Adjuvant and Neoadjuvant Chemotherapy for Breast Cancer
San Antonio Breast Cancer Symposium 2005
Lee Schwartzberg, MD, FACPDecember 8-11, 2005San Antonio, TexasLee Schwartzberg, MD, FACP
The 28th annual meeting of the San Antonio Breast Cancer Symposium (SABCS) held December 8-11, 2005, provided fresh insight into the entire spectrum of breast cancer care. Content of the numerous lectures, posters, and symposia ranged from the basic science of molecular genetics through prevention, early detection, adjuvant chemo and hormonal therapy all the way to the future application of nanotechnology.
If there was a dominant theme emerging from this year’s meeting it was the notion that breast cancer must now be considered as several discrete diseases rather than one, and it should be treated accordingly. It is increasingly clear that molecular taxonomy performed by microchip gene array sorts breast cancer into several distinct genetic profiles, including basal, HER-2 positive, normal, and luminal A and B types. These findings have now been replicated by multiple laboratories and are poised to be incorporated into clinical use. Already, as Dr. Maxine Piccart-Gebhart put it in her introductory plenary talk, we must begin to change our approach to the adjuvant treatment of breast cancer by focusing more on predictive factors for response (“responsiveness”) to either endocrine or chemotherapeutic approaches as opposed to thinking first and foremost about risk factors such as tumor size and number of positive lymph nodes.
Evolving data suggests an inverse relationship between endocrine responsiveness and response to chemotherapy. Thus, patients with good risk features and high endocrine responsiveness may be treated with hormonal therapy alone while non-endocrine responsive tumors may benefit from the most aggressive types of multi-agent chemotherapy, including taxanes and dose dense schedules. These concepts, coupled with the new diagnostic tools for subsetting breast cancer, offer plentiful hypotheses for testing in future clinical trials. For now, SABCS 2005 offered mature results to adjuvant clinical trials designed and conducted over the past several years. Rather than blazing new treatment trails, these presentations tended to fill in many of the blanks in our understanding of the value of various drugs and combinations.
Adjuvant Therapy – Use of Herceptin®
Early this year, the results presented at ASCO 2005 of a combined analysis of Intergroup Trial N-9781 and the NSABP Trial B-31 demonstrated a marked 50% improvement in disease free survival for the addition of Herceptin (trastuzumab) to an anthracycline plus taxane based adjuvant chemotherapy program in HER-2 + patients. Anticipation was high for the presentation by Dr. Slamon of the interim results of BCIRG-006, a Herceptin study that took a somewhat different approach. Like the other trials, the control arm had sequential AC followed by a taxane (AC-T) but utilized Taxotere® (docetaxel) instead of Taxol® (paclitaxel). There were two experimental arms in the 006 trial; the first added Herceptin (AC-TH) for a total duration of one year similar to the study design of the other North American trials. The second experimental arm employed a non-anthracycline regimen. Paraplatin® (carboplatin) and Taxotere were administered with concurrent Herceptin (TCH) followed by Herceptin to complete one full year of therapy. Sufficient events have now occurred to provide interim results. Herceptin improved disease free survival by 51% when added to AC-T and 39% when used in the TCH combination compared to the control arm. The two Herceptin arms were not significantly different from each other. However, cardiac toxicity was more pronounced with the AC-TH combination: 2.4% of patients had an LVEF decline of greater than 15% compared to 0.6% for AC-T and 0.4% for TCH. Other toxicities were similar across arms. This study confirms the worth of Herceptin added to various chemotherapy regimens in HER-2 + tumors.
The HERA trial, first presented at ASCO 2005, was updated at SABCS 2005. This European trial differed from the North American studies and BCIRG-006 in the design which scheduled Herceptin initiation after all neoadjuvant or adjuvant chemotherapy was completed and did not specify the adjuvant regimen to be used. While the vast majority of patients received an anthracycline, only one-quarter of patients in the HERA trial additionally received a taxane. Also, one-third of patients enrolled were node negative. The two-year DFS was significantly better for the one-year arm Herceptin, 85.5% vs. the observation arm, 77.4% with a hazard ratio of 0.54 (p < 0.0001). At two years, there is not yet any significant difference in OS. Significantly more cardiac toxicity was noted in the Herceptin arm. This trial suggests that using Herceptin for one year after chemotherapy confers much of the same benefits as beginning it concurrently with chemotherapy. The definitive answer to best scheduling of Herceptin must await final analysis of both HERA, which also included a two year duration Herceptin arm and N-9781, which included an arm starting Herceptin following AC-T as well as a concurrent AC-T plus Herceptin arm.
A different and provocative approach to using Herceptin with chemotherapy in HER-2 positive patients was presented in the FinHer trial.The primary end point of this study, recurrence-free survival, was a comparison of Taxotere to Navelbine® (vinorelbine) following CEF. Taxotere was superior with a significantly better outcome than Navelbine. A subgroup of 252 patients who were HER-2 + were randomized to chemo plus or minus concurrent Herceptin for nine weeks. The RFS was 89.3% at three years when Herceptin was added compared to 77.6% for chemotherapy alone (p = 0.01) and overall survival at three years is 96.3% vs. 89.7% (p = 0.07). No decrease in LVEF was seen for the Herceptin treated arm after three years of follow up. Clearly these results should be considered in a larger trial assessing the optimal duration of Herceptin.
The Biology of HER-2 Positive Tumors – Predicting Benefit
Perhaps the most important findings at SABCS 2005 with regard to treatment of HER-2 positive tumors were the biological insights derived from explorations into the mechanisms of action. In BCIRG-006, a large subgroup of patients had their tumors subjected to genetic analysis., The HER-2 gene resides on chromosome 17-q and is amplified in HER-2 positive disease with increased gene copy number. HER-2 + tumors often have other genes in close physical proximity that are also amplified. The entire area displaying increased gene copies is called an amplicon. Interestingly, many important genes involved in the malignant phenotype of breast cancer and its response to therapy are located close to HER-2. The topoisomerase II alpha gene, a major target of anthracyclines, is coamplified in about 35% of patients who have HER-2 amplification. Patients with topo II amplification in BCIRG-006 treated with AC-TH had significantly better outcome than those receiving TCH or AC-T. Patients with non-amplified Topo II responded better to either TCH or AC-TH compared to AC-T. There was no significant difference in benefit between the two Herceptin containing chemotherapy programs for non-amplified Topo II patients. These patients, therefore, may be best suited for a non-anthracycline approach such as TCH.
Further genetic investigations into the B-31 trial were also presented by Dr. Paik. cMyc is co-amplified in 30% of HER-2 positive patients. In contrast to the a priori assumption that patients with cMyc amplification would derive less benefit from Herceptin, patients receiving chemotherapy and Herceptin actually had a markedly improved outcome with a HR of 0.24 compared to 0.63 for those without cMyc amplification receiving chemo and Herceptin. While the cMyc amplified patients treated with chemotherapy alone fared worse than the non-amplified patients, when Herceptin was added the outcomes were superior both in terms of recurrence and risk of death.
Taken together, these results suggest that further genetic sub-classification of breast tumors in the HER-2 positive group will help guide both prognosis and type of therapy. The era of multi-targeted therapy is here and allows more clearly defined subgroups to derive large benefits from specific molecularly targeted agents.
Adjuvant Chemotherapy – Refining the Role of Taxanes
Several large adjuvant trials evaluating the worth of taxanes were presented this year. The most eagerly awaited was ECOG-1199, testing two different hypotheses in a 2 x 2 design: First, whether there was a clinical advantage to Taxotere vs. Taxol and, secondly, whether weekly or every-three-week scheduling of taxanes was superior. Five thousand women were randomized to one of four arms, 88% had lymph node positive disease and 20% were HER-2 positive. Taxol given every three weeks was considered the standard arm and was compared to Taxol weekly or Taxotere given weekly or every three weeks as the experimental arms. At a median follow up of 47 months at this fourth interim analysis there is no significant difference between Taxol and Taxotere (p = 0.83) nor between dose schedules weekly vs. every three weeks. However, an explanatory analysis revealed that weekly Taxol vs. every-three-week Taxol was 20% better, p = 0.06. The Taxotere arms did not differ significantly from Taxol every three weeks but had more Grade III and IV hematologic toxicity. So far the findings of E-1199 provide no reason to alter our current approaches to adjuvant chemotherapy of breast cancer.
A German adjuvant study compared 6 cycles of FEC to 4 cycles of FEC plus eight weeks of Taxol in node positive patients. At 46 months of median follow up, FEC plus Taxol had a DFS of 85% vs. 79% for FEC alone for an HR of 0.063 (p = 0.006). Overall survival is numerically better for FEC plus taxol, 94% vs. 92% for FEC, which is not yet statistically significant. Toxicity was manageable in both arms.
Other approaches using taxanes were also discussed. Jones presented the final analysis of a trial comparing Taxotere and cyclophosphamide (TC) to standard AC for four cycles of each in node negative (48%) and node positive Stage 1-3 breast cancer. The TC combination was superior to AC for DFS, HR of 0.67 (p = 0.015), with a trend towards improved overall survival. In adhoc subgroup analyses, TC was particularly better in younger patients, those with HR negative tumors and those with positive lymph nodes. Patients treated with TC had more febrile neutropenia and myalgia, while nausea and vomiting were more common in the AC group. For patients who are appropriate candidates for four cycles of a two drug combination, TC can now certainly take its place as an acceptable and non-cardiotoxic regimen.
The BCIRG is evaluating adjuvant TAC (Taxotere, Adriamycin, cyclophosphamide) with all three drugs given simultaneously compared to AC followed by Taxotere (AC-T) in lymph node positive patients with HER-2 tumors in the BCIRG-005 study. Safety data for the two arms were presented; efficacy data is not yet available. Both arms achieved excellent relative dose intensity with about 90% of patients receiving greater than 90% of scheduled drug. Febrile neutropenia (FN) was more common in patients treated with TAC while neuropathy and myalgias were more common with AC-T. Overall, non-hematologic toxicity was manageable with no Grade III/IV toxicity experienced by greater than 5% of patients except asthenia (5.7% TAC and 6.3% AC-T). Since 17.6% of patients developed FN in the TAC arm while only 11% had first cycle prophylaxis starting in the first cycle, it is likely that more uniform use of growth factors for the triple drug regimen would reduce the Grade III/IV neutropenia and FN rates substantially. The efficacy comparisons of these two regimens are eagerly anticipated.
Another approach to refining taxane usage is to substitute Abraxane, nanoparticle albumin-bound paclitaxel, for standard Taxol formulated in cremaphor. Robert presented preliminary results of 30 early stage breast cancer patients treated with dose dense AC times 4 cycles followed by Abraxane 260 mg/m2 times 4 every two weeks. Growth factor was not given initially and was used only in case of a dose delay for neutropenia. In general, the therapy was well tolerated; approximately one-third of patients required Neulasta® (pegfilgrastim) for dose delays and one-third required dose reduction of Abraxane for non-hematologic Grade III/IV toxicity. Neuropathy tended to improve rapidly often resolving within 28 days of onset. This study demonstrates that maintaining dose density while increasing dose intensity of a taxane is feasible with Abraxane; further studies of the regimen are indicated.
An eagerly awaited presentation was the updated results of Intergroup C-9741, the trial which proved the benefit of the dose dense approach. This report by Dr. Hudis was based on 6.5 years of median follow up. Lymph node positive patients received either sequential single agent Adriamycin, Taxol and cyclophosphamide or AC followed by Taxol given either every 3 weeks or every 2 weeks (dose dense) with growth factor. The primary end point was disease-free survival. Outcomes previously reported from this trial continued to hold: DFS is superior for every 2 week dose dense treatment, HR 1.25, p = 0.02. Overall survival was also significantly better, p = 0.05. There was no difference between concurrent chemotherapy vs. sequential single agent. Neutropenia was lower in the dose dense arms undoubtedly due to mandatory use of myeloid growth factors in this group, while the concurrent AC dose dense arm had the highest risk of severe anemia.
Important long term toxicity, including hematologic and cardiac events, were presented. There was a 0.7% incidence of MDS/AML overall with no indication that the dose dense arms had an increased occurrence. The rate of severe cardiac events was 2% overall and not associated with any particular treatment arm of this trial. An unplanned subgroup analysis of outcome by hormone receptor status demonstrated that ER- patients showed significant benefit from dose dense chemotherapy, p = 0.014 for DFS and p = 0.039 for OS. The adjusted cumulative hazard ratio over eight years of follow up was 0.76 for DFS and 0.79 for OS in the ER- group and 0.92 for DFS and 0.92 for OS for the ER+ group.
The greatest potential advantage for neoadjuvant chemotherapy is the ability to determine in vivo, for an individual patient, the breast cancer response to specific therapy. From a research perspective, the opportunity to easily sample tissue that might offer fundamental insights into the biology of chemotherapy sensitivity or resistance is tantalizing. While progress is being made in this area, a clear signal of biological determinance has not yet been found except for the subset of patients with HER-2 + disease.
Buzdar, et al. updated their fascinating results of neoadjuvant Herceptin in HER-2 + breast cancer. An additional 22 patients have now been treated with Herceptin and Taxol followed by FEC (T-FEC +H). The overall pathologic complete response rate was 60% in the Herceptin treated group compared to 26% for the T-FEC arm alone. Hormone receptive negative patients did somewhat better than hormone receptor positive patients in each cohort. The incidence of clinically significant cardiac events was similar in the Herceptin treated and controlled arms. No patient treated with Herceptin has relapsed to date compared to 11% in the group without Herceptin. These impressive pilot results set the stage for a larger trial evaluating neoadjuvant Herceptin.
In patients receiving neoadjuvant chemotherapy, one issue has been whether early clinical response predicts later clinical response and subsequent breast conservation. It has been tempting to speculate that non-responders might benefit from a switch in chemotherapy to a potentially non-cross resistant regimen. Dr. Von Minckwitz tested these concepts in the Gepar-Trio Trial (14) and reported preliminary results at this meeting. Patients with operable breast cancer and tumors greater than 2 cm were treated with 2 cycles of neoadjuvant TAC. If less than a 50% reduction in tumor volume was noted at that point, patients were randomized to receive 4 additional cycles of TAC vs. switching to 4 cycles of Navelbine and Xeloda® (capecitabine) (NX). At the end of chemotherapy, overall clinical PR + CR rate was similar in the two groups as was response by sonography and the percentage of patients undergoing breast conservation. The pCR rate was 6.6% for TAC and 6.2 % for NX. The toxicity profile was somewhat better for patients who switched to NX. These results are somewhat sobering and give pause to the temptation to use a non-cross resistant regimen after a full course of a TAC-like program in the neoadjuvant setting with less than a pCR achieved at surgery. Gepar-Trio appears to demonstrate the lack of benefit from simply trying an empirically different combination. We will likely need further insights from the genetic study of tumors after exposure to chemotherapy in order to more carefully design trials to prove the benefit of non-cross resistant therapy.
SABCS 2005 leaves no doubt that patients with node positive breast cancer benefit from the addition of a taxane to the chemotherapy regimens. Multiple trials have now demonstrated the benefit of using Adriamycin, cyclophosphamide, and either Taxol or Taxotere. Dose density continues to be more effective than every 3 week schedules and appears to also show somewhat more benefit than weekly schedules. Triple drug combinations vs. sequential schedules are being tested in the current generation of clinical trials but results of these head to head comparisons are still forthcoming.
It appears unlikely that simply manipulating dose or schedule of these drugs will dramatically improve the outcome for breast cancer patients requiring chemotherapy. In part, this is good news. The large adjuvant trials presented at SABCS 2005 demonstrate that the large majority of patients, even unselected for HER-2 status, have five year disease-free survival in the 80-85% range and overall survival greater than 90%. Given the dramatic impact of Herceptin on the HER-2 subset coupled with the Will Rogers phenomenon of improving outcome when the worst group is subdivided out, future results should be even better. New generations of breast cancer trials should focus on smaller groups picked to test new biologicals or chemotherapy that is more specifically targeted.
It is entirely likely that we will soon enter a phase of adjuvant breast cancer treatment development similar to what has come before in the development of therapy for Hodgkin’s disease. That is we will focus on preserving efficacy while attempting to reduce both short and long term toxicity. Perhaps one day the awful impact of hearing “You have breast cancer” will be tempered by a reasonable expectation for non-toxic adjuvant therapy leading to a lifespan and quality of life not dissimilar from those without the disease.
 Piccart-Gebhart MJ. Treatment guidelines for systemic adjuvant therapy of breast cancer: strengths and weaknesses. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract P1.
 Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC®T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC®TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 1.
 Hera Study Team, Trastuzumab (H: Herceptin®) following adjuvant chemotherapy (CT) significantly improves disease-free survival (DFS) in early breast cancer (BC) with HER2 overexpression: the HERA Trial. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 11.
 Joensuu H, Kellokumpu-Lehtinen P-L, Bono P et al. Trastuzumab in combination with docetaxel or vinorelbine as adjuvant treatment of breast cancer: the FinHer Trial. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 2.
 Slamon D. Update on HER-2 directed therapy. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract ML1.
Kim C, Bryant J, Horne Z, et al. Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated cMYC in vivo. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 46.
 Sparano JA, Wang M, Martino S, et al. Phase III study of doxorubicin-cyclophosphamide followed by paclitaxel or docetaxel given every 3 weeks or weekly in patients with axillary node-positive or high-risk node-negative breast cancer: results of North American Breast Cancer Intergroup Trial E1199. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 48.
 Martin M, Rodriguez-Lescure A, Ruiz A, et al. Multicenter, randomized phase III study of adjuvant chemotherapy for node positive breast cancer comparing 6 cycles of FE90C versus 4 cycles of FE90C followed by 8 weekly paclitaxel administrations: interim efficacy analysis of GEICAM 9906 Trial. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 39.
 Jones SE, Savin MA, Holmes FA, et al. Final analysis: TC (docetaxel/cyclophosphamide, 4 cycles) has a superior disease-free survival compared to standard AC (doxorubicin/cyclophosphamide) in 1016 women with early stage breast cancer. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 40.
 Eiermann W, Pienkowski T, Crown J, et al. Phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (AC®T) in Her-2/neu negative early breast cancer patients with positive axillary lymph nodes: Interim analysis of the BCIRG 005 study. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 1069.
 Robert N, Ambro S, Krekow L, et al. Pilot study of dose dense doxorubicin + cyclophosphamide followed by ABI-007 in patients with early stage breast cancer. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 2073.
 Hudis C, Citron M, Berry D, et al. Five year follow-up of INT C9741: dose-dense (DD) chemotherapy (CRx) is safe and effective. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 41.
 Buzdar AU, Valero V, Ibrahim N, et al. Prospective data of additional patients treated with neoadjuvant therapy with paclitaxel followed by FEC chemotherapy with trastuzumab in HER-2 positive operable breast cancer, and an update of initial study population. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 5049.
 von Minckwitz G, Blohmer JU, Loehr A, et al. Comparison of docetaxel/doxorubicin/cyclophosphamide (TAC) versus vinorelbine/capecitabine (NX) in patients non-responding to 2 cycles of neoadjuvant TAC chemotherapy- first results of the phase III GEPARTRIO-Study by the German Breast Group. Proceedings of the 28th Annual San Antonio Breast Cancer Symposium. San Antonio, Texas. 2005. Abstract 38.