Breast Cancer Study Group Trial Research Articles

Bayesian joint modeling of multivariate longitudinal and survival outcomes using Gaussian copulas.

There is an increasing interest in the use of joint models for the analysis of longitudinal and survival data. While random effects models have been extensively studied, these models can be hard to implement and the fixed effect regression parameters must be interpreted conditional on the random effects. Copulas provide a useful alternative framework for joint modeling. One advantage of using copulas is that practitioners can directly specify marginal models for the outcomes of interest. We develop a joint model using a Gaussian copula to characterize the association between multivariate longitudinal and survival outcomes. Rather than using an unstructured correlation matrix in the copula model to characterize dependence structure as is common, we propose a novel decomposition that allows practitioners to impose structure (e.g., auto-regressive) which provides efficiency gains in small to moderate sample sizes and reduces computational complexity. We develop a Markov chain Monte Carlo model fitting procedure for estimation. We illustrate the method's value using a simulation study and present a real data analysis of longitudinal quality of life and disease-free survival data from an International Breast Cancer Study Group trial.

Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer

BackgroundAdjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor–positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti–receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes.MethodsABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor–positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome–related end points were disease-free survival (DFS), bone metastasis–free survival (BMFS), and overall survival (OS).ResultsFor this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed.ConclusionsDFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)

Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18

BackgroundStatins are cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, statins may possess anticancer properties and interact with receptor activator of nuclear factor κB ligand expression. We aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18.Patients and methodsABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor-positive BC receiving a nonsteroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post hoc analysis, we investigated the effects of concomitant statin therapy on recurrence risk (RR) of BC, fracture risk and bone mineral density (BMD).ResultsIn the study population (n = 3420), statin therapy (n = 824) was associated with worse disease-free survival (DFS) [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.04-1.75; P = 0.023]. While no significant effect of lipophilic statins (n = 710) on RR was observed (HR 1.30, 95% CI 0.99-1.72; P = 0.062), patients on hydrophilic statins (n = 87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; P = 0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21-5.68; P = 0.014). However, this effect subsided after correction for confounders in the sensitivity analysis. No association between statin use and fracture risk or osteoporosis was observed.ConclusionAccording to this analysis, hydrophilic statins showed a detrimental effect on DFS in the main model, which was attenuated after correction for confounders. Our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins.

Abstract P1-15-01: Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18

Abstract Background Statins are a common class of cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, it was suggested that statins may possess anti-cancer properties and interact with RANK ligand expression. Therefore, we aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. Methods ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor (HR) positive BC receiving a non-steroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post-hoc analysis, we investigated the potential effects of concomitant statin therapy on recurrence risk of BC, fracture risk and bone mineral density (BMD) using time-dependent Cox proportional hazards models. Sensitivity analyses accounting for immortal time and confounding bias were performed. Results In the analysis of the study population (n=3,420), statin therapy (n=824) was associated with worse disease-free survival (DFS) (HR 1.35, 95%; CI 1.04-1.75; p=0.023). Sensitivity analysis relativized these results (HR 1.22, 95% CI 0.94 - 1.59; p=0.14). While there was no significant effect of lipophilic statins (n=710) on recurrence risk (HR 1.30, 95% CI 0.99 - 1.72; p=0.062), patients on hydrophilic statins (n=87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; p=0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21 - 5.68; p=0.014). No association between statin use and fracture risk or osteoporosis was observed. Conclusion In this population of early-stage breast cancer patients from a prospective randomized study, an association of hydrophilic statins with increased recurrence risk was observed. According to this retrospective analysis hydrophilic statins may increase recurrence risk especially in patients treated with denosumab. Still, our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins. Therefore, no final conclusion is possible. This hypothesis generating result warrants further exploration. Citation Format: Christoph Minichsdorfer, Thorsten Fuereder, Michael Leutner, Christian F. Singer, Stephanie Kacerovsky-Strobl, Daniel Egle, Richard Greil, Marija Balic, Florian Fitzal, Georg Pfeiler, Sophie Frantal, Rupert A. Bartsch, Michael Gnant. Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-01.

Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.

Performance of standard imputation methods for missing quality of life data as covariate in survival analysis based on simulations from the International Breast Cancer Study Group Trials VI and VII*

Imputation methods for missing data on a time-dependent variable within time-dependent Cox models are investigated in a simulation study. Quality of life (QoL) assessments were removed from the complete simulated datasets, which have a positive relationship between QoL and disease-free survival (DFS) and delayed chemotherapy and DFS, by missing at random and missing not at random (MNAR) mechanisms. Standard imputation methods were applied before analysis. Method performance was influenced by missing data mechanism, with one exception for simple imputation. The greatest bias occurred under MNAR and large effect sizes. It is important to carefully investigate the missing data mechanism.

Imputing missing quality of life data as covariate in survival analysis of the International Breast Cancer Study Group Trials VI and VII

ABSTRACTQuality of life (QoL) was an important endpoint in the adjuvant breast cancer trials International Breast Cancer Study Group (IBCSG) Trial VI and VII. Here, QoL was considered as a time-dependent effect. The hypothesis explored is that poorer QoL throughout the trial is associated with poorer disease-free survival (DFS) and vice-versa. Potential bias in the parameter estimates is an important concern associated with missing observations. Standard simple and multiple imputation methods were applied to missing QoL assessments before analysis in a time-dependent Cox model. There was no evidence that the patient's QoL is related to the patient's DFS.

Timing of Radiation Therapy and Chemotherapy After Breast-Conserving Surgery for Node-Positive Breast Cancer: Long-Term Results From International Breast Cancer Study Group Trials VI and VII

To update the previous report from 2 randomized clinical trials, now with a median follow-up of 16years, to analyze the effect of radiation therapy timing on local failure and disease-free survival. From July 1986 to April 1993, International Breast Cancer Study Group trial VI randomly assigned 1475 pre-/perimenopausal women with node-positive breast cancer to receive 3 or 6 cycles of initial chemotherapy (CT). International Breast Cancer Study Group trial VII randomly assigned 1212 postmenopausal women with node-positive breast cancer to receive tamoxifen for 5years, or tamoxifen for 5years with 3 early cycles of initial CT. For patients who received breast-conserving surgery (BCS), radiation therapy (RT) was delayed until initial CT was completed; 4 or 7months after BCS for trial VI and 2 or 4months for trial VII. We compared RT timing groups among 433 patients on trial VI and 285 patients on trial VII who received BCS plus RT. Endpoints were local failure, regional/distant failure, and disease-free survival (DFS). Among pre-/perimenopausal patients there were no significant differences in disease-related outcomes. The 15-year DFS was 48.2% in the group allocated 3months initial CT and 44.9% in the group allocated 6months initial CT (hazard ratio [HR] 1.12; 95% confidence interval [CI] 0.87-1.45). Among postmenopausal patients, the 15-year DFS was 46.1% in the no-initial-CT group and 43.3% in the group allocated 3months initial CT (HR 1.11; 95% CI 0.82-1.51). Corresponding HRs for local failures were 0.94 (95% CI 0.61-1.46) in trial VI and 1.51 (95% CI 0.77-2.97) in trial VII. For regional/distant failures, the respective HRs were 1.15 (95% CI 0.80-1.63) and 1.08 (95% CI 0.69-1.68). This study confirms that, after more than 15years of follow-up, it isreasonable to delay radiation therapy until after the completion of standard CT.

Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V.

Predicting the pattern of recurrence can aid in the development of targeted surveillance and treatment strategies. We identified patient populations that remain at risk for an event at a median follow-up of 24 years from the diagnosis of operable breast cancer. International Breast Cancer Study Group clinical trials I to V randomly assigned 4,105 patients between 1978 and 1985. Annualized hazards were estimated for breast cancer-free interval (primary end point), disease-free survival, and overall survival. For the entire group, the annualized hazard of recurrence was highest during the first 5 years (10.4%), with a peak between years 1 and 2 (15.2%). During the first 5 years, patients with estrogen receptor (ER)--positive disease had a lower annualized hazard compared with those with ER-negative disease (9.9% v 11.5%; P = .01). However, beyond 5 years, patients with ER-positive disease had higher hazards (5 to 10 years: 5.4% v 3.3%; 10 to 15 years: 2.9% v 1.3%; 15 to 20 years: 2.8% v 1.2%; and 20 to 25 years: 1.3% v 1.4%; P < .001). Among patients with ER-positive disease, annualized hazards of recurrence remained elevated and fairly stable beyond 10 years, even for those with no axillary involvement (2.0%, 2.1%, and 1.1% for years 10 to 15, 15 to 20, and 20 to 25, respectively) and for those with one to three positive nodes (3.0%, 3.5%, and 1.5%, respectively). Patients with ER-positive breast cancer maintain a significant recurrence rate during extended follow up. Strategies for follow up and treatments to prevent recurrences may be most efficiently applied and studied in patients with ER-positive disease followed for a long period of time.

Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12

Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease-free survival (DFS) at 48- and 62-month follow-up in the ABCSG-12 trial. We present efficacy results of a final additional analysis after 94.4 months. Patients were premenopausal women who had undergone primary surgery for stage I/II estrogen-receptor-positive and/or progesterone-receptor-positive breast cancer with <10 positive lymph nodes, and were scheduled for standard goserelin therapy. All 1803 patients received goserelin (3.6 mg every 28 days) and were randomized to tamoxifen (20 mg/days) or anastrozole (1 mg/days), both with or without ZOL (4 mg every 6 months) for 3 years. The primary end point was DFS; recurrence-free survival and overall survival (OS) were secondary end points. After 94.4-month median follow-up (range, 0-114 months), relative risks of disease progression [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.60-0.99; P = 0.042] and of death (HR = 0.66; 95% CI 0.43-1.02; P = 0.064) are still reduced by ZOL although no longer significant at the predefined significance level. Overall, 251 DFS events and 86 deaths were reported. Absolute risk reductions with ZOL were 3.4% for DFS and 2.2% for OS. There was no DFS difference between tamoxifen alone versus anastrozole alone, but there was a pronounced higher risk of death for anastrozole-treated patients (HR = 1.63; 95% CI 1.05-1.45; P = 0.030). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. These final results from ABCSG 12 suggest that twice-yearly ZOL enhances the efficacy of adjuvant endocrine treatment, and this benefit is maintained long-term. NCT00295646 (http://www.clinicaltrials.gov/ct2/results?term=00295646).

Should We Embrace or Ablate Our Urge to (Ovarian) Suppress?

The quest to define optimal endocrine therapy for premenopausal women with early-stage breast cancer began more than 50 years ago but is still unfulfilled. Multiple strategies have emerged, including tamoxifen, ovarian function suppression (OFS) by surgery, luteinizing hormone–releasing hormone agonist or radiation, and combination strategies such as tamoxifen plus OFS or aromatase inhibitor plus OFS. An added confounder is that these strategies have frequently been assessed in the context of adjuvant chemotherapy, which is commonly used in premenopausal women and may have indirect endocrine effects because of chemotherapy-induced menopause. This complex landscape was reviewed in a 2011 American Society of Clinical Oncology (ASCO) endorsement of the 2010 Cancer Care Ontario guideline recommending against the routine use of OFS in addition to tamoxifen or chemotherapy and a 2014 ASCO guideline endorsing consideration of 10 years of tamoxifen for these young women with hormone-responsive disease. Against this backdrop, in the article that accompanies this editorial, Tevaarwerk et al report the final results of a phase III Eastern Cooperative Oncology Group trial (E-3193, INT-0142) in which 345 premenopausal women with lymph node–negative, hormone receptor–positive breast cancer measuring 3 cm were randomly assigned from 1994-1997 to receive 5 years of tamoxifen alone or 5 years of tamoxifen plus OFS; no chemotherapy was permitted. With a median follow-up of almost 10 years, there were no significant differences in the primary end points of disease-free survival (DFS; 87.9% v 89.7% P .62) or overall survival (95.2% v 97.6%; P .67). Secondary end points included toxicity and several patient-reported outcomes (PROs) including menopausal symptoms, sexual function, and health-related quality of life. These results suggest that tamoxifen plus OFS leads to increased toxicity, more menopausal symptoms, and reduced sexual function, peaking around year 3 and then diminishing over time. The strengths of this study include the importance of the question, the clean design that enabled the testing of hormone therapies in the absence of chemotherapy, the focus on hormone-responsive tumors, the balance between the arms, the long follow-up, and the assessment of PROs. The major limitation is, of course, that the study’s early closure as a result of poor accrual left it vastly underpowered for its primary end points; this trial fell victim to the 1997 report of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, which recommended the use of chemotherapy in addition to tamoxifen for women with axillary lymph node–negative, hormoneresponsive breast cancer, especially women younger than 50 years of age. However, E-3193 was a success in its collection of detailed PROs, and it is noteworthy that it met the prespecified target accrual for these secondary end points. Given the exceptional outcomes for patients enrolled onto this trial, which had greater than 95% overall survival in the absence of chemotherapy, such patient-reported data are valuable contributions to the discussion between physicians and patients about the risks and benefits of individual therapies. Several crucial questions remain. Given the statistical limitations of this trial, might the combination of OFS plus tamoxifen actually be better than tamoxifen? What about the combination of OFS plus an aromatase inhibitor, given the efficacy of aromatase inhibitors in postmenopausal hormone receptor–positive breast cancer? Three large trials are helping to address these two questions: ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12), SOFT (Suppression of Ovarian Function Trial), and TEXT (Tamoxifen and Exemestane Trial). A lingering concern is how we can integrate the results of all of these trials that use 3 to 5 years of adjuvant endocrine therapy with the findings of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (Adjuvant Tamoxifen—To Offer More?) trials, which support the use of 10 years of tamoxifen. In the SOFT trial, 3,066 premenopausal women with hormoneresponsive breast cancer were randomly assigned to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS; (neo)adjuvant chemotherapy was permitted as long as patients remained premenopausal at its completion. In the TEXT trial, 2,672 premenopausal patients with hormone-responsive breast cancer were randomly assigned to receive 5 years of tamoxifen plus OFS or exemestane plus OFS; endocrine therapy was started concurrently with chemotherapy if chemotherapy was planned. Because of lower than expected event rates, the statistical plans for these two trials were revised some years ago to enable a joint analysis of 4,690 women receiving tamoxifen plus OFS versus exemestane plus OFS. In contrast to E-3193, 42% of these women were lymph node positive, and 57% received some type of chemotherapy. At a median follow-up of 68 months, a significantly improved DFS was seen with exemestane plus OFS (91.1% v 87.3%; HR, 0.72; 95% CI, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1

Comparison of Treatments for HR+ Early Breast Cancer

This article presents the joint analysis of 2 randomized comparative trials coordinated by the International Breast Cancer Study Group, the Tamoxifen and Exemestane Trial [TEXT; NCT0006670] and the Suppression of Ovarian Function Trial [SOFT; NCT00066690]. The trials compared adjuvant exemestane plus ovarian function suppression versus tamoxifen plus ovarian function suppression in the treatment of premenopausal women with hormone receptor—positive (HR+) early breast cancer [Pagani O et al. J Clin Oncol 2014].

Abstract P1-08-13: Predictive value of intrinsic luminal subtypes in premenopausal women with endocrine-responsive early breast cancer: Results from Austrian breast and colorectal cancer study group trial 5

Abstract Purpose: The aim of the present study was to assess the predictive value of intrinsic luminal subtypes in premenopausal hormone receptor-positive early breast cancer patients who received adjuvant endocrine treatment or chemotherapy. Patients and Methods: Intrinsic luminal breast cancer subtypes were centrally assessed by immunohistochemistry on whole tissue sections of breast cancer patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 5 and received either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 &amp;lt;20%, Luminal B/HER2-negative subtype as Ki67≥20%. Luminal B/HER2-positive subtype displayed HER2 overexpression by IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathological factors. Results: 155 (36%), 217 (50%) and 59 (14%) of 431 tumors were classified as Luminal A, Luminal B/HER2-negative and Luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with Luminal B tumors had a significantly shorter RFS (adjusted hazard ratio [HR] for recurrence: 2.29, 95% confidence interval [CI] 1.44-3.64, P &amp;lt; 0.001) and OS (adjusted HR for death: 3.97, 95% CI 1.94-8.08, P &amp;lt; 0.001) as compared to patients with Luminal A disease. No interaction between intrinsic luminal subtypes and treatment was observed (test for interaction: P = 0.42 for RFS; P = 0.32 for OS). Combination endocrine treatment with goserelin/tamoxifen tended to be more effective than CMF chemotherapy in both luminal A and luminal B subtypes. Conclusion: Intrinsic luminal subtype is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor positive breast cancer but is not predictive for outcome of adjuvant treatment with either goserelin/tamoxifen or chemotherapy with CMF. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-13.

Impact of SERM adherence on treatment effect: International Breast Cancer Study Group Trials 13-93 and 14-93

The degree of adherence to oral anticancer agents may influence treatment efficacy. Tamoxifen and toremifene usage data from two International Breast Cancer Study Group (IBCSG) studies were used to evaluate the impact of treatment adherence on the efficacy of these two selective estrogen receptor modulators (SERMs). Between 1993 and 1999, IBCSG Trial 13-93 randomized premenopausal women with node-positive disease to tamoxifen or no endocrine therapy and IBCSG Trial 14-93 compared tamoxifen and toremifene in postmenopausal women with node-positive disease. 690 women with estrogen-receptor positive enrolled in these two trials were alive and disease-free 4years after the start of SERM. The median follow up for this analysis was 9.0years. Using a Kaplan-Meier landmark analysis at 4years, the 609 women completing at least 4years of SERM had improved 10-year disease-free survival (DFS) (71%) compared with the 81 women taking less than 4years (64%), but these differences did not reach statistical significance [DFS hazard ratio (<4year/4+year) 1.31, 95% CI 0.86-1.98), p value=0.20]. Women who completed less than 4years of SERM treatment (12%) appeared not to have achieved the full benefit from their therapy. These results suggest that more effort should be made to educate women regarding the benefits of a full course of treatment. This is especially important in light of the results of the recently reported ATLAS and aTTom trials which suggest a benefit of 10years of tamoxifen.

Axillary Dissection Can Be Avoided in the Majority of Clinically Node-Negative Patients Undergoing Breast-Conserving Therapy, by Dengel et al.

Since the presentation of the American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical trial results at the American Surgical Association 2010 meeting and the American Society of Clinical Oncology (ASCO) 2011 meeting with subsequent publications in Annals of Surgery and the Journal of the American Medical Association (JAMA), breast surgeons around the United States and indeed worldwide have been considering how to incorporate the results of this study into their clinical practice. Many breast surgeons are now forgoing axillary lymph node dissection (ALND) in selected patients undergoing breast conservation surgery (BCS) with one or two positive sentinel lymph nodes (SLN). There remains debate about what proportion of the clinical practice is subject to benefit from the Z0011 results. Even prior to the presentation of the Z0011 results, breast surgeons in the United States were increasingly avoiding ALND for those patients diagnosed with microscopic disease in the SLNs as documented both in the National Cancer Database (NCDB) as well as the Surveillance Epidemiology and End Results Registry (SEER). In the NCDB, use of SLN only in patients with micrometastatic disease increased from 25 % in 1998 to 45 % in 2005 and similarly in SEER from 21 % in 1998 to 38 % in 2004. Most recently, the results of the International Breast Cancer Study Group (IBCSG) trial 23-01, which also randomized patients with positive SLNs to ALND versus no ALND, were published. The IBCSG 23-01 study limited enrollment to patients with isolated tumor cells or micrometastatic disease; however, it did allow patients undergoing BCS or mastectomy. Interestingly, in the IBCSG 23-01 study design, 6681 patients were registered preoperatively and only 934 patients were randomized based on the operative findings. Thus, only 14 % of registered breast cancer patients met the inclusion criteria of this study. Unfortunately, the paper does not disclose the reasons for the 86 % not randomized, which is presumably mainly accounted for by node-negative patients and patients with positive SLNs with macrometastatic disease. In the manuscript entitled ‘‘Axillary Dissection Can Be Avoided in the Majority of Clinically Node-Negative Patients Undergoing Breast-Conserving Therapy,’’ the breast surgeons from Memorial Sloan-Kettering Cancer Center (MSKCC) describe their practice since adopting the Z0011 results. Over the 27-month time period from August 2010 to November 2012, they treated a total of 2,157 patients with invasive breast cancer who elected to undergo BCS for a clinical T1 or T2 breast cancer. Only 380 patients (17.6 %) were actually found to have histologic nodal metastasis and were therefore candidates for consideration of Z0011 results. Of these 380 patients, 93 did not meet Z0011 criteria because of SLN metastasis detected by immunohistochemistry only, conversion to mastectomy, or use of neoadjuvant chemotherapy. An additional 45 patients did not meet Z0011 criteria for axillary preservation (avoidance of ALND) because of the presence of metastases in more than two sentinel nodes, matted nodal disease, or extracapsular extension. Thus, overall 242 patients were able to avoid ALND as a result of incorporation of Z0011 results into the clinical practice. The authors report that ALND was avoided in 84 % of patients undergoing BCS (242 of 287). Society of Surgical Oncology 2013

Personalized adjuvant therapies: Lessons from the past: The opening address by the St. Gallen 2013 award recipient

For several decades, personalized adjuvant therapies have been prescribed based on features that predict response to specific types of treatment. In this summary four specific issues regarding adjuvant therapies are described. Each one developed using information from past experience and is ready to be challenged by future findings from clinical trials and maturation of follow-up data. 1) Accuracy of determination of steroid hormone receptors and of HER2-status was the key feature in International Breast Cancer Study Group (IBCSG) and Breast International Group (BIG) trials. 2) Investigations on ovarian function suppression in IBCSG clinical trials led to the design of two trials (SOFT and TEXT), which are likely to lead to improved adjuvant therapy for premenopausal women with breast cancer. 3) Data from the BIG 1–98 trial of letrozole vs tamoxifen for postmenopausal patients with endocrine-responsive breast cancer provided information on which patients might obtain increased benefit from aromatase inhibitors and which might achieve similar treatment outcome with tamoxifen alone. 4) Finally, low-dose, frequently administered cytotoxics (metronomic chemotherapy) were tested in advanced disease with surprisingly favorable disease control and very low incidence of side effects. Personalized treatments are likely to improve substantially with increasingly accurate determination of their targets and by using risk- and toxicity-modulated therapies.

Patterns of Recurrence and Outcome According to Breast Cancer Subtypes in Lymph Node–Negative Disease: Results From International Breast Cancer Study Group Trials VIII and IX

To retrospectively evaluate the pattern of recurrence and outcome of node-negative breast cancer (BC) according to major subtypes. In all, 1,951 patients with node-negative, early-stage BC randomly assigned in International Breast Cancer Study Group Trials VIII and IX with centrally reviewed pathology data were included. BC subtypes were defined as triple negative (TN; n = 310), human epidermal growth factor receptor 2 (HER2) positive (n = 369), and hormone receptor positive with high (luminal B-like [LB-like]; n = 763) or low (luminal A-like [LA-like]; n = 509) proliferative activity by Ki-67 labeling index. BC-free interval (BCFI) events were invasive BC recurrence in local, contralateral breast, nodal, bone, or visceral sites. Time to first site-specific recurrence was evaluated by using cumulative incidence and competing risks regression analysis. Median follow-up was 12.5 years. The 10-year BCFI was higher for patients with LA-like (86%) BC compared with LB-like (76%), HER2 (73%), and TN (71%; P < .001) BC. TN and HER2 cohorts had higher hazard of BCFI event in the first 4 years after diagnosis (pre-trastuzumab). LB-like cohorts had a continuously higher hazard of BCFI event over time compared with LA-like cohorts. Ten-year overall survival was higher for LA-like (89%) compared with LB-like (83%), HER2 (77%), and TN (75%; P < .001) BC. LB-like subtypes had higher rates of bone as first recurrence site than other subtypes (P = .005). Visceral recurrence as first site was lower for the LA-like subgroup, with similar incidence among the other subgroups when treated with chemotherapy (P = .003). BC subtypes have different distant recurrence patterns over time. Defining different patterns of BC recurrence can improve BC care through surveillance guidelines and can guide the design of clinical studies.

Axillary lymph node dissection in sentinel node positive breast cancer: is it necessary?

PURPOSE OF REVIEW: Sentinel lymph node biopsy (SLNB) has become a gold standard procedure for axillary lymph node evaluation in clinically node-negative patients. In those patients with positive SLNB, completion axillary lymph node dissection (ALND) has been routely performed. Recent clinical trials suggest that ALND is not necessary in some cases, even when the sentinel lymph node (SLN) is positive. The appropriate conditions under which ALND may be eliminated are defined in this review. RECENT FINDINGS: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial studied the impact of SLNB alone versus completion axillary node dissection (AND) on survival in clinically node-negative breast cancer patients undergoing partial mastectomy and whole breast irradiation who were found to have a positive SLN on pathological evaluation. Results of this study showed no survival advantage for complete AND in patients with one or two positive SLNs. In other words, those patients appeared to be treated safely without completion AND. SUMMARY: Despite the small sample size and limited stastical power and the relatively short median follow up for ACOSOG Z0011, many breast cancer teams no longer believe it mandatory to perform axillary dissection for patients with one or two positive SLNs. The results of other prospective randomized trials called After Mapping of the Axilla: Radiotherapy Or Surgery study and International Breast Cancer Study Group trial 23-01 study will be available soon, and may further change the confidence with which ALND is performed or eliminated.

Diagnostic and Therapeutic Implications of Tumor-Infiltrating Lymphocytes in Breast Cancer

In the age of personalized medicine, the multitude of scientific publications describing new biomarkers has raised a lot of criticism, as many of these results have been rather difficult to validate. As a consequence to this criticism, we are observing a considerable improvement in the design of clinical biomarker studies, which are increasingly based on large sample cohorts from clinical trials. The article by Loi et al that accompanies this editorial exemplifies this. Loi et al report a prognostic role for tumor-associated lymphocytes in triple-negative breast cancer in a large prospective clinical trial, evaluating more than 2,000 tumor samples from patients with nodepositive breast cancer treated within the Breast International Group (BIG) 02-98 trial. The main finding of the study was that in estrogen receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative breast cancer (n 256) an increased lymphocytic infiltrate was linked to a reduced relapse rate and improved survival. This association was independent of the type of chemotherapy and was not observed in hormone receptor–positive tumors (n 1,078). In the subgroup of HER2-positive tumors (n 297) there was a significant interaction with benefit from anthracycline-only chemotherapy. It should be noted, however, that trastuzumab was not part of the adjuvant treatment in BIG 2 to 98, which limits the interpretationof theresults intheHER2-positivesubset inthecontextofcurrent therapeutic approaches. The study by Loi et al shows that tumor-infiltrating lymphocytes can be evaluated as a distinctive histological parameter using the predefined standardized definitions of intratumoral lymphocytes, stromal lymphocytes and lymphocyte-predominant breast cancer (LPBC). We have evaluated the nearly identical parameters in tumor samples from the neoadjuvant GeparTrio study, with a slightly different definition of LPBC. In this study, we have shown that a pretherapeutic immunological infiltrate is a predictive factor for response to neoadjuvant therapy. In the neoadjuvant situation, an increased rate of pathological complete response was observed in different tumor subtypes including hormone receptor–positive tumors. In contrast, the survival effect in the study by Loi et al was present only in the triple-negative subgroup. This difference could be explained by the fact that pathological complete remission is a surrogate end point for survival for triple-negative, but not for hormone receptor–positive breast cancer. The results of this report are consistent with the functional model that is emerging from preclinical studies. Zitvogel et al has evaluated the interaction between tumor cells and the immune system in various cellular and animal models. From their research the concept is emerging that the response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. In a recent paper, it has been shown that in particular those cancer cells that are hyperploid become immunogenic due to an increased accumulation of calreticulin on the cell surface. Those results from preclinical models as well as translational studies suggest that the combination of standard chemotherapy with immunomodulatory concepts might be worth an evaluation in clinical trials. It should be noted that a similar prognostic effect of increased lymphocytic infiltrate in triple-negative tumors has been observed in another study by West et al using immunohistochemistry as well as gene expression analysis of inflammatory markers. Molecular immunological parameters, such as immunoglobulin kappa C and IL8 have been reported as prognostic parameters in breast cancer, suggesting that those parameters could form a basis for future molecular diagnostic tests. From a pathologist’s point of view, the concept of a tumor that has a predominant lymphocytic infiltrate is similar to the classical tumor type of medullary breast cancer that has been described by Moore and Foote already in 1949. In classical pathology several definitions for medullary breast cancer have been suggested including parameters such as a predominant lymphocytic infiltrate, a so-called syncytial cell architecture and a well-defined border of the tumor. It has been shown that this tumor type has a particularly good prognosis. However, true medullary carcinoma is extremely rare, a recent evaluation of 12,409 patients from International Breast Cancer Study Group trials has found only 127 medullary carcinomas (1%). In addition to medullary breast cancer, a prominent lymphoplasmacellular infiltrate is observed in certain types of hereditary breast cancer. Evaluation of tumor-associated lymphocytes by standard hematoxylin and eosin staining is extremely inexpensive and can be performed easily in the setting of the routine histopathological evaluation. Considering that medullary breast cancer is an old pathology concept and that tumor-associated lymphocytes are also relevant for BRCA-mutation–associated breast cancer, pathologists should perhaps get used to reporting this parameter as a part of the standard histological description of breast cancer. In addition, the parameters of stromal and intratumoral infiltrate should be added to the standard parameters evaluated in the context of clinical studies. This is already JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 7 MARCH 2013

CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

Controversy exists about CYP2D6 genotype and tamoxifen efficacy. A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30). In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.