Can We Abandon Anthracyclines for Early Breast Cancer Patients?
The anthracyclines doxorubicin and epirubicin are among the most effective cytotoxic treatments developed for the treatment of breast cancer.
Anthracycline-containing regimens improve disease-free and overall survival of patients with early breast cancer, but the toxicity, especially the cardiotoxicity, of the anthracyclines make them unattractive in the adjuvant setting. Two large, randomized trials, one in unselected patients and one in those with HER2-positive tumors, suggest that a taxane combination without an anthracycline might be just as effective as more traditional regimens. These and other studies also suggest that the anthracyclines might reasonably be used only for those with more aggressive forms of breast cancer, as defined by molecular markers. The results of these studies are provocative but insufficient to justify the conclusion that anthracyclines can be either abandoned or used only for a very select group of patients.
Background
The anthracyclines doxorubicin and epirubicin are among the most effective cytotoxic treatments developed for the treatment of breast cancer. In the adjuvant setting they significantly improve both disease-free and overall survival. Although all anthracycline regimens are not equally efficacious, when the results of all trials were pooled in an overview comparing anthracycline regimens to no chemotherapy at all, they reduced the odds of recurrence by 33% (standard error [SE] +/- 8%) and the odds of death by 26% (SE +/- 9%).[1] Compared to chemotherapy regimens that did not contain an anthracycline, they reduced the odds of recurrence by an additional 11% (SE +/- 3%) and the odds of death by an additional 16% (SE +/- 3%) over what can be achieved with a CMF (cyclophosphamide, methotrexate, and 5-fluorouracil)-like combination.
TABLE 1
Frequency of a Cardiac Event or Cardiac Death in Randomized Trials Comparing an Anthracycline-Containing Regimen Plus Trastuzumab[4]
The anthracyclines are also among the most toxic drugs ever developed. They induce nausea and vomiting that, in the days before the introduction of 5-HT3-receptor antagonist antiemetics, was severe enough to sometimes necessitate hospitalization and intravenous hydration. The majority of patients lose nearly all their scalp hair. Myelosuppression can be profound, although fortunately its time course is very predictable and short, so granulocyte colony-stimulating factors are rarely needed at doses that are of proven value. The incidence of leukemia associated with anthracycline use is clearly greater than that seen with older regimens such as CMF; depending on the acute and cumulative dose and type of anthracycline used, this incidence ranges between 0.4% and 1.7% in the 5 to 10 years following treatment.[2] A cardiomyopathy related to the cumulative dose of the anthracycline limits the duration of drug treatment and is likely the greatest impetus to finding new, non-cardiotoxic alternatives. Adjuvant anthracycline regimens typically use 240 to 360 mg/m2 of doxorubicin or 240 to 720 mg/m2 of epirubicin over 4 to 6 cycles, and with these doses the percentage of patients who develop a cardiac event such as congestive heart failure within the 5 years following completion of chemotherapy ranges from 0.5% to 1.5%.[2] Subclinical cardiac dysfunction has been reported to occur in 10% to 15% of patients.[3] The frequency of cardiac events is about four times greater when trastuzumab (Herceptin) is administered with or following the anthracycline (Table 1). This cardiotoxicity is more often reversible and likely has a different underlying pathophysiology,[4, 5] but it is still a cause of considerable concern since it is as yet unknown whether the incidence of serious cardiac disease will expand as the normal risks of cardiovascular disease associated with aging are superimposed on the cardiac damage from anthracyclines and trastuzumab.[3]
In the past decade it has been repeatedly shown that the addition of a taxane to an anthracycline combination reduces the hazard of recurrence by yet another 15%.[6] However, the taxanes induce neurotoxicity, and in many cases the taxane regimen is more toxic because it is administered for a longer duration than the non-taxane combination. Most investigators have felt that this increased toxicity was justified by the increased benefit. Recently, a taxane has been substituted for the anthracycline in two trials in an effort to circumvent toxicity, especially cardiotoxicity.
The Questions
Should these new, non-anthracycline, taxane combinations be used routinely in place of the older anthracycline or anthracycline/taxane regimens for all patients with early breast cancer? Or should they be used in selected patients for whom the anthracyclines might have only limited benefit? Or is it too early to use them at all outside of a clinical trial?
New Regimen #1: Docetaxel Plus Cyclophosphamide
TABLE 2
Results of USO Trial 9735, in Which Patients Were Randomly Assigned to Treatment With Either an Anthracycline Regimen (AC) or a Non-Anthracycline Regimen (DC)[7,8]
In US Oncology trial 9735, 1016 relatively unselected patients were randomly assigned to receive either doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, (AC) or docetaxel (Taxotere), 75 mg/m2, plus cyclophosphamide, 600 mg/m2 (DC) (Table 2).[7, 8] The duration of therapy in the two arms was identical. After a median follow-up of 7 years, the disease-free and overall survival of patients treated with the DC combination were significantly better than for those treated with AC. One patient in the AC arm died without relapse but with cardiomyopathy and congestive heart failure thought to be related to her exposure to doxorubicin.[8] Significantly more patients in the AC arm had nausea and vomiting (Table 2). Significantly more patients in the DC arm had arthralgia, myalgia, and edema. Neutropenia and febrile neutropenia also occurred more frequently with DC, especially among women aged 65 or over. The incidence of neurotoxicity was not reported but may have been subsumed under the category “myalgia” and “arthralgia.” One older woman died of myelodysplasia and another of myelofibrosis. Neither of these women had relapsed, and the investigators thought their deaths were “probably related to treatment” with AC.
This was a well designed clinical study. Since the only difference in the two study arms was the substitution of docetaxel for doxorubicin, this was a true test of the relative efficacy of these two drugs in combination with intravenous cyclophosphamide.
Is DC superior? Equivalent? Possibly inferior to AC?
There was an increased number of deaths in the AC arm that cannot be attributed to either breast cancer or the complications of treatment. The investigators used a standard definition of event-free survival and included among the events either breast cancer relapse or death from any cause. There were 118 events in the AC arm and 88 events in the DC arm-a difference of 30. However, 25 patients in the AC arm and only 13 patients in the DC arm died without relapse-but one of the former 25 patients died of cardiac complications from doxorubicin. If we adjust events to include only breast cancer relapse or death from breast cancer, the difference in the number of events shrinks from 30 to 18. Thus, breast cancer–specific event-free and breast cancer–specific overall survival differences are not statistically significant. This does not negate the results of this study but should cause us to be less comfortable about accepting them without confirmation of the results in another trial.
If DC is not unequivocally superior to AC, can’t we conclude that it is at least equivalent to and less toxic than AC? It is not uncommon for investigators to design a superiority trial and then, if and when the trial fails to meet the primary endpoint, conclude that the experimental regimen is equivalent to the one it is being compared with. This happened in the analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-15 (see below). However, many statisticians, including those at the FDA, argue that this is an inappropriate practice.[9] In a superiority trial it is assumed there is no difference between the two arms, and the trial is designed to reject that hypothesis and accept the alternative hypothesis that the treatments do differ. A non-inferiority or equivalence trial assumes there is a difference between the arms and is designed to reject this hypothesis and conclude that the treatments do not differ. Non-inferiority trials are usually much larger. This is because a non-inferiority trial usually compares a new treatment with an established treatment; physicians are unlikely to accept a new treatment that is otherwise “equivalent” if there is even a small decrease in an important endpoint, such as survival. A large trial is required to reliably detect small decreases of this sort. Conversely, a new treatment that is thought a priori to be better must usually be shown to be “a lot better” to replace an established therapy, and a smaller trial will reliably detect this larger benefit. Thus, a superiority trial that is interpreted as an inferiority trial is usually an underpowered inferiority trial. Practically, this means that the lower end of theconfidence interval is unreliable and that the two treatments may appear to be similar when in fact one treatment is less effective. Patients treated with the inferior regimen will be unknowingly shortchanged.
Is DC equivalent to the best anthracycline regimens?
Because of doxorubicin's unfavorable toxicity profile, its use in the adjuvant setting was initially met with considerable resistance. The first randomized trial evaluating an anthracycline in the adjuvant setting administered either 5 or 10 cycles of AC (cumulative doxorubicin doses of 225 or 450 mg/m2) to determine whether the shorter, less toxic regimen was as effective.[10] This single-institution trial was seriously underpowered. Overall, the shorter arm was non-significantly better, but among premenopausal women there was a trend favoring the longer arm.
The efficacy results of this trial were not yet available when the first large randomized comparison of an anthracycline and CMF (NSABP B-15) was initiated with 4 cycles (3 months) of doxorubicin and cyclophosphamide administered intravenously once every 3 weeks at doses of 60 and 500 mg/m2, respectively.[11] The trial was designed as a superiority trial. The null hypothesis could not be rejected, but the authors concluded that “. . . the outcome from AC and CMF was almost identical . . .” and that this “. . . indicate[s] the merit of 2 months of AC therapy for all positive-node breast cancer patients.” Following this report, 4 cycles of AC became one of the most popular adjuvant chemotherapy regimens in the United States.
TABLE 3
Characteristics of Anthracycline Regimens Commonly Used as Adjuvant Chemotherapy
A number of other anthracycline regimens have been developed subsequently. The most widely used of these are shown in Table 3. There are no direct randomized comparisons of these regimens, but the relative effectiveness of various regimens is suggested by the meta-analysis shown in Figure 1A. Six cycles of po FAC/FEC (CAF [cyclophosphamide, doxorubicin, and 5-fluorouracil] or CEF [cyclophosphamide, epirubicin, and 5-fluorouracil] with oral cyclophosphamide) appears to be superior to other regimens. In four studies, AC or EC (epirubicin plus cyclophosphamide) was compared to CMF; even when the results from these studies are pooled, there is no evidence that AC/EC imparts any benefit over classic CMF. Differences in the regimens that might account for differences in outcome include the route and/or frequency of cyclophosphamide administration, the duration of treatment, and the addition of 5-fluorouracil to the combination; the acute dose of doxorubicin is not an important variable (Table 4; also, see below).
FIGURE 1
Odds or Hazard Ratios From Two Separate Meta-Analyses of Recurrence in Randomized Trials, One Comparing Anthracycline Regimens With CMF[1] (A) and the Other Comparing Taxane Regimens With Anthracycline Regimens[6] (B)
Most anthracycline regimens in common use today include a taxane-either paclitaxel or docetaxel. In the first of these regimens, paclitaxel was given as a single agent for 4 cycles following 4 cycles of AC; this sequential treatment was compared to 4 cycles of AC.[12] Five additional trials using a similar, sequential regimen have confirmed the results of the first study, and a meta-analysis of these 6 trials together demonstrates a reduction in the hazard of recurrence of 18% (Figure 1B). However, it has been argued that some of the benefit from the sequential regimen of AC followed by paclitaxel could be a result of the longer duration of treatment with the sequence.[6, 12] A meta-analysis of 5 studies using a taxane and anthracycline in sequence in which the duration of treatment was the same in both arms demonstrated a somewhat smaller reduction in risk (9%); however, there was still a statistically significant advantage for the taxane combination (Figure 1B).
DC as used in US Oncology trial 9735 is almost certainly inferior to the best anthracycline regimens shown in Figures 1A and 1B, whether these are combinations of doxorubicin, cyclophosphamide, and 5-fluorouracil-or doxorubicin, cyclophosphamide, and a taxane. The advantage of the best regimens may result from one or more of the factors listed in Table 4, but the duration of treatment is almost certainly one of the causes.
New Regimen #2: Docetaxel, Carboplatin, and Trastuzumab
TABLE 4
Factors That May Alter-or That Are Unlikely to Alter-the Effectiveness of Current Chemotherapy RegimensTABLE 5
Results of BCORG Trial 006
In the second taxane/non-anthracycline study, Breast Cancer International Research Group (BCIRG) trial 006, 3222 patients with tumors amplified for HER2/neu were randomly assigned to treatment with one of three regimens: ACD (AC, 60 and 600 mg/m2 every 3 weeks for 4 cycles, followed by docetaxel, 100 mg/m2 every 3 weeks for 4 cycles); ACD-H (AC and docetaxel as in arm 1, with weekly trastuzumab starting after 4 cycles of AC and continuing every 3 weeks for a year); or DCarboH (docetaxel, 75 mg/m2, plus carboplatin AUC [area under the curve]=6, together every 3 weeks for 6 cycles, along with trastuzumab administered as in arm 2).[13, 14] Only arms 2 and 3, both of which included trastuzumab, are germane to this discussion. A full report of this study has not yet been published in the peer reviewed literature, but some of the data have been published,[15] and the study has been presented twice at the San Antonio Breast Cancer Symposium.[13, 14] At the time of the third planned interim analysis in 2009, the median follow-up was 65 months and there were 348 deaths and 656 events (breast cancer relapses, second malignancies, and/or death). At 5 years, 84% of the patients treated with ACD-H and 81% of those treated with DCarboH were disease-free (P = .21); 92% of those treated with ACD-H and 91% of those treated with DCarboH were alive (P = .14). DCarboH was less toxic. Grade 3/4 arthralgia, myalgia, hand-foot syndrome, stomatitis, or vomiting occurred about half as often among patients treated with DCarboH as they did in those treated with ACD-H; however, the incidence of any one of these symptoms was less than 7% in both groups. Neuropathies, both sensory and motor, and leukopenia were also significantly less frequent with DCarboH, but anemia and thrombocytopenia occurred 2 to 3 times more frequently (Table 5). There were no cardiac deaths in the trial, but the incidence of grade 3/4 decreases in left ventricular cardiac function was significantly greater for patients treated with doxorubicin (n = 4 vs 20+; P < .001). The difference in cardiac function between patients treated with DCarboH and those treated with ACD (ie, the arm without trastuzumab) was not as striking; 4 and 7 patients, respectively, had grade 3/4 left ventricular cardiac function following treatment.
Is DCarboH equivalent to the best anthracycline regimens?
BCIRG 006 is a very large, well designed trial, and it involves a comparison with one of the most popular and more effective regimens currently in use to treat early breast cancer. The duration of chemotherapy was 6 weeks longer in the ACD-H arm than in the DCarboH arm, and it is plausible that if equal durations of chemotherapy had been used, results in the DCarboH arm would have been superior (although the differences in toxicity might have been less striking).
However, as with the US Oncology 9735 trial, this study was not designed as a non-inferiority trial, and the same limitations apply to the interpretation of “equivalency” (see above). The failure to demonstrate superiority does not mean that the DCarboH and ACD-H regimens are “equal” and “interchangeable.”
Further, only patients with HER2-positive cancers were enrolled in this study, and it is not clear that the results can be generalized to any other group of patients with early breast cancer.
Are There Subsets of Patients Who Should or Should Not Receive an Anthracycline?
Amplified HER2/neu
TABLE 6
Hazard Rates for Recurrence of Anthracycline vs Non-Anthracycline Regimens in a Meta-Analysis of Four Randomized Trials, Using Subsets Defined by Molecular Profiles[18]
The use of biomarkers as a method for identifying patients who might not benefit from a particular drug began in earnest after the observation in a Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trial that dose escalation of doxorubicin benefited only those whose tumors overexpressed HER2/neu receptors.[16] Subsequently, it has been shown in other studies and in meta-analyses of trials comparing anthracycline regimens with non-anthracycline regimens that an anthracycline regimen is superior to CMF regimens primarily in patients whose tumors have amplified or overexpressed HER2/neu.[17, 18] In one of these meta-analyses, the hazard for recurrence was decreased by 30% (significant) for those with amplification of HER2/neu-but only by a modest 10% (not significant [NS]) among those with a normal HER2/neu (Table 6). Another meta-analysis identified 3 studies, including the CALGB trial described above, in which more intensive (either higher or more frequently administered) doses of anthracycline and cyclophosphamide (and in one study, 5-fluorouracil as well) were compared with more conventional dosing schedules of these drugs.[17] The more intensive regimens resulted in a 46% reduction in the hazard of recurrence among those with HER2-positive tumors but no reduction in those with HER2-negative tumors. However, there were other differences beside doxorubicin dose or dose intensity in the regimens included in these studies, and it is plausible that the observed differences were not simply a result of different doses of anthracycline. In CALGB 9344, simple escalation of the doxorubicin dose from 60 mg/m2 to either 75 mg/m2 or 90mg/m2, with a constant dose of cyclophosphamide, did not improve disease-free or overall survival in patients with either HER2-positive or HER2-negative tumors.[19]
A scientific rationale for this interaction between anthracyclines and HER2/neu amplification or overexpression has not been established, and the predictive value of HER2/neu is not limited to the anthracyclines. A similar correlation exists with the use of taxanes. In CALGB trial 9344, patients were randomly assigned not only to receive different doses of doxorubicin but also to receive either paclitaxel or no paclitaxel following 4 cycles of doxorubicin and cyclophosphamide. Paclitaxel significantly reduced the hazard of recurrence by 50% in those with HER2-positive tumors but reduced the hazard by only 16% (NS) in those with HER2-negative tumors.[19] In a small meta-analysis of three studies (one of which was CALGB 9344) comparing a taxane in one arm to no taxane in the other and for which the HER2 status of the patients was reported, the hazard of recurrence was reduced by 40% among those with HER2-positive tumors and by only 17% in those with HER2-negative tumors.[17]
From these studies we can conclude that patients with HER2-positive tumors derive greater benefit than other patients from either an anthracycline or a taxane, and they likely derive greater benefit from more intensive chemotherapy regimens as well. However, this may be equally true for cyclophosphamide, 5-fluorouracil, and any other drug we use in the adjuvant setting.
Amplified topoisomerase IIα
One, but not the only, mechanism of anthracycline anti-tumor action is suppression of topoisomerase IIα (TOP2A), an enzyme important in the repair of double-strand DNA breaks that occur after treatment with some cytotoxics. The gene for TOP2A is located very close to the gene for HER2/neu on chromosome 17, and it is often amplified when HER2 is amplified. TOP2A amplification is uncommon in tumors without HER2 amplification; however, not all tumors with HER2 amplification have TOP2A amplification as well. There are also problems in accurately identifying tumors with TOP2A amplification. In the studies in Table 6, 123 of the samples were assessed for HER2 and TOP2A using fluorescence in-situ hybridization (FISH) in both a local and a central laboratory, and the results were compared.[18] Only 6% of the HER2 results but 31% of the TOP2A results were discordant. Another study concluded that FISH assays lead to an overestimation of the number of tumors with amplified TOP2A because the commercially available FISH probes hybridize to more than the TOP2A gene.[20] These investigators found that 9 of 40 specimens they assessed using FISH were co-amplified for HER2 and TOP2A, but that only 2 of these 9 specimens (22%) were found to be amplified for TOP2A when assessed by high resolution representational oligonucleotide microarray analysis (ROMA).
In spite of these problems with defining this group of tumors, it makes sense that tumors with amplification of TOP2A might be particularly sensitive to anthracyclines, and there is considerable evidence to demonstrate that this is true. In the four-trial meta-analysis shown in Table 6, the reduction in the hazard of recurrence was 39% for patients with TOP2A amplification and only 11% (NS) for patients with normal TOP2A.[18] However, almost as many patients had deletion of TOP2A as had amplification, and in this group the hazard rate was reduced by 45% as a result of anthracycline treatment! This is not explained by the working hypothesis that tumors with excessive TOP2A will be particularly sensitive to inhibition by anthracyclines.
Further evidence for the possible importance of TOP2A as a predictor of response to anthracyclines comes from an as yet unpublished analysis of BCIRG 006 (see above).[14] All tumors in this trial were HER2-positive, and 35% of these tumors were co-amplified for TOP2A. The addition of trastuzumab to ACD significantly improved the disease-free survival of patients whose tumors were not co-amplified for TOP2A (5-year survival, 70% vs 80% for ACD and ACD-H, respectively; P < .001). However, for patients with co-amplification of TOP2A there was no advantage from adding trastuzumab (5-year survival, 83% vs 85% for ACD and ACD-H, respectively; P = .60). This suggests that the doxorubicin in the ACD regimen is so effective for patients with co-amplified HER2 and TOP2A that there is no advantage from using trastuzumab as well. Alternatively, one might argue that the use of a non-anthracycline combination (such as DCarboH in the BCIRG 006 study) is as effective as and less toxic than the anthracycline regimen (5-year survival, 83% vs 82% for ACD and DCarboH, respectively; P = .30).[21]
As provocative as these observations on TOP2A are, it is too early to use them in standard practice. There is not agreement on the way tumors are defined as being TOP2A-amplified. The important factor may be expression rather than amplification of TOP2A, and, unlike with HER2, there is poor correlation between gene copy number and gene product. Almost all of the evidence is retrospective, and the analysis of the BCIRG 006 study has not yet been published in a peer-reviewed journal. None of the results have been confirmed in an independent, prospective randomized trial, and the results from trials reporting a correlation between TOP2A and anthracycline treatment are inconsistent. Some large trials and meta-analyses of these studies have failed to show any correlation at all.[21]
Triple-negative and BRCA1-associated cancers
Patients whose tumors are negative for estrogen receptors (ER), progesterone receptors (PR), and HER2 have a worse prognosis than any other groups of patients. However, this entity is not easily defined by a single set of molecular characteristics. Most, but not all, cancers defined as basal-like in tissue microarrays are triple negative, and most, but not all, triple-negative cancers are basal-like.[22] TOP2A is regularly amplified in one subgroup of basal tumors, but triple-negative tumors may overexpress TOP2A without amplification.[18] Many, if not most, triple-negative tumors have loss of BRCA1 function even though the gene is rarely mutated the way it is in patients with heritable breast cancer.[22] One function of BRCA1 is repair of double-strand DNA breaks. Thus, tumors without BRCA1 or BRCA1 function are likely to be particularly susceptible to drugs, such as the anthracyclines or platinum agents, that induce double-strand DNA breaks-or to drugs, such as the poly(adenosine-disposphate-ribose) polymerase (PARP) inhibitors, that inhibit alternative mechanisms for repairing DNA breaks. In vitro, tumor cells with a mutant BRCA1 are relatively more resistant to spindle poisons, such as paclitaxel and vinorelbine, than to topoisomerase inhibitors such as etoposide.[23]
In two retrospective analyses, a higher response to anthracycline-containing neoadjuvant regimens was seen among tumors that were triple negative than among those with other molecular profiles.[24, 25] Similar results were obtained in a prospective trial of neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel in 144 women.[26] In the meta-analysis shown in Table 6, the advantage from an anthracycline in patients with triple-negative tumors (23% reduction in hazard of recurrence) is almost as great as that seen in patients with HER2-positive tumors (33% reduction).[18] However, drugs other than anthracyclines were included in the regimens used in these studies, so they do not prove that anthracyclines, taxanes, or any other form of cytotoxic treatment is more or less effective against triple-negative breast cancer.
The results from a number of other studies are inconsistent with these results. In one of the trials included in the meta-analysis shown in Table 6, CEF treatment resulted in inferior overall survival compared with CMF in 70 patients whose tumors had a core basal phenotype; the two regimens were equally effective in 29 patients with triple-negative, non-basal tumors.[27] In BCIRG trial 001, patients were randomly assigned to treatment with either TAC (docetaxel, doxorubicin, and cyclophosphamide) or FAC (5-fluorouracil, doxorubicin, and cyclophosphamide).[28] Among the patients with triple-negative tumors, there was a marginally significant (P = .051) advantage for TAC, with a 3-year survival of 74% vs 60% for TAC and FAC, respectively. Similarly, in the PACS 01 trial comparing 6 cycles of FEC with 3 cycles of FEC followed by 3 cycles of docetaxel, there was a significantly better metastasis-free survival and overall survival for the taxane regimen than for FEC alone among patients with a basal-like profile; however, there was no significant difference in outcome among patients with a luminal pattern.[29]
Anthracyclines are clearly effective in triple-negative breast cancer, but the available data are insufficient to conclude that they should be used preferentially in this group of patients, especially since “triple negative” is not really a homogenous category but rather a composite of several different molecular subtypes for which the optimal therapy may differ.
Conclusions and Recommendations
Treat the most aggressive breast cancer with the most effective hemotherapies
Considerable evidence has been published over the past 15 to 20 years demonstrating that the proportional benefits from any and all cytotoxic therapies are greater in patients with hormone receptor–negative tumors. This is not merely a matter of a smaller absolute benefit in patients at lower risk of recurrence; cytotoxic drugs are more effective against receptor-negative tumors. This is true for CMF regimens[1] as well as for anthracycline and taxane combinations.[17, 18, 30] Newer molecular markers may be merely refining this process (Table 6). The evidence is still insufficiently robust to justify choosing among cytotoxics on the basis of a molecular profile.
. . . and consider “no chemotherapy” for the rest
The same studies have shown that the benefits of cytotoxic therapy are very small or even non-existent in the remaining patients, ie, those with a low risk of recurrence as determined by estrogen receptor status along with the newer molecular markers. For these patients, the toxicity associated with the most effective regimens may not be justified by the meager improvement in progression-free or overall survival. A common response to the poor therapeutic index of adjuvant chemotherapy in these low-risk patients is to use less toxic treatments, such as AC and now the non-anthracycline regimens such as DC. In doing so, however, it is important to recognize that the benefits from these treatments may be even smaller than the small benefits seen with standard regimens. Four cycles of AC is clearly not the most effective regimen in common use for the treatment of early breast cancer. It is likely inferior to other anthracycline regimens and has been proven inferior to taxane combinations.
Future studies should compare a non-anthracycline, taxane-containing regimen with a combination containing both an anthracycline and a taxane for a minimum of 6 months. (It might be advisable to use a regimen that also employs oral cyclophosphamide and 5-fluorouacil or that uses a dose-dense schedule). Until a non-anthracycline regimen has been shown to be significantly superior in such a trial (or equivalent in a properly powered non-inferiority trial), anthracyclines should not be dropped from adjuvant chemotherapy regimens.
Adjuvant trials that provide no information on the molecular profile of the patients enrolled on the study cannot be considered definitive. In US Oncology trial 9733, a sample of 170 tumors was evaluated for HER2 status. Unfortunately, the specimens were not randomly selected from all patients enrolled in the trial but were taken from “. . . those patients who had relapsed as of December 2005 as well as cases available at Baylor University Medical Center (in Dallas), the primary hospital for several of the coauthors.”[8] Thus, the tumors selected were biased towards those with an early relapse. The percentage of tumors that were positive for HER2 was 21% for the AC arm of the study and 34% for the DC arm. The authors report that DC was superior (but not significantly) to AC in both the HER2-positive and HER2-negative patient subsets, but because of the way the samples were selected, this cannot be accepted as valid. If in fact there was a significantly greater number of HER2-positive tumors in the DC arm, this could account for some differences in outcome, since HER2-positive tumors seem to derive the greatest value from treatment.
As new trial results appear in the literature, be cautious when:
• A trial designed to show that one regimen is superior to another fails to meet its endpoint and the investigators conclude the two regimens are equally effective. One of two apparently equivalent regimens may still be inferior.
• A molecular marker has been shown to identify a subset of patients who will benefit from a particular regimen. All regimens may be ineffective in the group without the marker.
Financial Disclosure:The author has served as a consultant for Genentech (although not for any agent mentioned in this article).
References:
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