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There were 4 abstracts that addressed surgical controversies in the setting of breast cancer. Each of these abstracts could be found to be practice-changing in the future.
Abstract CRA504: ACOSOG Z0010: A multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer
Dr Richard Cote and colleagues presented data from the ACOSOG Z0010 trial. Sentinel lymph node biopsy (SNB) with immunohistochemistry (IHC) of histologically negative sentinel node (SN) is common practice in some institutions and can identify metastases not seen by standard histology. Immunohistochemistry can also be performed on bone marrow looking for evidence of micrometastases as well. This trial was performed in order to understand the clinical significance of SN and bone marrow metastases discovered by IHC. In this trial, 5539 patients with early breast cancer underwent segmental mastectomy and SNB along with bilateral iliac crest bone marrow aspiration. Bone marrow and histologically negative SN were evaluated with IHC in a central laboratory and the treating physicians and the patients were told of the results. Statistical endpoints include overall survival (OS), disease-free survival (DFS), and locoregional recurrence. Of the 5210 eligible and evaluable patients, 1215 were sentinel lymph node hematoxylin and eosin stain (H&E)–positive, and 3995 (76%) were H&E-negative. Of this later group of patients, 2977 (90%) were IHC-negative and 349 (10%) were IHC-positive. Of 3413 bone marrow specimens, 104 (3%) were IHC-positive. Patients who were SLN-negative by H&E received no further axillary surgery and were then offered breast radiation therapy and adjuvant systemic therapy. Of the 3995 patients who were SLN-negative by H&E, 85% had T1 cancers, 81% of tumors were ER-positive, 18% of patients underwent an axillary lymph node dissection (ALND), 91% received radiation therapy, and 98% received some sort of adjuvant systemic therapy. Because nearly all patients received adjuvant systemic therapy, the true impact of IHC-positivity may not be understood.
For overall survival, the 5-year overall survival was significantly higher with a negative versus positive result for SLN by H&E (96% vs 93%, P = .0009) and for bone marrow IHC (95% vs 90%, P = .01) Surprisingly, SLN IHC was NOT significantly associated with overall survival (P = .93). In addition, there was no concordance of SLN IHC status with bone marrow IHC with only 6/68 patients who were bone marrow IHC-positive, also SLN IHC-positive. The conclusions of the presenters was that
1. Micrometastases detected in bone marrow by IHC correlate with increased risk of death in patients with T1/2 N0 M0 breast cancer
2. Micrometastases in SLN detected by H&E stain is associated with significantly shorter OS and DFS
– Overall a very good survival outcome (>90%) in patients with histologically positive SLN
3. Micrometastases detected in SLN by IHC do not appear to impact OS of these patients
– Routine examination of SLN by IHC is not supported in this patient population
Abstract CRA506: ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node
Giuliano and colleagues presented the data from the ACOSOG Z011 trial. Axillary lymph node dissection (ALND) has been the gold standard for women with an H&E-positive sentinel lymph node. The main objective of ACOSOG Z0011 was to compare outcomes of patients with H&E detected metastasis in SN managed with or without ALND and no axillary irradiation. In this trial, 891 women with clinically node-negative breast cancer who underwent SN biopsy and had 1 or 2 SN positive for tumor cells by H&E were randomized to ALND or no further axillary treatment. All patients were treated with lumpectomy and tangential field radiation therapy. Systemic therapy choices were at the discretion of the treating physician. Clinical characteristics of the patients in the study included about 70% of women having tumors that were T1, 83% of tumors were ER-positive, 75% of patients had tumors that were intermediate or high grade. The median number of lymph nodes removed in the SLN alone group was 2, and was 17 in the ALND group. Twenty-seven percent of the patients had additional positive lymph nodes found in this latter group.
Results: At a median follow-up of 6.3 years, total locoregional recurrence events were similar between the 2 groups. When comparing the outcomes of patients with a sentinel lymph node dissection (SLND) versus an ALND, in breast recurrences were 2% versus 4%, and regional lymph node recurrences were <1% in each arm. None of these differences were statistically significant. There was also no difference in DFS or OS between the 2 groups. The authors concluded that ALND provides no survival or recurrence benefit versus SLND in patients who have 1 or 2 positive sentinel lymph nodes and are undergoing lumpectomy and radiation therapy. Factors that impacted survival and locoregional recurrence by multivariate analysis were not related to the operation or lymph nodes. The study does not support the routine use of ALND in patients who meet the criteria set out in this study.
Abstract LBA505: Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients
An outstanding theoretical question is whether those patients with a negative SLN receive any benefit at all from an ALND. Presumably, some of these women have micrometastases that could be detected by IHC. This National Surgical Adjuvant Breast and Bowel Project (NSABP) study was performed to definitively and finally answer this question. The trial was designed to determine in patients who are SN-negative whether SNR alone results in the same survival and regional control as SNR + ALND, while reducing morbidity. In this trial, 5611 women with clinically node negative invasive breast cancer were randomly assigned to undergo SND versus SND + ALND. The study examines the outcome of the 1975 women who underwent SND + ALND (group 1) and the 2011 women who underwent SND alone (group 2). The median time on study was 95 months.
Results: There was no difference in overall survival between the 2 groups with the 5-year estimates for OS at 96% for the SND + ALND group and 95% for the SND alone group. Eight-year estimates for DFS are 82.4% and 81.5% respectively. There were 54 local recurrences in group 1 and 49 in group 2. With regards to morbidity, there was a significantly increased risk of morbidity with an ALND. When comparing groups 1 and 2, the percentage of patients with the following entities was described: shoulder abduction deficit (19%/13%), arm volume difference >5% (28%/17%), arm numbness (31%/8%), and arm tingling (13%/7%). The authors concluded that there were no significant differences were observed in OS, DFS, or regional control between the trial groups. Within the limits of this trial, SND without ALND is validated as a safe and effective method for regional node treatment of patients with SN negative breast cancer.
Abstract 507: Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer
Hughes and colleagues presented a 12-year median follow-up update of Cancer and Leukemia Group B (CALGB) 9343 which was designed to evaluate outcomes in women 70 years of age or older with early breast cancer undergoing lumpectomy and tamoxifen with or without radiation therapy. Between 1994 and 1999, 636 women aged 70 years and older with clinical stage I, ER-positive breast cancer and receiving lumpectomy and tamoxifen were randomly assigned to receive tamoxifen alone, or tamoxifen with radiation. The primary statistical endpoints were time to locoregional recurrence, mastectomy for recurrence, distant metastases, and breast cancer-specific and all-cause mortality.
Results: Ipsilateral breast recurrence was reported in 2% and 9% of women for the tamoxifen with radiation and tamoxifen groups, respectively. In addition, axillary recurrence was seen in 0%/3%, mastectomy was performed in 2%/4%, distant metastases were seen in 5%/5%, respectively, and 33% of patients died in each arm of which only 3% and 2% were breast cancer-specific deaths. The authors concluded that in an elderly population of patients with early-stage breast cancer, the benefits of radiation after lumpectomy are minimal. There was no radiation benefit on survival, breast preservation, development of a second primary cancer, or distant metastases.
Abstract 533: Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer
Gnant and colleagues presented an update of the ABCSG-12 trial, which had originally been reported at ASCO 2008. In this trial, 1803 premenopausal women with endocrine responsive early breast cancer were randomly assigned to receive goserelin (3.6 mg q 28 days) and tamoxifen 20 mg per day or anastrozole 1 mg/day for 3 years. Patients were also randomized to receive zoledronic acid 4 mg every 6 months for 3 years. None of the women received adjuvant systemic chemotherapy. Statistical endpoints were DFS and OS.
Results: With a median follow-up of 62 months, 186 total events have occurred, including 100 patients with distant metastases and 73 deaths. When comparing DFS events for women who did not versus those who did receive zoledronic acid, there were 110/903 events versus 76/900 events representing a 33% reduction in events with a P = .0072. Zoledronic acid use decreased not only distant events, but also locoregional events as well. There was no differential effect on benefit regardless of whether the patient had been randomized to receive anastrozole or tamoxifen. There were 43/903 deaths in the patients who did not receive zoledronic acid, and 30/900 deaths for those who did with a non-significant P = .0853. There were no differences for DFS between patients randomized to tamoxifen versus anastrozole, however, patients treated with anastrozole did worse with respect to OS versus tamoxifen (P = .04), probably due to differences in post-relapse treatment.
Abstract 512: Impact of body mass index (BMI) on endocrine therapy in premenopausal breast cancer patients: An analysis of the ABCSG-12 trial
As an accompaniment to the previous report, a second analysis was performed on the ABCSG trial in order to investigate the influence of body mass index (BMI) on the efficacy of the aromatase inhibitors. It has been well described that patients who gain weight or maintain an elevated BMI after a diagnosis of breast cancer have a worse outcome. Pfeiler and his colleagues sought to understand the influence of BMI when comparing the use of tamoxifen versus anastrozole in premenopausal women with early breast cancer who were receiving goserelin. For this analysis, BMI was calculated prospectively in the trial using their height and weight at study entry. Body mass index definitions of the World Health Organization (WHO) were used and include normal 18.5 kg/m2 – 24.9 kg/m2; overweight: BMI >25 kg/m2, and underweight <18.5 kg/m2.
Results: 64% of patients were normal weight and 33% were overweight. At a median follow-up of 5 years, overweight patients who received anastrozole had a significant short DFS (HR 1.6, P = .02) and OS (HR 2.3, P = .008) compared to normal weight patients who received anastrozole. No differences in DFS or OS were observed in overweight and normal weight patients receiving tamoxifen. In overweight patients, anastrazole led to a shorter DFS and OS (P = .006) compared to tamoxifen. The authors concluded that BMI significantly impacts on the efficacy of anastrozole plus goserelin, but not with tamoxifen plus goserelin in the adjuvant treatment of early breast cancer in premenopausal women not receiving systemic chemotherapy.
And finally, I would like to highlight 1 trial in the setting of metastatic breast cancer using a new class of chemotherapy agents.
Abstract CRA1004: A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician's choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane
Eribulin mesylate is a synthetic analog of halichondrin B, a natural marine sponge product. It is a non-taxane microtubule dynamics inhibitor with a novel mode of action. It is active against beta-tubulin mutated cell lines and has a wide therapeutic window, inducing less neuropathy in mice than paclitaxel. Twelves and colleagues presented data on the EMBRACE study. This was a global, randomized, open-label phase III trial which randomized 762 women with locally recurrent or metastatic breast cancer to eribulin mesylate 1.4 mg/m2 IV days 1 and 8, q 21 days versus treatment of physician’s choice (TPC), using any monotherapy (chemotherapy, hormonal therapy, or biologic therapy), or supportive care only. Patients could have received between 2 to 5 prior chemotherapies and had to have received at least 2 prior regimens in the metastatic setting, including an anthracycline and a taxane. The women had to have progressed within 6 months of their last chemotherapy and have a neuropathy grade no greater than 1. The primary endpoint of the trial was overall survival.
Results: The median overall survival for the TPC group was 10.65 months, and the OS for the eribulin group was 13.12 months for a P = .041. The 1-year survival for the TPC group was 43.7% compared to 53.9% for the eribulin group. Progression-free survival was also significant favoring the eribulin group by both independent and investigator reviews. Although overall response rates were low in this heavily pre-treated population of women (4.7% versus 12.2%), the clinical benefit rate was 16.8% versus 22.6%, favoring eribulin. Grade 3/4 treatment-related adverse events of interest for eribulin were asthenia (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). The authors concluded that the study met its primary endpoint of overall survival by an absolute increase of 2.5 months, with tolerable side effects. Further clinical trials continue with eribulin in the breast cancer and other solid tumor arenas.
Cote R, Giuliano AE, Hawes D, et al. ACOSOG Z0010: A multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer. J Clin Oncol. 2010;28(18s). Abstract CRA504.
Giuliano AE, McCall LM, Beitsch PD, et al. ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1-2 N0 M0 breast cancer who have a positive sentinel node. J Clin Oncol. 2010;28(18s). Abstract CRA506.
Krag DN, Anderson SJ, Julian TB, et al. Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients. J Clin Oncol. 2010;28(18s). Abstract LBA505.
Hughes KS, Schnaper LA, Cirrincione C, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. J Clin Oncol. 2010;28(18s). Abstract 507.
Gnant M, Mlineritsch B, Stoeger H, et al. Mature results from ABCSG-12: Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with endocrine-responsive early breast cancer. J Clin Oncol. 2010;28(18s). Abstract 533.
Pfeiler G, Königsberg R, Singer CF, et al. Impact of body mass index (BMI) on endocrine therapy in premenopausal breast cancer patients: An analysis of the ABCSG-12 trial. J Clin Oncol. 2010;28(18s). Abstract 512.
Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician's choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(18s). Abstract CRA1004.