2004).
The AIs are also superior to tamoxifen for treatment of advanced breast cancer. However, since they are being used increasingly as adjuvant treatment, additional endocrine therapies for advanced disease are required. The ER downregulator, fulvestrant, has proven to be a useful additional treatment for advanced breast cancer. Trials have shown that it is equivalent in efficacy to anastrozole as second line therapy after failure on tamoxifen, and equivalent to tamoxifen as first line therapy for advanced disease (Howell et al. 2002, Osborne et al. 2002). At present there are no other new endocrine therapies for advanced disease so that the introduction of fulvestrant is timely. For premenopausal patients, an overview study of four trials demonstrated that OA and tamoxifen treatment was better than either treatment used alone for advanced breast cancer and is thus the standard for this group of women (Klijn et al. 2001). Trials are in progress to determine whether treatment with OA and an AI will be superior to OA and tamoxifen.
The relative lack of toxicity of tamoxifen and the reduction in contralateral cancers in the adjuvant trials led to the initiation of several prevention trials in high risk women in the 1980s and 1990s. An overview of the four tamoxifen trials indicated that 38% of cancers were prevented (Cuzick et al. 2003). However, gynaecological and cardiovascular side effects have meant that tamoxifen is not widely used for prevention. A prevention trial using the selective estrogen receptor modulator (SERM), raloxifene, in women with osteoporosis also showed a reduction in breast cancers (Multiple Outcomes of RaloxifenE Trial (MORE)). The trial has been extended for up to seven years and shows a 59% relative risk reduction compared with placebo (Martino et al. 2004). Other prevention trials are in progress. Raloxifene is being compared with placebo in 10 000 women at risk of and with heart disease (Raloxifene Use and The Heart—the RUTH trial) and is also being compared with tamoxifen in 19 000 women at increased risk (the STAR trial). Anastrozole is being compared with placebo in 6000 high-risk women (IBISII) and exemestane with placebo in North America. All these studies will help define the value of endocrine prevention and set the scene for the possible additional use of growth factor inhibitors for prevention in the future.
Chemotherapy
Combination chemotherapy was first used to induce responses in advanced breast cancer and subsequently it has been shown to improve the cure rate when given after surgery in women at risk of relapse. In the sixties and seventies regimens based on cyclophosphamide, fluorouracil and methotrexate were introduced (Early Breast Cancer Trialists’ Collaborative Group 2005). Later, the anthracyclines were shown to be an improvement and more recently (1990 to the present) the taxanes, taxotere and taxol, have been associated with further improvement.
Adjuvant chemotherapy was initially employed in axillary node-positive breast cancer especially in younger women, but is increasingly being used in nodenegative breast cancer particularly steroid hormone receptor-negative tumours, and in older women. It improves both disease-free survival (DFS) and overall survival (OS). The meta-analysis published by the Early Breast Cancer Trialists’ Collaborative Group shows a clear benefit of some months of adjuvant polychemotherapy (e.g. with cyclophosphamide, methotrexate and fluorouracil (CMF)) typically producing an absolute improvement of about 7–11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2–3% for those aged 50–69 (unless their prognosis is likely to be extremely good even without such treatment) (Early Breast Cancer Trialists’ Collaborative Group 2005). Early anthracycline-based chemotherapy improved on CMF-type chemotherapy by an average of 3%. Modern anthracycline regimens appear to offer greater improvement (~30% reduction in hazard ratio) over CMF (Poole et al. 2003). There remains some controversy about the optimal anthracycline regimen particularly the dose of epirubicin. The dose of doxorubicin is less controversial mainly as a result of the work of the Cancer and Leukemia Group B trial (CALGB 8541 and 9344) (Budman et al. 1998, Henderson et al. 2003) and the NSABP (B-22 trial) (Fisher et al. 1997). The French Adjuvant Study Group (FASG) has demonstrated that epirubicin 100 mg.m–2 (when administered with fluorouracil 500 mg.m–2 and cyclophosphamide 500 mg.m–2 every 21 days (FEC 100) for six cycles) is superior to epirubicin 50 mg.m–2 (6 FEC 50) (French Adjuvant Study Group 2001). They previously demonstrated that the 6 FEC 50 regimen is superior to 3 FEC 50 and 3 FEC 75 (Fumoleau et al. 2003). Although the optimal dose of epirubicin remains uncertain, particularly in view of the results of the Jules Bordet trial (Piccart et al. 2001), it is generally accepted that 90–100 mg.m–2 represents an acceptable standard for epirubicin if administered in a q21day schedule.
The 1990s saw the initiation of many large randomised controlled trials of taxanes in the adjuvant therapy of breast cancer. First generation taxane trials compared taxane-based chemotherapy with the standard of care anthracycline-based chemotherapy and second generation taxane trials are comparing different taxane regimens. Results from four first generation taxane trials are available and have resulted in licensing of taxanes for the adjuvant treatment of node-positive breast cancer.
The addition of 4 cycles of paclitaxel after 4 cycles of doxorubicin and cyclophosphamide reduces the risk of recurrence by 17%, with manageable toxicity (Henderson et al. 2003, Mamounas et al. 2003). The effect on OS is conflicting with no benefit to 18% improvement (Henderson et al. 2003, Mamounas et al. 2003), which may be partially accounted for by differences in the patient populations (including patient, tumour size, number of lymph nodes involved, starting dose of paclitaxel, difference in dose administered and the use of tamoxifen (concurrent with chemotherapy or sequential)). The Intergroup 01-00 trial, most recently updated by Dr Albain at SABCS 2004, showed that concurrent administration of tamoxifen with cyclophosphamide, adriamycin and fluorouracil (CAF) chemotherapy resulted in a significant reduction in both DFS and OS compared with sequential tamoxifen deferred until completion of CAF chemotherapy (Albain et al. 2004). Two large randomised controlled trials comparing docetaxel/anthracycline chemotherapy to non-taxane containing anthracycline combination chemotherapy showed a risk reduction of 17–30% for DFS and 23–32% for OS (Martin et al. 2003, Roche et al. 2004). Exploratory analyses show no difference according to numbers of nodes involved or steroid hormone receptor status. Toxicity was greater for the triplet docetaxel containing regimen, with, in particular, a high rate of febrile neutropaenia (Martin et al. 2003), mucosal toxicity and asthenia. Toxicity was much more manageable with the sequential use of docetaxel after anthracycline (Roche et al. 2004).
Whether a combination or sequential taxane regimen will prove optimal in the adjuvant setting remains uncertain, as does the question of which taxane is better. The answers to these questions and many others will have to await the results of the many trials involving more than ten thousand women addressing some of the questions. Some of these results, including the comparison of taxanes and weekly vs 3-weekly regimens (ECOG 1199) can be anticipated in the coming months. In the meantime, an absolute gain of 4–7% DFS and 3–6% OS offered by taxanes represents an important advancement in adjuvant chemotherapy for breast cancer. It represents the potential of thousands of patients with prolonged DFS (and possibly cure). This can be achieved without considerably prolonging the duration of adjuvant chemotherapy. It is potentially an equivalent gain to that obtained by the addition of anthracyclines. Translational research associated with the many ongoing trials of docetaxel, such as in the National Cancer Research Institute Breast Cancer Studies Group (UK) TACT Trial and tAnGo trials in the UK may help to answer the question of whether certain breast cancers benefit more than others from the addition of taxanes.
Biological therapy
What may be achieved by biological therapy into breast cancer treatment is exemplified by the introduction of herceptin. First, the target of overexpression of HER/neu was identified and an antibody to the receptor was introduced into treatment of advanced disease in addition to chemotherapy. These studies demonstrated that herceptin was effective only in the target population of tumours with amplification or overexpression of genes for the growth factor receptor and that the response rate, duration of response and survival was increased when herceptin was added to chemotherapy compared with chemotherapy alone in women with this tumour sub-type (Tripathy 2005). Now herceptin is being tested in the appropriate population as adjuvant therapy in addition to chemotherapy in four large clinical trials. Three of these reported preliminary results at the recent ASCO meeting showing an approximate 50% reduction in relapse. All have completed recruitment and the eagerly awaited results will be available in the near future. If these trials are positive, other adjuvant studies will almost certainly be initiated with other inhibitors such as lapatinib which have the potential advantage of being orally bioavailable.
Just as overexpression of Erb B2 is vital for selecting tumours likely to respond to herceptin, measurement of steroid hormone receptors is vital for selecting tumours for the use of endocrine therapy. Multiple studies have now demonstrated that hormone receptor negative tumours do not respond to endocrine therapies. However, just as with herceptin, not all tumours with the target protein respond. The reasons for this are not clear but are an important subject for further study (Bardou 2003, Konecny et al. 2003, Osborne et al. 2003). Tumours with low levels of ER or ER in the absence of progesterone receptor (PR) have a worse prognosis than tumours with high levels of ER or ER+PR+ tumours. The presence of at least two groups of tumours based on ER has been shown by the 70 gene expression profiles reported by Sorlie et al. (2003). These investigators reported that a group with greater expression of ER and associated genes (group A) had a much better prognosis than a group with lower ER and their associated gene profiles (group B). It is thought that in tumours with lower ER, proliferation may be driven through the steroid receptor by growth factor signalling. Endocrine therapies such as tamoxifen which act by causing translocation of the ER to appropriate oestrogen response elements (EREs) could allow agonist action by growth factor signalling through phosphorylation of serines in the AF1 part of the molecule. AIs, by depriving the cell of oestrogen, prevent ER translocation to EREs. Thus we would expect a better response in this tumour type from AIs rather than from tamoxifen. In a preoperative study, Ellis et al. (2003) demonstrated that letrozole was more effective in low ER tumours, and in adjuvant trials where the AI used was anastrozole, patients with tumours which were ER+PR– fared better on the AI than on tamoxifen (Dowsett et al. 2003, Jakesz et al. 2004, Howell et al. 2005). Paradoxically, no difference in outcome was seen between ER+PR+ and ER+ PR– tumours with the adjuvant use of exemestane and letrozole (Coombes et al. 2004, Thurliman 2005). The reasons for these contrasting results are not clear and are the subject of active investigation. However, there is great potential for the use of signal transduction inhibitors to increase responsiveness in low ER tumours and to prevent resistance in the high ER group.
The ER may also be an indicator of response to chemotherapy. There is no doubt that chemotherapy is maximally active in tumours without measurable ER whereas endocrine therapy is completely inactive in this group. Chemotherapy appears less active in ER+ve tumours. In some studies there is no activity at all in this group whereas in others there is some. There is some evidence for the hypothesis that chemotherapy may be more active in ER-poor than in ER-rich tumours. This may be the mechanism of the effect seen using the 21 gene profile reported by Paik et al. (2004). They assessed the profile in the tumours of patients entered in the NSABP B20 study. In this study all patients had ER+ve, node-negative tumours and were treated with tamoxifen with a randomisation to chemotherapy or no chemotherapy. The 21 gene profile divided patients into three prognostic subgroups. In the best prognostic subgroups there was no additional benefit from chemotherapy compared with that assumed to have occurred with tamoxifen. In the third group with the poorest prognosis on tamoxifen, which could be assumed to have low or relatively inactive ER, chemotherapy was superior to no chemotherapy (Paik et al. 2004). The recent St Gallen Consensus Conference recommendations now divide tumours into three strata as suggested above recognising that the ER-poor group may be more responsive to chemotherapy and less responsive to endocrine therapy whereas the working hypothesis that ER-rich tumours gain minimal benefit from chemotherapy is reasonable but requires further test.
the results of the Oxford overview and subsequent studies many patients given adjuvant chemotherapy and endocrine therapy are cured by treatment (Early Breast Cancer Trialists’ Collaborative Group 2005). However, other tumours where we expect an effect of treatment are resistant or they may respond for a period (subclinically) but later recur and cause patient death. Few patients are cured after relapse. This makes it imperative that combinations of standard therapy with growth factor therapy are moved into the adjuvant setting as soon as reasonable results are seen in advanced disease. Treatment with herceptin is a model for what might be achievable using additional growth factor treatment in the future. Herceptin added to the effect of chemotherapy in advanced disease and has now shown to be highly effective as adjuvant therapy. It is possible, given that endocrine resistance may be mediated by increased surface receptor signalling, that herceptin may abrogate this resistance in studies under way in advanced disease and may be used in the adjuvant situation with endocrine therapy (Kurokawa & Arteaga 2003). The herceptin story exemplifies the importance of defining the target for therapy and ensuring that the tumours treated express or have overactivity of the target molecule. Thus, in the future, we may have a series of tailored therapies for women with early breast cancer. Early results from such studies are outlined in subsequent chapters in this issue. These studies must go hand in hand with studies to define, more precisely, women with micrometastases at surgery. With advances in early detection, more and more women have small, good prognosis tumours which do not require adjuvant therapy. Because our prognostic methods are imperfect women are treated unnecessarily and on the basis that they could possibly have metastases. Gene arrays and other methods show promise in defining prognosis more precisely.
References
Albain K, Barlow W, O’Malley F & Siziopikou K Concurrent (CAFT) versus sequential (CAF-T) chemohormonal therapy (cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen) versus T alone for postmenopausal, node-positive, estrogen (ER) and/or progesterone (PgR) receptor-positive breast cancer: mature outcomes and new biologic correlates on phase III intergroup trial 0100 (SWOG-8814). San Antonio Breast Cancer Conference 2004. Breast Cancer Research and Treatment Abstract 37.
Bardou VJ, Arpino G, Elledge RM, Osborne CK & Clark GM 2003 Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. Journal of Clinical Oncology 21 1973–1979.
Boccardo F, Rubagotti A, Amoroso D, Mesiti M, Massobrio M, Porpiglia M, Rinaldi M, Paladini G, Distante V, Franchi R, Failla G, Bordernaro R, Sismondi P on behalf of the Italian Tamoxifen Arimidex (ITA) Trial 2003 Anastrozole appears to be superior to tamoxifen in women already receiving adjuvant treatment. Breast Cancer Research and Treatment 82 (Suppl 1) S6.
Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M & von Euler M 2000 Anastrozole versus tamoxifen as first line therapy for advanced breast cancer in 668 postmenopausal women: results of the Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability Study. Journal of Clinical Oncology 18 3748–3757.
Budman DR, Berry DA, Cirrincione CT, Henderson IC, Wood WC, Weiss RB, Ferree CR, Moss HB, Green MR, Norton L & Frei E 3rd 1998 Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. Journal of the National Cancer Institute 90 1205–1211.
Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eirmann W, Wolter JM, Azab M, Webster A & Plourde PV 1996 Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. Journal of Clinical Oncology 14 2000–2011.
Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X & Brady C 2001 Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. Journal of Clinical Oncology 19 3357–3366.
Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Anderson J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpenterie M, Massimini G & Bliss JM; Intergroup Exemestane Study 2004 A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New England Journal of Medicine 350 1081–1092.
Cuzick J, Powles T, Veronesi U, Forbes J, Edwards R, Ashley S & Boyle P 2003 Overview of the main outcomes in breast cancer prevention trials. Lancet 361 296–300.
Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U & Trunet PF 1998 Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. Journal of Clinical Oncology 16 453–461.
Dowsett M on behalf of the ATAC Trialists Group 2003 Analysis of time to recurrence in the ATAC trial according to estrogen receptor and progesterone receptor status. Breast Cancer Research and Treatment 83 (Suppl 1) S27.
Early Breast Cancer Trialists’ Collaborative Group 2005 Effects of chemotherapy and hormonal therapy for early breast cancer on recurrance and 15-year survival: an overview of the randomised trials. Lancet 365 1687–1717.
Ellis MJ, Coop A, Singh B, Tao Y, Liombart-Cussac A, Janicke F, Mauriac L, Quebe-Fehling E, Chaudri-Ross HA, Evans DB & Miller WR 2003 Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Research 63 6523–6231.
Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P & Deckers P 1997 Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project B-22. Journal of Clinical Oncology 15 1858–1869.
French Adjuvant Study Group (2001). Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 Randomized Trial. Journal of Clinical Oncology 19 602–611.
Fumoleau P, Kerbrat P, Romestaing P, Fargect P, Bremond A, Namer M, Schraub S, Goudier MJ, Mihura J, Mannier A, Clavere P, Serin D, Seffert P, Pourney C, Facchini T, Jacguin JP, Sztermer JF, Datchary J, Ramos R & Luporsi E 2003 Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 Trial. Journal of Clinical Oncology 21 298–305.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ & Pater JL 2003 A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. New England Journal of Medicine 349 1793–1802.
Gnant M, Jakesz R, Mlineritsch B, Luschin-Ebengreuth G, Schmid M, Menzel C, Kubista E, Samonigg H, Hausmaninger H, the ABCSG Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria 2004 Zoledronic acid effectively counteracts cancer treatment induced bone loss (CTIBL) on premenopausal breast cancer patients receiving adjuvant endocrine treatment with goserelin plus anastrozole versus goserelin plus tamoxifen — bone density subprotocol results of a randomised multicenter trial (ABCSG-12). Breast Cancer Research and Treatment 88 (Suppl 1) S8.
Henderson IC, Berry DA & Demetri GD 2003 Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology 21 976–983.
Howell A, Robertson JFR, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A & Morris C 2002 Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. Journal of Clinical Oncology 20 3396–3403.
Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY & Tobias JS 2005 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 2131–2139.
Jakesz R, Kaufmann M, Gnant M, Jonat W, Mittleboek M, Greil R, Tausch C, Hilfrich J, Kwasny W, Samonigg H, on behalf of the ABCSG 2004 Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: combined results from 3123 women enrolled in the ABCSG Trial 8 and the ARNO 95 Trial. Breast Cancer Research and Treatment 88 (Suppl 1) S7.
Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL & Massimini G 2000 Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. Journal of Clinical Oncology 18 1399–1411.
Klijn JG, Blamey RW, Boccardo F, Tominaga T & Duchateau L 2001 Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. Journal of Clinical Oncology 19 343–353.
Konecny G, Pauletti G, Pegram M, Untch M, Dandekar S, Aguilar Z, Wilson C, Rong HM, Bauerfeind I, Felber M, Wang HJ, Beryt M, Seshadri R, Hepp H & Slamon DJ 2003 Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. Journal of the National Cancer Institute 95 142–153.
Kurokawa H & Arteaga CL 2003 ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clinical Cancer Research 9 (Suppl) 511–515.
Mamounas EP, Bryant J, Lembersky BC, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DC, Yothers G, Soran A & Wolmark N 2003 Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Proceedings of the American Society of Clinical Oncology 22 4 (Abstract 12).
Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla J-P, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A & Vogel C for the Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. New England Journal of Medicine 352 2302–2313.
Martino S, Cauley JA, Barrett-Connor E, Powles TJ, Mershon J, Disch D, Secrest RJ, Cummings SR; CORE Investigators 2004 Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomised trial of raloxifene. Journal of the National Cancer Institute 96 1751–1761.
Milla-Santos A, Milla L, Portella J, Rallo L, Pons M, Rodes E, Casanovas J & Puig-Gali M 2003 Anastrozole versus tamoxifen as first-line therapy in postmenopausal patients with hormone-dependent advanced breast cancer. American Journal of Clinical Oncology 26 317–322.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleebom HP, Joenicke F, Pluzanska A, Dank M, Becquart D, Bopsy PB, Salminen E, Snyder R, Chaudri-Ross H, Lang R, Wyld P & Bhatnagar A 2003 Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Journal of Clinical Oncology 21 2101–2109.
Osborne CK, Pippen J, Jones SE, Parker LM, Ellis M, Come S, Gertler SZ, May JT, Burton G, Dimery I, Webster A, Morris C, Elledge R & Buzdar A 2002 Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. Journal of Clinical Oncology 20 3386–3395.
Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, Wong J, Allred DC, Clark GM & Schiff R 2003 Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. Journal of the National Cancer Institute 95 353–361.
Paik S, Shak S, Tang G, Kim C, Joo H, Baker J, Cronin M, Watson D, Braynt J, Costantino J & Wolmark N 2004 Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NASBP study B-14 and chemotherapy in NASBP study B-20. Breast Cancer Research and Treatment 88 (Suppl 1) S24.
Paridaens R, Dirix L, Lohrisch C, Beex L, Nooij M, Cameron D, Biganzoli L, Cufer T, Duchateau L, Hamilton A, Lobelle JP & Piccart M 2003 Mature results of a randomised phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Annals of Oncology 14 1391–1398.
Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M & Nogaret JM 2001 Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. Journal of Clinical Oncology 19 3103–3110.
Poole CJ, Earl HM, Dunn JA, Hiller L, Bathers S, Spooner D, Grieve R, Agrawall RK, Foster E & Twelves C for the NEAT and SCTBG 2003 NEAT (National Epirubicin Adjuvant Trial) and SCTBG BR9601 (Scottish Cancer Trials Breast Group) phase III adjuvant breast trials show a significant relapse-free and overall survival advantage for sequential ECMF. Proceedings of the American Society of Clinical Oncology 22 4 (Abstract 13).
Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Kerbrat P, Serin D, Lortholary A, de Ghislain C & Viens P 2004 Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node positive breast cancer. Breast Cancer Research and Treatment 88 (Suppl 1) S16.
Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Dementer J, Perou CM, Lonning PE, Brown PO, Borreson-Dale AL & Botsein D 2003 Repeated observation of breast tumour subtypes in independent gene expression data sets. PNAS 100 8418–8423.
Thurliman B 2005 BIG 1-98: a prospective randomised double-blind double dummy phase III study. Letrozole versus tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. St Gallen 2005. The Breast 14 (Suppl 1) S3.
Tripathy D 2005 Targeted therapies in breast cancer. Breast Journal 11 (Suppl 1) S30–S35.(Anthony Howell and Andrew)