Node-Positive Breast Cancer--8-Year Results
With 8-year follow-up in BIG 02–98, the incorporation of docetaxel regardless of the schedule showed no significant difference in DFS compared with doxorubicin-based control in women with node-positive early breast cancer.
Sequential doxorubicin–docetaxel–CMF resulted in significant improvement in outcomes: better DFS than sequential doxorubicin–CMF (absolute improvement 5.9%, P = 0.036), and better DFS and OS than concurrent doxorubicin–docetaxel before CMF (absolute improvement DFS 4.6%, P = 0.035; OS 4.0%, P = 0.028). With longer follow-up and more deaths, the OS benefit suggested at 5 years now reaches nominal statistical significance.
Benefit from sequential but not concurrent docetaxel may be attributable to a higher docetaxel dose intensity (100 versus 75 mg/m), higher doxorubicin dose intensity (60 versus 50 mg/m) and longer treatment duration (30 versus 24 weeks). Concurrent docetaxel–doxorubicin requires dose reductions for feasibility which, in the absence of synergy, may compromise efficacy. Sequential therapy superiority is in keeping with the Norton–Simon hypothesis, which relates cytotoxic effects on the tumor size to tumor growth dynamics. As a tumor shrinks, the regrowth rate increases, such that the chemotherapy level capable of initiating regression may be insufficient to maintain regression and produce cure. The slowing regression rate may be overcome by switching to alternative cytotoxics, which may also kill clones resistant to the initial drug(s). Intratumoral polyclonality may necessitate multiple drugs for micrometastatic disease eradication; not, however, at the expense of dose intensity as was required for concurrent docetaxel–doxorubicin.
In early breast cancer, addition of taxanes to anthracycline-based therapy has been tested in many clinical trials, with conflicting results. Two meta-analyses have examined adjuvant taxanes in over 20 000 women. De Laurentiis et al. reported DFS benefit from taxane addition, independent of taxane type, ER status and nodal status. Laporte et al. in an analysis restricted to docetaxel reported DFS and OS benefits in node-positive, but not node-negative disease. The meta-analyses have limitations and the results cannot be considered conclusive. A recently published meta-analysis by the Early Breast Cancer Trialists' Collaborative Group concluded that breast cancer mortality was reduced in randomized trials in which the addition of a taxane extended the duration of chemotherapy compared with the anthracycline-based control, while no significant difference in breast cancer mortality was observed in trials with taxane and control regimens of similar durations.
A consensus from available data is impeded by substantial heterogeneity in trial designs, use of paclitaxel (Taxol) or docetaxel, taxane doses, sequential or concurrent taxane administration, control therapy and follow-up duration. The extent to which docetaxel and paclitaxel results are interchangeable is unknown. Specifically for docetaxel, there is consensus for superiority of 3-weekly over weekly dosing, and dose-dependent activity. However, debate persists regarding sequential or concurrent administration, and optimal partner drugs (see Supplement Table S2,availableatAnnals of Oncology online).
The absolute benefit in BIG 02–98 from sequential docetaxel compared with no docetaxel after 8-year follow-up is in keeping with 8-year results of PACS01. Compared with fluorouracil, epirubicin and cyclophosphamide (FEC)100, sequential FEC–docetaxel improved absolute DFS by 4.4% (P = 0.035) and OS by 5.2% (P = 0.024). Similarly, in TAXit216 addition of sequential docetaxel to E-CMF improved relapse-free survival (HR = 0.75, 95% CI = 0.59–0.96, P = 0.039) and OS (HR = 0.67, 95% CI = 0.48–0.94, P = 0.017). In contrast, the TACT trial reported no benefit but more toxicity from sequential FEC60-docetaxel compared with anthracycline-based control (HR = 0.95, 95% CI = 0.85–1.08. P = 0.44), and preliminary ADEBAR results showed no difference between FEC120 and sequential EC-docetaxel (HR = 0.88, 95% CI: 0.69–1.11).
No benefit was seen in BIG 02–98 for concurrent docetaxel over control. This is similar to PACS04 which compared ET and FEC100, and E2197 which compared AT and AC. In contrast, TAC (docetaxel, doxorubicin, cyclophosphamide) was superior to FAC (fluorouracil, doxorubicin, cyclophosphamide) for DFS and OS in node-positive disease in BCIRG001, and for DFS in high-risk node-negative disease in GEICAM 9805, and TC (docetaxel, cyclophosphamide) was superior to AC for DFS and OS in USO 9735.
Superiority of sequential docetaxel over concurrent docetaxel in BIG 02–98 concords with NSABP-B30, in which sequential AC × 4 followed by docetaxel × 4 improved DFS and OS compared with AT × 4 (DFS: HR = 0.80; P = 0.001; OS: HR = 0.83; P = 0.03), and improved DFS compared with concurrent TAC × 4 (DFS: HR = 0.83, P = 0.01). Like BIG 02–98, NSABP-B30 had substantial interarm differences in docetaxel and doxorubicin doses, and treatment duration. In contrast to BIG 02–98 and NSABP-B30, BCIRG005 showed TAC to be as effective as sequential AC-docetaxel, but higher cumulative doxorubicin and docetaxel doses in TAC pose increased risk for late toxicity. Ten-year follow-up of TAC-treated patients in BCIRG001 showed important cardiotoxicity.
In 1998 when BIG 02–98 commenced, CMF was a standard therapy, adjuvant trastuzumab for HER2-positive disease was not an option and molecular subtyping into biological subtypes beyond hormone receptor status was not a consideration. Disparities between 1998 and 2012 are testament to the progress made in diagnostics and therapy. However, how are the BIG 02–98 results applicable in current practice? In HER2-positive disease, HER2-targeted therapy plus chemotherapy is indicated and the current trial results are redundant. In HER2-negative disease, exploratory retrospective analysis by biological subtypes may identify subgroups likely to obtain the benefit observed in the biologically unselected trial population. Subtype-specific molecular events may impart taxane sensitivity.
The current biological subtype analysis was enabled by prospective tumor tissue collection and was strengthened by a central pathology review using current methods and thresholds. The prevalence of the HER2-positive subtype seems low (149/1777, 8%); however, HER2-positive tumors (N = 330/1777, 19%) were subtype classified as HER2 positive (N = 149/149) or luminal-B (N = 181/1034), depending on the ER status. The prevalence of subtypes was similar to BCIRG001. Both the studies used similar thresholds, including Ki-67 ≥14% in the distinction between luminal-A and B. The low prevalence of luminal-A tumors might, in part, be explained by investigators not proposing the trial for patients with low risk, good prognosis tumors. The prevalence of luminal-B was high (BIG 02–98: 58%; BCIRG001: 61%) compared with other analyses using similar parameters: among all BIG 02–98 luminal subtype patients, 78% were luminal-B (including luminal HER2-positive) compared with 41% in the pivotal validation series by Cheang et al.. Higher rates of luminal-B disease may in part be a cohort selection-bias based on the nodal status (node-positive: BIG 02–98 and BCIRG001:100%; Cheang et al.: 42%). Furthermore, the validation assessed tissue microarray, while BIG 02–98 and BCIRG001 assessed whole sections. Ki-67 may be lower in tissue microarrays compared with whole sections due to non-homogenous intratumoral expression.
In this article, luminal-A disease had the best DFS and showed no differential chemosensitivity. Lack of taxane benefit in luminal-A is in keeping with exploratory analyses of docetaxel in BCIRG001, and PACS01. Luminal-A disease, accounting for 35%–40% of all breast cancers, has not been shown in any trial to benefit from taxane addition, or indeed from any chemotherapy above and beyond the benefit of endocrine therapy.
HER2-postive and triple-negative subtypes had the worst DFS. In luminal-B, HER2-positive and triple-negative disease, there was no significant difference between treatment arms; however, HRs are in favor of sequential docetaxel. This trend is statistically relevant only in luminal-B patients, possibly because this is numerically the largest group. Subtype analyses from other adjuvant docetaxel trials have been reported. In BCIRG001, ER-negative tumors showed worse outcome, despite showing a better response to TAC over FAC. There was significant DFS benefit from TAC over FAC in luminal-B disease (P = 0.025), and a trend in triple-negative and HER2-positive diseases. In PACS 01, the greatest docetaxel benefit was in the basal-like subtype. GEICAM 9805 suggested greatest DFS benefit from docetaxel in HER2-negative patients, regardless of the hormone receptor status. In TACT, the subgroup of patients with ER-negative, HER2-positive, node-positive tumors benefited from the addition of docetaxel (see Supplement Table S3,availableatAnnals of Oncology online).
It was hypothesized that the concurrent control therapy would be more active than the sequential control therapy in the triple-negative basal-like subset due to higher dosing of DNA damaging cyclophosphamide coupled with DNA repair dysfunction. Limited patient numbers in these cohorts prevent robust conclusions; however the HRs favor concurrent AC in both the groups.
In summary, with 8-year median follow-up, the incorporation of sequential docetaxel showed a statistically significant improvement in DFS compared with sequential doxorubicin-based control, and for both DFS and OS compared with concurrent administration of both drugs. Patients classified as luminal-A subtype had the best outlook compared with all other sybtypes, despite no differential chemosensitivity.
Discussion
With 8-year follow-up in BIG 02–98, the incorporation of docetaxel regardless of the schedule showed no significant difference in DFS compared with doxorubicin-based control in women with node-positive early breast cancer.
Sequential doxorubicin–docetaxel–CMF resulted in significant improvement in outcomes: better DFS than sequential doxorubicin–CMF (absolute improvement 5.9%, P = 0.036), and better DFS and OS than concurrent doxorubicin–docetaxel before CMF (absolute improvement DFS 4.6%, P = 0.035; OS 4.0%, P = 0.028). With longer follow-up and more deaths, the OS benefit suggested at 5 years now reaches nominal statistical significance.
Benefit from sequential but not concurrent docetaxel may be attributable to a higher docetaxel dose intensity (100 versus 75 mg/m), higher doxorubicin dose intensity (60 versus 50 mg/m) and longer treatment duration (30 versus 24 weeks). Concurrent docetaxel–doxorubicin requires dose reductions for feasibility which, in the absence of synergy, may compromise efficacy. Sequential therapy superiority is in keeping with the Norton–Simon hypothesis, which relates cytotoxic effects on the tumor size to tumor growth dynamics. As a tumor shrinks, the regrowth rate increases, such that the chemotherapy level capable of initiating regression may be insufficient to maintain regression and produce cure. The slowing regression rate may be overcome by switching to alternative cytotoxics, which may also kill clones resistant to the initial drug(s). Intratumoral polyclonality may necessitate multiple drugs for micrometastatic disease eradication; not, however, at the expense of dose intensity as was required for concurrent docetaxel–doxorubicin.
In early breast cancer, addition of taxanes to anthracycline-based therapy has been tested in many clinical trials, with conflicting results. Two meta-analyses have examined adjuvant taxanes in over 20 000 women. De Laurentiis et al. reported DFS benefit from taxane addition, independent of taxane type, ER status and nodal status. Laporte et al. in an analysis restricted to docetaxel reported DFS and OS benefits in node-positive, but not node-negative disease. The meta-analyses have limitations and the results cannot be considered conclusive. A recently published meta-analysis by the Early Breast Cancer Trialists' Collaborative Group concluded that breast cancer mortality was reduced in randomized trials in which the addition of a taxane extended the duration of chemotherapy compared with the anthracycline-based control, while no significant difference in breast cancer mortality was observed in trials with taxane and control regimens of similar durations.
A consensus from available data is impeded by substantial heterogeneity in trial designs, use of paclitaxel (Taxol) or docetaxel, taxane doses, sequential or concurrent taxane administration, control therapy and follow-up duration. The extent to which docetaxel and paclitaxel results are interchangeable is unknown. Specifically for docetaxel, there is consensus for superiority of 3-weekly over weekly dosing, and dose-dependent activity. However, debate persists regarding sequential or concurrent administration, and optimal partner drugs (see Supplement Table S2,availableatAnnals of Oncology online).
The absolute benefit in BIG 02–98 from sequential docetaxel compared with no docetaxel after 8-year follow-up is in keeping with 8-year results of PACS01. Compared with fluorouracil, epirubicin and cyclophosphamide (FEC)100, sequential FEC–docetaxel improved absolute DFS by 4.4% (P = 0.035) and OS by 5.2% (P = 0.024). Similarly, in TAXit216 addition of sequential docetaxel to E-CMF improved relapse-free survival (HR = 0.75, 95% CI = 0.59–0.96, P = 0.039) and OS (HR = 0.67, 95% CI = 0.48–0.94, P = 0.017). In contrast, the TACT trial reported no benefit but more toxicity from sequential FEC60-docetaxel compared with anthracycline-based control (HR = 0.95, 95% CI = 0.85–1.08. P = 0.44), and preliminary ADEBAR results showed no difference between FEC120 and sequential EC-docetaxel (HR = 0.88, 95% CI: 0.69–1.11).
No benefit was seen in BIG 02–98 for concurrent docetaxel over control. This is similar to PACS04 which compared ET and FEC100, and E2197 which compared AT and AC. In contrast, TAC (docetaxel, doxorubicin, cyclophosphamide) was superior to FAC (fluorouracil, doxorubicin, cyclophosphamide) for DFS and OS in node-positive disease in BCIRG001, and for DFS in high-risk node-negative disease in GEICAM 9805, and TC (docetaxel, cyclophosphamide) was superior to AC for DFS and OS in USO 9735.
Superiority of sequential docetaxel over concurrent docetaxel in BIG 02–98 concords with NSABP-B30, in which sequential AC × 4 followed by docetaxel × 4 improved DFS and OS compared with AT × 4 (DFS: HR = 0.80; P = 0.001; OS: HR = 0.83; P = 0.03), and improved DFS compared with concurrent TAC × 4 (DFS: HR = 0.83, P = 0.01). Like BIG 02–98, NSABP-B30 had substantial interarm differences in docetaxel and doxorubicin doses, and treatment duration. In contrast to BIG 02–98 and NSABP-B30, BCIRG005 showed TAC to be as effective as sequential AC-docetaxel, but higher cumulative doxorubicin and docetaxel doses in TAC pose increased risk for late toxicity. Ten-year follow-up of TAC-treated patients in BCIRG001 showed important cardiotoxicity.
In 1998 when BIG 02–98 commenced, CMF was a standard therapy, adjuvant trastuzumab for HER2-positive disease was not an option and molecular subtyping into biological subtypes beyond hormone receptor status was not a consideration. Disparities between 1998 and 2012 are testament to the progress made in diagnostics and therapy. However, how are the BIG 02–98 results applicable in current practice? In HER2-positive disease, HER2-targeted therapy plus chemotherapy is indicated and the current trial results are redundant. In HER2-negative disease, exploratory retrospective analysis by biological subtypes may identify subgroups likely to obtain the benefit observed in the biologically unselected trial population. Subtype-specific molecular events may impart taxane sensitivity.
The current biological subtype analysis was enabled by prospective tumor tissue collection and was strengthened by a central pathology review using current methods and thresholds. The prevalence of the HER2-positive subtype seems low (149/1777, 8%); however, HER2-positive tumors (N = 330/1777, 19%) were subtype classified as HER2 positive (N = 149/149) or luminal-B (N = 181/1034), depending on the ER status. The prevalence of subtypes was similar to BCIRG001. Both the studies used similar thresholds, including Ki-67 ≥14% in the distinction between luminal-A and B. The low prevalence of luminal-A tumors might, in part, be explained by investigators not proposing the trial for patients with low risk, good prognosis tumors. The prevalence of luminal-B was high (BIG 02–98: 58%; BCIRG001: 61%) compared with other analyses using similar parameters: among all BIG 02–98 luminal subtype patients, 78% were luminal-B (including luminal HER2-positive) compared with 41% in the pivotal validation series by Cheang et al.. Higher rates of luminal-B disease may in part be a cohort selection-bias based on the nodal status (node-positive: BIG 02–98 and BCIRG001:100%; Cheang et al.: 42%). Furthermore, the validation assessed tissue microarray, while BIG 02–98 and BCIRG001 assessed whole sections. Ki-67 may be lower in tissue microarrays compared with whole sections due to non-homogenous intratumoral expression.
In this article, luminal-A disease had the best DFS and showed no differential chemosensitivity. Lack of taxane benefit in luminal-A is in keeping with exploratory analyses of docetaxel in BCIRG001, and PACS01. Luminal-A disease, accounting for 35%–40% of all breast cancers, has not been shown in any trial to benefit from taxane addition, or indeed from any chemotherapy above and beyond the benefit of endocrine therapy.
HER2-postive and triple-negative subtypes had the worst DFS. In luminal-B, HER2-positive and triple-negative disease, there was no significant difference between treatment arms; however, HRs are in favor of sequential docetaxel. This trend is statistically relevant only in luminal-B patients, possibly because this is numerically the largest group. Subtype analyses from other adjuvant docetaxel trials have been reported. In BCIRG001, ER-negative tumors showed worse outcome, despite showing a better response to TAC over FAC. There was significant DFS benefit from TAC over FAC in luminal-B disease (P = 0.025), and a trend in triple-negative and HER2-positive diseases. In PACS 01, the greatest docetaxel benefit was in the basal-like subtype. GEICAM 9805 suggested greatest DFS benefit from docetaxel in HER2-negative patients, regardless of the hormone receptor status. In TACT, the subgroup of patients with ER-negative, HER2-positive, node-positive tumors benefited from the addition of docetaxel (see Supplement Table S3,availableatAnnals of Oncology online).
It was hypothesized that the concurrent control therapy would be more active than the sequential control therapy in the triple-negative basal-like subset due to higher dosing of DNA damaging cyclophosphamide coupled with DNA repair dysfunction. Limited patient numbers in these cohorts prevent robust conclusions; however the HRs favor concurrent AC in both the groups.
In summary, with 8-year median follow-up, the incorporation of sequential docetaxel showed a statistically significant improvement in DFS compared with sequential doxorubicin-based control, and for both DFS and OS compared with concurrent administration of both drugs. Patients classified as luminal-A subtype had the best outlook compared with all other sybtypes, despite no differential chemosensitivity.