Adjuvant treatment for early breast cancer

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1 Annals of Oncology 16 (Supplement 2): ii182 ii187, 2005 doi: /annonc/mdi709 Adjuvant treatment for early breast cancer I. Smith The Royal Marsden Hospital, London, UK Introduction Survival rates from breast cancer have been increasing in Western Europe and the USA during the last decade, despite a rising incidence [1], and this can be attributed in large part to the widespread use of adjuvant medical therapy after surgery. The specific selection of adjuvant treatment is influenced by a series of prognostic and predictive factors. Prognostic factors relate to the likelihood of disease relapse independent of treatment and include nodal status, tumour size, histological grade and age. Predictive factors relate to the likelihood of response to therapy; currently the main predictive factor is the estrogen receptor (ER) status for adjuvant endocrine therapy. The risk:benefit ratio can often be subtle for more toxic treatments including, in particular, chemotherapy, and the final choice should be influenced by the patient s own preference, following a careful and unbiased discussion of the options. Adjuvant hormonal therapy Hormone receptor status ERs are present in 75% of breast cancers depending upon the age group [2], and it is now widely accepted that patients whose tumours are ER-negative and progesterone receptor (PgR)-negative do not benefit from adjuvant endocrine therapy [3]. There are, however, data to suggest that the small proportion of patients whose tumours are ER-negative but PgR-positive may benefit from this treatment [4]. Tamoxifen The Early Breast Cancer Trialists Collaborative Group (EBCTCG) Oxford overview firmly established the clinical benefit of adjuvant tamoxifen in all women whose tumours were ER-positive or unknown, with a 47% proportional reduction in recurrence and 26% in mortality in women treated for at least 5 years [3]. Proportional reductions in recurrence and mortality were similar for node-positive and node-negative tumours, but the absolute improvements were greater in patients with node-positive tumours. These benefits were independent of age, menopausal status, dose of tamoxifen and administration of chemotherapy. There was also a q 2005 European Society for Medical Oncology proportional reduction in contralateral breast cancers of 47% after 5 years of tamoxifen. Duration of tamoxifen. The current recommendation for tamoxifen duration is 5 years. The EBCTCG overview compared 1, 2 and 5 years of tamoxifen and showed a significant trend towards a greater effect with longer treatment [3]. The proportional reductions in recurrence from 1, 2 and 5 years of tamoxifen after 10 years of follow-up were 21%, 29% and 47%, respectively. The corresponding proportional reductions in mortality were 12%, 17% and 26%, respectively. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 trial randomised patients with ER-positive and node-negative breast cancer after 5 years of tamoxifen to placebo or more prolonged tamoxifen therapy [5]. After 7 years beyond re-randomisation there was no additional benefit from prolonged tamoxifen and indeed, there appeared to be a slight advantage in patients who discontinued tamoxifen after 5 years of treatment in disease-free survival (DFS) (82% placebo versus 78% tamoxifen; P = 0.03) and overall survival (OS) (94% versus 91%; P = 0.07). The patients on the prolonged arm had more breast cancer recurrences and endometrial cancers, but the differences were not statistically significant. Other trials have not supported the use of tamoxifen beyond 5 years [6, 7]. The issue of duration will not be completely resolved till the findings from two further large trials become available: the Adjuvant Tamoxifen Treatment, Offer More? (attom) trial [8] and the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial [9]. Timing of tamoxifen with chemotherapy. A recent finding from one of the HSA Intergroup trials is that sequential tamoxifen started after chemotherapy is superior to both treatments given concurrently in postmenopausal, node-positive women [10]. Aromatase inhibitors Currently, there are at least 10 adjuvant trials comparing third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) with tamoxifen in postmenopausal women. These have been stimulated by encouraging results in metastatic disease indicating their superiority. The long-term importance of these adjuvant trials is emphasised by the fact that almost women are involved. These trials directly compare aromatase inhibitors with tamoxifen

2 (i) upfront, (ii) in combination, (iii) as extended adjuvant therapy after 5 years tamoxifen or (iv) in sequence. Up front and combination trials. The first and largest of these trials is the ATAC (Anastrozole or Tamoxifen Alone or in Combination) trial, which randomised 9366 postmenopausal women with invasive breast cancer (ER-positive or unknown) to 5 years of adjuvant anastrozole, tamoxifen or a combination of the two [11]. Around one-third had positive lymph nodes, two-thirds had tumours <2 cm and 21% had prior chemotherapy. The first analysis, after a median follow-up of 33 months, showed a small but statistically significant improvement in DFS with anastrozole compared with tamoxifen: 89% were relapse-free at 3 years compared with 87% (relative risk reduction, 17%; P = 0.013). There was greater benefit in the hormone receptor-positive group. Interestingly, there was no difference in DFS between the combination arm and the tamoxifen arm, and anastrozole alone was superior to both. A recent update shows an increasing gain over tamoxifen with time, with a 3.6% absolute gain in DFS after 6 years [12]. So far, there have been no differences in the rates of death from any cause [hazard ratio (HR) 0.97] and few breast cancerrelated deaths have occurred. A further important finding of potential significance for prevention trials was the decreased incidence of contralateral breast cancer with anastrozole (0.3%) compared with the tamoxifen (1%; P = 0.001). Both treatments were well tolerated, but in the anastrozole group there was a significantly lower incidence of hot flushes, vaginal bleeding, vaginal discharge, endometrial cancer and venous thromboembolism, and a higher incidence of musculoskeletal symptoms and fractures. BIG The second major upfront aromatase inhibitor trial (BIG 1-98) compared letrozole with tamoxifen in patients with receptor-positive breast cancer, and first results were recently presented at the St Gallen Breast Cancer Conference This was a four arm trial as follows: (i) tamoxifen for 5 years; (ii) letrozole for 5 years; (iii) tamoxifen for 2 years then letrozole for 3 years; and (iv) letrozole for 2 years then tamoxifen for 3 years. The primary core analysis simply compared upfront letrozole with tamoxifen, with patients in the cross-over arms censored at the 2 year point. Median followup for this primary core analysis was 26 months, with a predictive 5-year DFS for letrozole of 84% versus 81.4% for tamoxifen (P = 0.003; HR 0.81). When deaths without breast cancer and second malignancies were taken out of the analysis (for comparability with the ATAC trial) the HR for DFS was These preliminary results (not yet published) are similar to those seen with ATAC trial. Extended adjuvant endocrine therapy MA-17 trial. The MA-17 trial was a double-blind, placebocontrolled trial [13] involving postmenopausal women with breast cancer who had completed 5 years of tamoxifen and were randomised to a further 5 years of letrozole or placebo. This trial involving over 5000 women was stopped at its first interim analysis at 2.4 years follow-up at the recommendation of the independent data and safety monitoring committee after results indicated a significantly higher DFS in the letrozole group with an estimated 4-year DFS of 93% versus 87% (P <_ 0.001) with the placebo. There was surprisingly little difference in side-effects between the two groups, although low-grade hot flushes, arthritis, osteoporosis, arthralgia and myalgia were more frequent with letrozole; fracture rates were similar, but there was less vaginal bleeding in the letrozole group. An important finding was a further relative reduction in the frequency of contralateral breast cancer of 46% in women treated with letrozole, comparable to that seen in the ATAC trial [11]. In an update presented at ASCO in 2004 an OS difference had emerged for patients with node-positive disease, with mortality reduced by 39% in this group for patients on letrozole (P = 0.04). Another similar maintenance trial, the NSABP B-33, assessing the value of exemestane after tamoxifen, is now unlikely to be completed [14]. Sequential adjuvant endocrine therapy Sequential adjuvant endocrine therapy means the switching of treatment from tamoxifen to an aromatase inhibitor after 2 3 years, continuing for a total of 5 years. The first of these trials to report (IES) randomised 4742 postmenopausal women to tamoxifen for 5 years versus tamoxifen for 2 3 years followed by exemestane to complete 5 years [15]. This showed a significant DFS in favour of exemestane, with updated results from the San Antonio Breast Cancer Conference in 2004 showing a 4.7% absolute benefit in 3-year DFS (P <0.01; HR 0.73). No survival difference has so far emerged from this trial. More recently, combined results were presented in San Antonio (December 2004) from two further similar trials, the Italian ARNO 905 and the Austrian Breast Cancer Study Group (ABCSG8), in which women were switched from tamoxifen to anastrozole after 2 years. The absolute gain in DFS at 3 years was 3.1% (95.8% versus 92.7% in favour of switching to anastrozole), with an HR of 0.60 (P = ). Conclusions from adjuvant aromatase inhibitor trials ii183 It is clear from these trials that aromatase inhibitors offer a small but significant DFS benefit over tamoxifen either upfront or as sequential therapy. It is not yet clear whether the optimum use of these drugs should be upfront or switching after 2 years, and data from further trials are required to solve this question. The data on extended adjuvant therapy with letrozole after 5 years tamoxifen are persuasive and this option should be offered to patients, making an individual assessment based on risk as defined by the primary histology. In general the safety profile of the aromatase inhibitors compares favourably with tamoxifen, with a decreased incidence of uterine cancer and venous thromboembolism. This is balanced against a small but significant increase in osteoporosis, and bone mineral density monitoring will be required for patients on adjuvant aromatase inhibitor therapy.

3 ii184 It is important to note that in contrast to tamoxifen, aromatase inhibitors are only indicated in the treatment of women who are clearly postmenopausal. The prognostic significance of amenorrhoea in younger women after chemotherapy In a recent update of the INT-0101 trial [16] with 9 years follow-up, the DFS was 59% in the women achieving amenorrhoea after treatment in the chemotherapy-only arm and 40% in those who did not. This is consistent with other reports showing a lower incidence of disease-related events in patients rendered amenorrheic after chemotherapy [17, 18]. A further international trial is now underway to address this important question prospectively. Adjuvant chemotherapy Patient selection Axillary lymph node involvement remains the most powerful prognostic factor for recurrence and current standards are that women under the age of 70 years with lymph node-positive disease should generally be offered adjuvant chemotherapy. In women with negative nodes, the decision on chemotherapy depends upon other prognostic factors. The St Gallen Consensus guidelines have traditionally divided women with nodenegative disease into two at risk groups [19]. The first is minimal risk of recurrence (for whom chemotherapy would not be indicated) and the second is average risk of recurrence, based on ER/PgR status, tumour size, histological grading and age. Lymphovascular invasion is also sometimes considered a high-risk factor and pure tubular or mucinous histological subtypes as minimal risk factors. These guidelines are not absolute, however, and should serve as a discussion point with the patient to determine the risk:benefit balance. Recent data presented at the San Antonio Breast Cancer Conference in 2004 but not yet published throw more light on patient selection for adjuvant chemotherapy. In a retrospective analysis of a SWOG/TPCI trial in which postmenopausal node-positive patients were randomised to tamoxifen alone versus CAF (cyclophosphamide, adriamycin and 5-fluorouracil) chemotherapy with tamoxifen, an overall gain was shown for patients randomised to CAF, but this was only seen in patients whose tumours had low or intermediate levels of ER. There was no chemotherapy gain in the large subgroup of patients who had high ER levels, no Her2 overexpression and one to three nodes involved [20]. In a similar analysis from the B-20 adjuvant chemotherapy trial in which patients were randomised to tamoxifen with or without CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy, a 21- gene assay [21] showed a large gain in patients treated with CMF who had a gene expression pattern predicting for a high distant disease recurrence. In contrast, there was no chemotherapy gain for those with the pattern predicting low or intermediate recurrence. These findings were not age-related. Such findings suggest that we are entering an era where we can predict much more accurately which patients are likely to gain from chemotherapy. They also suggest that the apparent lack of benefit of treatment in older patients may in fact be much more related to the biology of the tumour than to age. CMF chemotherapy CMF was the mainstay of adjuvant chemotherapy for many years and the Oxford overview analysis of 47 trials, the majority of which used CMF-based regimens, clearly established the role of adjuvant chemotherapy in significantly reducing the risk of recurrence and death [22]. These results were significant irrespective of lymph node status, ER status and tamoxifen use, but the degree of benefit was influenced by age and menopausal status. For all women under the age of 50 years, chemotherapy significantly improved the absolute 10-year survival by >10% for those with node-positive disease (53% versus 42%) and by 6% for those with node-negative disease (78% versus 71%). When results were analysed by age in decades, there was a strong trend towards the younger the age, the greater the benefit. No significant benefit was demonstrated for patients over the age of 70 years, but the number of patients involved was small. Anthracylines The EBCTCG overview also showed a small but significant benefit in relapse-free survival and OS for anthracyclines compared with the more traditional CMF regimens (68.4% versus 64.1% for OS) [22]. Since this overview, other supportive studies have confirmed the benefit of anthracyclines-based therapy [23 26]. Dose of anthracyclines. The two main anthracyclines currently in use are adriamycin (doxorubicin) and epirubicin. The Cancer and Leukaemia Group B (CALGB) 9344 trial randomised women with node-positive breast cancer to receive four courses of adriamycin/cylcophophamide (AC) chemotherapy to one of three different adriamycin dose levels (60, 75 or 90 mg/m 2 ), followed by four cycles of paclitaxel or not [27]. This important dose-escalation trial showed no benefit for adriamycin doses above 60 mg/m 2, and this dose should now be considered standard. With epirubicin, a dose effect was shown in the French Adjuvant Study Group (FASG-05) trial that randomised lymph node-positive women with poor prognosis in favour of six cycles of FEC 100 (epirubicin 100 mg/m 2 ) over six cycles of FEC 50 (epirubicin 50 mg/m 2 ) [28]. A significant improvement in the 5-year DFS (66.3% versus 54.8%) and 5-year OS (77.4% versus 65.3%) was seen in the FEC 100 group, but there was significantly more toxicities in the FEC 100 group, including neutropenia, anaemia, nausea and vomiting, stomatitis, alopecia, and grade 3 infections. Taxanes The potential importance of the taxanes as adjuvant therapy is emphasised by the large number of major trials currently

4 running. Four important trials assessing the addition of a taxane to anthracycline chemotherapy in patients with nodepositive disease have been reported. In the CALGB 9344 trial, 3121 women who had received four cycles of AC chemotherapy at different dose levels were randomised to receive four further courses of paclitaxel or no further chemotherapy [27]. The addition of paclitaxel resulted in a small but statistically significant improvement in DFS (absolute 5%; P = ) and OS (absolute 3%; P = ). In a similarly designed trial, the NSABP B-28 randomised 3000 women to four courses of AC chemotherapy followed by four courses of paclitaxel versus four courses of AC chemotherapy alone [29]. Sixty-six per cent of the patients were ER-positive and received concurrent tamoxifen, including all women aged >50 years regardless of ER status. These results showed a significant absolute 4% improvement in the DFS in the paclitaxel arm (72% versus 76%; P = 0.008) but no difference in OS (both 85%; P = 0.46). These two trials are open to the criticism that efficacy differences could be explained by differences in treatment duration rather than the addition of paclitaxel. The third trial, Breast Cancer International Research Group (BCIRG) 001, involved docetaxel, used concurrently with an anthracycline rather than sequentially [30]. The study included 1491 women, who were randomised to receive six cycles of standard FAC versus six cycles of TAC (docetaxel, adriamycin, cyclophosphamide). The second interim results after a median follow-up of 55 months and 399 events showed a significant improvement in DFS (75% versus 68%; P = 0.001) and OS (87% versus 81%; P = 0.008) at 5 years for the TAC group. The rate of febrile neutropenia was 24.7% in the TAC arm (despite prophylactic use of oral ciprofloxacin) compared with 2.5% in the FAC arm. In the fourth trial, a French group compared six cycles of FEC using epirubicin 100 mg/m 2 versus three cycles of FEC followed by three courses of docetaxel 100 mg/m 2 for women with node-positive cancer (PACS01), and first results were presented at San Antonio 2004, but have not yet been published. These showed a significant improvement in DFS in favour of the switch to docetaxel (5-year DFS 78.3% versus 73.2%; P = 0.012; HR 0.83). Curiously, the benefit was significant in women over the age of 50 years, but not for those under 50 years. The trial also showed a small but significant OS advantage (90.7% versus 86.7% 5-year OS; P = 0.014; HR 0.77). Therefore, all four taxane trials that have so far produced data have shown a significant DFS gain, and three of the four have shown an OS gain. There is now good evidence to support the use of taxanes in patients with node-positive breast cancer. Dose density Recently, interest has developed in accelerated (sometimes called dose dense) chemotherapy, in which treatment is given at 2-week rather than 3-week intervals, with haematologic growth factor support to overcome the risk of neutropenic sepsis. The CALGB 9741 trial has shown that accelerated 2-weekly AC 4 followed by accelerated paclitaxel 4 has improved efficacy over the same eight courses given conventionally at 3-week intervals in women with node-positive breast cancer, with 4-year DFS of 82% and 75%, respectively [31]. In addition, the accelerated arm was associated with less neutropenic sepsis. Likewise an Italian trial, so far presented only in abstract form, has shown a similar increase in efficacy with reduced risk of neutropenic sepsis when six courses of FEC chemotherapy were given in accelerated fashion compared with the conventional approach [32]. The shortened duration of adjuvant treatment associated with accelerated chemotherapy is likely to be attractive to patients, and the reduced risk of neutropenic sepsis may save on resources. Further trials in this area are now indicated. Duration of treatment The optimal duration of chemotherapy remains uncertain. The EBCTG meta-analysis assessed five CMF-based trials and found no survival benefit for more than 6 months of treatment [22]. The French FASG-01 trial showed a significant benefit in DFS of six cycles of FEC 50 over three cycles of FEC 50 or 75, and improved OS with six cycles of FEC 50 over three cycles [33]. Further trials of chemotherapy duration are strongly indicated. Bisphosphonates as adjuvant therapy ii185 Three adjuvant trials have investigated the use of bisphosphonates to prevent the appearance of bone metastases in women with early breast cancer and showed conflicting results. The first trial [34] randomised 302 women with primary breast cancer and immunocytochemical evidence of cancer cells in a bone marrow aspirate to 2 years of clodronate 1600 mg/day or not. After nearly 5 years of follow-up, a reduction in the incidence of bone metastases, a trend to reduction in visceral metastases and an increase in OS were seen in the clodronate group [34, 35]. However, the effect of clodronate appeared to weaken with longer follow-up. The second trial [36] randomised 299 women with nodepositive breast cancer to 3 years of clodronate 1600 mg/day or control. This showed negative results. After a minimum of 5 years follow-up, significantly more bone metastases (26% versus 18%) and non-skeletal metastases (45% versus 27%) were seen in the clodronate group compared with the placebo group. The OS was also significantly worse in the clodronate group (68% versus 81%). There were, however, imbalances in node-positivity, tumour size and PgR status between the groups, which could account at least in part for these unexpected results. The third and largest trial randomised 1079 women to receive 2 years of clodronate 1600 mg/day or placebo starting within 6 months of surgery [37]. During the 2 years of treatment, there was a significant reduction in bone metastases in the clodronate group but at 5 years this effect was lost. No

5 ii186 differences in recurrence of visceral metastases were seen. OS was significantly improved in the clodronate group. The role of adjuvant clodronate therefore remains uncertain, although the balance of evidence may suggest clinical benefit. Further trials are now underway, including a NSABP study comparing 5 years of clodronate with placebo and a trial of the much more potent bisphosphonate Zoledronate (Zometa w ) also against placebo (AZURE). Trastuzumab (Herceptin w ) HER-2 overexpression is associated with an adverse prognosis, and the established efficacy of trastuzumab in metastatic breast cancer has generated much interest in its use in adjuvant setting. Four large, multicentre randomised adjuvant trials involving more than women are running to assess whether trastuzumab given after anthracycline chemotherapy (NSABP trial B-31; Intergroup N9831; BCIRG 006) or sequentially with a non-anthracycline regimen docetaxel and carboplatin (BCIRG 006), or after any standard chemotherapy schedule (HERA trial) can improve DFS and OS. First results may emerge later in Conclusions Adjuvant aromatase inhibitors are beginning to replace tamoxifen as front-line standard of care for postmenopausal patients with hormone receptor-positive cancer, although there is still debate whether these are best used upfront or sequentially after 2 years of tamoxifen. Extended adjuvant therapy with letrozole after 5 years of tamoxifen is also of proven benefit. Tamoxifen remains the standard of adjuvant endocrine therapy care for premenopausal women but there is some evidence that ovarian suppression in addition to this may be of further benefit. Anthracycline chemotherapy remains the standard of care for women with moderate risk breast cancer, but there is increasing evidence that the taxanes provide further benefit in women with node-positive disease. Evidence is emerging that the benefit of chemotherapy is likely to be confined to patients with low or absent expression of hormone receptor, and also those with Her2-positive disease. There is some evidence that adjuvant bisphosphonates provide protection against the development of bone metastases and further trials are underway. It is likely that current trials of adjuvant Herceptin will demonstrate survival benefit, given the encouraging results with Herceptin in advanced disease and for neo-adjuvant therapy. References 1. Peto R, Boreham J, Clarke M, et al. UK and USA breast cancer deaths down 25% in year 2000 at ages years. Lancet 2000; Li CI, Daling JR, Malone KE. 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