Partridge, Ann H.

Abstract BACKGROUND Fertility can be diminished by adjuvant chemotherapy or by age-related decline in ovarian reserve in young women with breast cancer (BC). We sought to better understand the burden of concern about fertility, utilization of fertility preservation strategies, and the impact of fertility concerns on treatment decision-making among young women newly diagnosed with BC enrolled in a large multi-site study. METHODS The Young and Strong study was a cluster-randomized study that tested the effect of an educational and supportive care intervention for young women with BC (≤45) and their oncologists, at community and academic sites across the US. Patients were surveyed following diagnosis at enrollment (within 3 months of diagnosis), and at 3, 6 and 12 months thereafter. The surveys included sociodemographic and psychosocial measures (HADS anxiety and depression; Perceived Stress Scale), as well as a modified Fertility Issues Survey, which assessed fertility concerns and preservation. Treatment and tumor pathology data were abstracted from the medical record. Logistic regression was used to identify sociodemographic, clinical, and psychosocial factors that were associated with fertility concern. Variables with p ≤ 0.20 in univariable analyses were evaluated in the multivariable model using stepwise selection; variables achieving significance at p < 0.05 were included in the final model. RESULTS Of 467 women enrolled from 54 sites (14 academic, 40 community), 419 had evaluable data regarding treatment decision-making. Median age of participants at diagnosis was 40 yrs (range 22-45), 11% were African American, 80% were married/lived with a partner, and 75% had children. 35% of tumors were stage I, 51% stage II, and 14% stage III; 82% of women were treated with chemotherapy. At the time of treatment decision-making, 133 (32%) were concerned about fertility, varying by age, with fertility concern reported by 73%, 28% and 13% of those age ≤35, 36-40 and >40 (p<.01), respectively. 67 (16%) said their treatment decisions had been affected by fertility concerns, including 62 of the 133 (47%) with fertility concern. 12/419 (3%) chose one chemotherapy regimen over another, 4 (1%) chose not to take hormonal medication, and 32 (8%) chose or may choose to take it for less than 5 years. 251 (60%) reported having discussed fertility issues with their physician before starting therapy, including 117/133 (88%) of women with fertility concern. 29 (7%), including 27/133 (20%) of the concerned, took special steps to lessen the chance of infertility: 14 underwent cryopreservation of embryos, 14 cryopreservation of eggs and 12 took GnRH agonist or pursued other strategies. In the multivariable model, history of difficulty becoming pregnant (versus none, OR=3.86, 95%CI: 1.84-8.1) was associated with greater concern about fertility. Older age (OR=.75 per 1-year increase, 95%CI: 0.69-0.81) and having more than one child at diagnosis (versus never delivered, OR=0.14, 95%CI: 0.05-0.40) were associated with less concern about fertility. Race, being partnered, high-education, income, symptoms of depression, stress or anxiety at diagnosis, tumor stage, hormone receptor status and receipt of chemotherapy were not independently associated with concern about fertility in the multivariable model. CONCLUSION In a geographically and ethnically diverse study of young women with newly diagnosed BC in the U.S., many were concerned about fertility, with potential impact on their treatment decisions. For the majority of women, these concerns were discussed with their providers, though only a minority underwent fertility preservation strategies prior to treatment. Citation Format: Elisabeth Etaix, Yue Zheng, Shoshana Rosenberg, Kathryn J Ruddy, J Russel Hoverman, Karen M Emmons, Ann H Partridge. Fertility concerns and treatment decision-making among young women with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-17.

Abstract Background: Fear of cancer recurrence (FCR) is prevalent among breast cancer survivors and more intense in younger women. Given that FCR is a powerful determinant of quality of life and is associated with healthcare utilization, identifying who may be at risk for experiencing elevated FCR without resolution can inform the timing and targeting of interventions. Methods: Participants included women diagnosed (dx’d) at age ≤40 enrolled in the Young Women’s Breast Cancer Study, a multi-site prospective cohort surveyed at baseline and regularly in follow-up. Surveys include the 3-item Lasry Fear of Recurrence Index which measures the degree of concern about recurrence and current health using 4-point Likert response options that provide a score ranging from 3-12; higher scores indicate greater concern. Group-based trajectory modeling was used to classify distinct FCR patterns from baseline (median of 5 months from dx) through 3 years post-dx. Multinomial logistic regression was used to identify the associated patient (socio-demographics and BRCA status), disease (stage, ER/PR/HER2) and treatment (surgery, chemotherapy) characteristics associated with each trajectory. Variables significant at p<0.05 in univariable models were entered into the final multivariable model. Results: 965 women with Stages 0-III breast cancer were included in the analysis, with a median age at dx of 37. Participants were predominantly non-Hispanic White (85%), partnered (76%) and had completed college (84%). There was a significant decrease in median FCR scores from baseline to year 3 (9 vs. 8, Wilcoxon signed-rank test P<0.01). Five FCR trajectories (Table) were identified: 1) 10.5% of participants reported low/stable FCR from baseline over follow-up; 2) 33.1% had moderate FCR that improved over time; 3) 5.5% had moderate FCR scores at baseline that worsened over time; 4) 30% had high FCR scores at baseline that improved over time; 5) 20.8% had high FCR at baseline that remained high at all time points. In the fully adjusted multinomial model, younger age at dx and Stage 3 and 2 (vs. 1) disease were associated with higher odds of being in the high/stable trajectory. Having a lumpectomy (vs. mastectomy) was associated with higher odds of being in a high/stable as well as moderate/improving trajectory while White (vs. non-White) women had higher odds of being in a trajectory of improving FCR. Receipt of chemotherapy and financial discomfort were significantly associated with assignment to specific FCR trajectories in univariate analyses, however did not remain significant in the adjusted model. Being partnered, BRCA mutation status, and ER/PR/HER2 status were not significantly associated with any FCR trajectory classification in univariate or multivariate analyses. Conclusion: While FCR improves over time for many young women with breast cancer, a substantial minority (26%) had FCR that was severe and did not improve or worsened over time. Younger women with higher stage disease who are at risk for high levels of unresolved FCR may benefit from intervention including early referral to mental health professionals. Ongoing monitoring of women at risk for developing FCR following active treatment is warranted. Table Mean FCR score for each trajectoryBaselineYear 1Year 2Year 3TrajectoriesLow/Stable (N=103)5.725.605.545.45Moderate/Improving (N=331)7.907.487.287.09Moderate/Worsening (N=34)6.748.329.6410.54High/Improving (N=294)9.889.419.088.67High/Stable (N=203)11.0211.0811.0310.88 Citation Format: Lidia Schapira, Yue Zheng, Shari Gelber, Philip Poorvu, Kathryn J Ruddy, Rulla Tamini, Jeffrey Peppercorn, Steve Come, Virginia Borges, Ann Partridge, Shoshana Rosenberg. Trajectories of fear of cancer recurrence in young breast cancer survivors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-09.

Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI<3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-13-02.

11574 Background: Weight gain after cancer diagnosis is common in cancer survivors and has been linked to increased treatment toxicity, poor quality of life, and increased risk of second cancers and overall mortality. Young breast cancer (BC) survivors may be especially susceptible to weight changes given the impact of treatments such as chemotherapy and hormonal therapy on menopausal status. Methods: We identified women with Stage 0-III breast cancer diagnosed at ≤40 years (y) between 2006-2016 from a multi-center prospective cohort study. Clinical data including self-reported pre-diagnosis and follow-up weights were obtained using baseline and follow-up patient surveys. Participants missing baseline weight, pregnant at diagnosis/within 1y of diagnosis or with BC recurrence within 1y were excluded; those pregnant or with BC recurrence between 1-3y from diagnosis were excluded from the 3y analysis. Menopausal status at baseline and treatment-related amenorrhea (TRA) in follow-up were defined by self-reported last menstrual period. Factors associated with weight gain (>5%) were evaluated using univariate two-sided Fisher's exact test. Results: At baseline, 1y and 3y post diagnosis, 956, 899 and 687 women were eligible for analysis respectively. Median age at diagnosis was 37y (17 - 40), 65% received endocrine therapy and 74% chemotherapy. Premenopausal status was verified in 94% at baseline. Mean BMI at baseline was 24.4 (SD 5.3) kg/m2; 20% (187/956) were overweight and 12% (116/956) obese. At 1y and 3y, mean BMI increased modestly to 24.7 (SD 5.6) and 24.9 (SD 5.2), respectively with weight gain (>5%) observed in 18% (164/899) and 13% (87/687) respectively. 37% (300/804) and 32% (196/615) of eligible premenopausal subjects experienced TRA at 1y and 3y, respectively. Receipt of chemotherapy, receipt of endocrine therapy and TRA were not associated with weight gain at any timepoint. Conclusions: In this large prospective cohort of young BC survivors, mean BMI increased only modestly over time. Self-reported weight gain was not associated with treatment and not exacerbated by TRA. Further analysis to understand the effects of physical activity and other predictors of weight gain in this population are ongoing.

6025 Background: Blinding patients to treatment regimen is an important component of high quality randomized clinical trials although concern exists about how receipt of a placebo will impact participants’ views. In ECOG5103, patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo (arm A) or bevacizumab (arms B and C) and treatment assignment was unblinded by 24 weeks. We sought to determine if unblinding was associated with differential changes in participants’ views. Methods: The Decision-Making/Quality of Life component (DM-QOL) included all patients enrolling on E5103 between 1/5- 6/8/10. Women were surveyed pretreatment and after unblinding. Wilcoxon rank sum testing was used to examine differences. Results: 572 patients on DM-QOL started protocol therapy; 118 on arm A, 454 on arm B/C; the two groups (arm A vs. B/C) were well balanced. 516 patients participated in pretreatment, 514 in unblinding survey. Pretreatment, 32% reported >moderate chance of recurrence in 5 years, 27% >moderate chance of serious problem from treatment, 99% feeling at least somewhat informed, 98% at least somewhat confident in study participation, most “extremely” confident. Overall, median response scores did not change over time, with no statistically significant differences between the groups in changes in perceptions of: recurrence risk (p=0.45); chances of a serious problem (p=0.12), feeling informed (p=0.99). However, they differed in confidence about study participation (p=0.04): after unblinding, a higher % of placebo-treated patients had increased confidence (38% vs. 25%), and a higher % of bevacizumab-treated patients had decreased confidence (29% vs. 22%), although 44% across all arms had no change. Conclusions: In a placebo-controlled, double-blinded RCT, unblinding did not significantly affect most participants’ views, regardless of receipt of placebo or experimental drug. However, confidence in study participation may have been affected by knowledge of receipt of bevacizumab; publicity surrounding this experimental therapy may have affected results.

6527 Background: Biomarker information can risk stratify patients based on potential for benefits/toxicity from therapy. Ideally, a biomarker will identify those who benefit with limited toxicity. However, the impact of biomarkers is unclear when indicting individuals with greatest benefit are also at increased risk for toxicity. Methods: We surveyed participants at 18 month follow-up in the Decision-Making/Quality of Life (DM-QOL) component of ECOG5103, a RCT where patients were randomized to receive adjuvant chemotherapy for breast cancer with either placebo or bevacizumab (in 2 schedules). We asked patients for the preferred treatment in two hypothetical scenarios: 1) preference for chemo A or chemo A + B without biomarker information; 2) preference for chemo A or chemo A+B when participants tested positive for a “B-receptor” which increased both the benefit and toxicity of chemo A+B. McNemar’s test was used to examine changes in preferences. Results: 439 patients completed both scenarios on 18-month survey. The Table shows the treatment preferences in each scenario. The positive biomarker information in scenario 2 led 60/439 (14%) participants to switch their preference. The main reason for treatment preference in scenario 2 was greater benefits of chemo A+B (64%), the lower risks with chemo A (20%) and positive biomarker (10%). Among participants who changed preference, those randomized to receive bevacizumab were more likely to switch to chemo A in scenario 2. Conclusions: Information about a positive biomarker, indicating increased benefit and increased risk from additional chemo, did not significantly change participants’ preferred treatment. All participants were involved in a large placebo controlled double blind trial and the majority (70%) preferred the most aggressive course of treatment in both scenarios. Whether patients not enrolled in the trial would be more sensitive to the increased risk information is unclear. [Table: see text]

PURPOSE The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles. METHODS The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2− breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node–negative (N0) and limited node–positive (N1) breast cancer. RESULTS Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively. CONCLUSION The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.

PURPOSE Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

6575 Background: Delays in diagnosis (dx) and treatment (tx) affect breast cancer (BC) outcomes. We sought to identify factors associated with delays among young women, who do not undergo routine screening and often have pregnancy or breastfeeding-related breast changes that may mask a BC. Methods: The Young Women’s Breast Cancer Study is a multicenter, prospective cohort that enrolled 1302 women with newly dx BC age ≤40 between 2006-2016. Women reported the method and timing of cancer detection on the baseline survey. 231 were ineligible or excluded due to missing information. Among those reporting self-detected cancers, using multivariable regression we evaluated factors associated with delays ≥90 days (d) from symptom to presentation (self delay) and presentation to dx (care delay); in stage 0-III BC we evaluated delays ≥60d from dx to tx (tx delay). Results: 1071 eligible women had median age at dx of 37 yrs (17-40) and 74% reported self-detected cancers. Self delay or care delay ≥90d was reported in 17% and 13%, respectively. Factors inversely associated with self delay included pregnancy at dx (vs nulliparous, OR 0.10, CI 0.01-0.78) and perceived financial comfort (vs not, OR 0.62, CI 0.41-0.93). Women dx ≤1 year post-partum who breastfed (vs nulliparous, OR 2.60, CI 1.14-5.93) and those with a family history of breast/ovarian cancer (vs none, OR 1.79, CI 1.00-3.19) were more likely to have a care delay. Age was inversely associated with care delays (OR 0.94, CI 0.89-0.99). Tx delay was reported by 10% (105/1015), and associated with being single (vs partnered, OR 1.61, CI 1.02-2.56 ), non-white (vs white, OR 1.85, CI 1.09-3.13) and having Stage 0 BC (vs stage 1, OR: 3.08, CI 1.65-5.77); women with stage 3 BC (vs stage 1, OR 0.13, CI 0.03-0.56) were less likely to have a tx delay. Conclusions: In this cohort, most young women with BC underwent timely dx and tx initiation. Women dx ≤1 year post-partum who breastfed were more likely to experience a care delay, likely because lactational changes may mask BC signs and symptoms. The associations of perceived financial status with self delay and non-white race with tx delay underscore the need for additional support to ensure timely care for underserved populations with the goal of eliminating disparities in outcomes.

1049 Background: CALGB 40503 randomized HR+ MBC postmenopausal pts to Let alone or Let+Bev as first-line therapy. Adding Bev to Let prolonged progression-free survival (PFS) but not overall survival (OS) (Dickler JCO 2016). We performed a correlative study to assess prognostic and predictive value of CTCs in this population. Methods: Blood was collected prior to initiation of treatment. CTCs were enumerated using US FDA-cleared CellSearch assay; samples with ≥5 CTCs per 7.5 mLs of blood were considered CTC-positive (CTC+). Correlation of CTCs with PFS and OS was assessed using Cox regression analysis. Median follow-up was 39 months (mo). Results: Of 343 pts treated, 294 had CTC data and were included in this analysis. Original study results that showed improved PFS (HR = 0.75; 95% CI: 0.59-0.96) but not OS (HR = 0.87; 95% CI: 0.65-1.18) in pts receiving Let+Bev compared to Let were recapitulated in this subset. In multivariable analysis, CTC+ pts (31%) had significantly reduced PFS (HR = 1.49; 95% CI: 1.12-1.97) and OS (HR = 2.08; 95% CI: 1.49-2.93) compared to CTC- pts. Moreover, CTC+ pts who did not receive Bev had worse PFS (HR = 2.31; 95% CI: 1.54-3.47) and OS (HR = 2.64; 95% CI: 1.59-4.40) (Table). CTC+ pts who received Bev had numerically longer median PFS (18.0 vs. 7.0 mo) and OS (33.6 vs. 27.1 mo) compared to CTC+ pts with no Bev; however, tests for interaction between CTC status and Bev (yes vs. no) were not statistically significant for PFS (p=0.70) or OS (p=0.84). Conclusions: CTCs were highly prognostic in this study involving addition of Bev to first-line Let in postmenopausal HR+ MBC. Further research to determine the potential predictive value of CTCs in the setting of both metastatic disease and early breast cancer is warranted. Support: U10CA180821, U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00601900. Survival in HR+ MBC pts receiving Let or Let+Bev stratified by CTC status. Clinical trial information: NCT00601900. [Table: see text]