Distant Recurrence-free Interval Research Articles

CALGB (Alliance) 40603: Long-term outcomes (LTOs) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) and bevacizumab (Bev) in triple-negative breast cancer (TNBC).

591 Background: Both Cb and Bev demonstrate activity when combined with standard chemotherapy in TNBC. CALGB 40603 is a 2x2 randomized trial that previously demonstrated that adding Cb to NACT significantly increased pathologic complete responses in the breast/axilla (pCR), while adding Bev did not (Sikov, JCO 2015). Here we report 5-year LTOs and assess factors that influenced them. Methods: 443 patients with clinical stage II-III previously untreated TNBC received 12 weeks of paclitaxel (wP) +/- Cb then dose-dense AC, +/- Bev before surgery. The primary endpoint was pCR. Analyses of LTOs (event-free survival (EFS), distant recurrence-free interval (DRFI) and overall survival (OS)), impact of residual cancer burden and other variables were secondary. Results: Median follow-up was 5.7 years (y); 5y EFS was 70.9% (95% CI; 66.7%-75.4%), DRFI 76.3% (72.3%-80.5%) and OS 76.9% (72.9%-81.2%). Pretreatment clinical stage and achieving pCR correlated with LTOs, while age, race, subtype (basal-like vs. not) and tumor grade did not. Among pCR 5y EFS was 86.4% vs. 57.5% for non-pCR (HR 0.28, 0.19-0.43), OS was 88.7% vs 66.5% (HR = 0.28, 0.17-0.44). This relationship was similar in all trial arms. Any residual disease conferred poorer outcome; compared with pCR/Residual Cancer Burden (RCB) 0, EFS HRs were 2.29 (1.32-3.97), 3.01 (1.90-4.74), and 9.67 (5.66-16.51) for RCBI, II and III, respectively. There were no improvements in LTOs with Cb (EFS HR 0.99, 0.70-1.40) or Bev (EFS HR 0.91, 0.64-1.29). In an exploratory analysis, receipt of ≥11 doses of wP was associated with better EFS (HR 1.92, 1.33-2.77); this was particularly notable in Cb-treated arms. Conclusions: As expected, regardless of treatment arm pCR was associated with markedly better LTOs, and pts with any residual disease had significantly worse outcomes. The addition of Cb or Bev to standard NACT for TNBC did not improve LTOs in this trial, although it should be noted that the trial was not powered for this endpoint. Omission of chemotherapy doses may result in poorer outcomes, especially among Cb-treated pts, which may warrant further evaluation. Support: U10CA180821; U10CA180882; Genentech; https://acknowledgments.alliancefound.org ; NCT00861705 Clinical trial information: NCT00861705.

Cctg MA.39 tailor RT: A randomized trial of regional radiotherapy in biomarker low-risk node-positive breast cancer (NCT03488693).

TPS602 Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score < 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is < 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.

PCN216 ADJUVANT CHEMOTHERAPY GUIDED BY A 21-GENE EXPRESSION ASSAY IN HORMONE-RECEPTOR POSITIVE EARLY-STAGE BREAST CANCER: USE OF SIMULATION MODELING TO EXTEND AND TRANSLATE CLINICAL TRIAL RESULTS INTO PRACTICE

Translation of clinical trial findings in to practice requires information on variation of trial results in real-world settings and outcomes beyond trial follow-up. We developed a simulation model to extend the "Trial Assigning IndividuaLized Options for Treatment” (TAILORx) and examine long-term outcomes and variation of trial findings for clinically-relevant subgroups of women. We conducted an empirical Bayesian analysis with a Monte Carlo sampling method for probabilistic sensitivity analysis using data independent of TAILORx. Women eligible were diagnosed with HER2-, hormone receptor positive (HR+), node–negative breast cancer and recurrence scores (RS) between 11-25. The trial was also simulated for alternative RS categories including 11-30, 18-30, and 26-30. Women were followed up to 20-years to assess long-term outcomes. Input parameters were derived from SEER, Oxford Overview and published data. Hazard ratios (HRs) of no-chemo vs chemo were estimated using Cox models. To assess predictive validity of the trial simulations, we compared estimates for each trial endpoint (invasive disease-free interval (iDFI) and distant recurrence-free interval interval (DRFI)) with TAILORx published results. The HRs for no-chemo vs. chemo for 9 and 20-year iDFI and DRFI were not statistically significant in the 11-25 and 18-30 RS groups. Majority (72%) of the simulations showed that omission of chemotherapy resulted in a statistically significant decrease in the 9-year iDFI rate among women with RS 26-30. The results varied by age. On average, simulated results were similar to the published TAILORx findings at 9-years in the RS 11-25 group. The model projections show that long-term recurrence rates remain low with omission of chemotherapy among women diagnosed with node-negative, HR+ breast cancer and RS 11-25 and 18-30. Chemotherapy may show some benefit in reducing recurrence risk in RS 26-30 category. Simulation modeling can be used to extend trial data by synthesizing information from historical trials.

Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone

PurposeEndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C).MethodsA total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses.ResultsEPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49–3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99–2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P-interaction = 0.022).ConclusionsIn this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.

Screening for distant metastases in patients with ipsilateral breast tumor recurrence: the impact of different imaging modalities on distant recurrence-free interval

PurposeIn patients with ipsilateral breast tumor recurrence (IBTR), the detection of distant disease determines whether the intention of the treatment is curative or palliative. Therefore, adequate preoperative staging is imperative for optimal treatment planning. The aim of this study is to evaluate the impact of conventional imaging techniques, including chest X-ray and/or CT thorax-(abdomen), liver ultrasonography(US), and skeletal scintigraphy, on the distant recurrence-free interval (DRFI) in patients with IBTR, and to compare conventional imaging with 18F-FDG PET-CT or no imaging at all.MethodsThis study was exclusively based on the information available at time of diagnoses of IBTR. To adjust for differences in baseline characteristics between the three imaging groups, a propensity score (PS) weighted method was used.ResultsOf the 495 patients included in the study, 229 (46.3%) were staged with conventional imaging, 89 patients (19.8%) were staged with 18F-FDG PET-CT, and in 168 of the patients (33.9%) no imaging was used (N = 168). After a follow-up of approximately 5 years, 14.5% of all patients developed a distant recurrence as first event after IBTR. After adjusting for the PS weights, the Cox regression analyses showed that the different staging methods had no significant impact on the DRFI.ConclusionsThis study showed a wide variation in the use of imaging modalities for staging IBTR patients in the Netherlands. After using PS weighting, no statistically significant impact of the different imaging modalities on DRFI was shown. Based on these results, it is not possible to recommend staging for distant metastases using 18F-FDG PET-CT over conventional imaging techniques.

Prognostic value of tumor cell DNA content determined by flow cytometry using formalin-fixed paraffin-embedded breast cancer tissues.

The use of formalin-fixed paraffin-embedded (FFPE) tumor tissues in flow cytometry (FCM)-based determination of tumor cell DNA content is more complicated than the use of fresh-frozen tissues. This study aimed to accurately measure tumor cell DNA content from FFPE tissues by separating tumor cells from stromal cells through FCM and investigating its prognostic impact. We separately measured the DNA contents of tumor cells and stromal cells by gating with pan-cytokeratin and vimentin (FCMC/V). We evaluated tumor cell DNA contents [DNA index (DI)] of 290 FFPE tumor tissues and classified them into low and high DI groups, using a cutoff DI value determined through an unbiased computational method. The distribution of DI was bimodal, and a cutoff value was determined at a DI of 1.26. The high-DI tumors were associated with aggressive phenotypes and had significantly worse distant recurrence-free intervals (DRFI) than low-DI tumors. Multivariate analysis revealed that lymph node metastasis, Ki67, and DI were independent factors affecting DRFI. Accordingly, patients with low-DI/low-Ki67 tumors had excellent outcomes compared with other tumor types. Multiploid tumors were associated with increased lymphocytic infiltration and aggressive phenotypes. The DI of FFPE tumors could be precisely determined through FCMC/V. A combination of DI and Ki67 analyses may be able to predict the prognoses of breast cancer patients with greater accuracy.

Abstract P4-14-02: Analysis of DRFI and OS of HR-positive, HER2-negative breast cancer patients treated on the BIG1-98 study, classified according to a novel, integrated, clinical-pathologic and genomic classification method

Abstract Background and Objectives HRpos, HER2neg early breast cancer is molecularly heterogeneous. Classifications that integrate genetic, genomic and clinical-pathologic data (nodal status, tumour size, tumour differentiation, Ki-67 status, PR expression) are lacking. In a previous study we have defined three different molecular groups of invasive ductal luminal breast cancer (IDLBC) using clinical prognostic variables, gene expression, copy number variation and mutation data from the METABRIC series [1, 2] and showed that IDLBC groups (IDLBC1, -2, -3) had distinct prognostic outcomes [3, 4]. The 3 groups differ by DNA damage load, predominant lesion type, characteristic lesion patterns, oncogenic driver mechanisms and time to first recurrence. Here we evaluated the prognostic and predictive value of these groups on patients treated on the BIG1-98 study. Methods We used our predefined subgroups (IDLBC1, -2, -3) to classify patients in the BIG1-98 set [5, 6]. A weighted Cox proportional hazards regression model was used to assess the association between IDLBC subtype, treatment on OS and DRFI endpoints in the BIG1-98 study. Weighted chi-squared tests were used for categorical variables and weighted t-tests for mutational burden. All statistical computations were carried out in R v.3.2.3. Results Five hundred thirty eight breast cancers (ductal 75%, lobular 17%, 8% other) were included in this study. The DNA damage burden of IDLBC1 or -2 type tumours was significantly lower compared to IDLBC3 (mean lesion numbers: 9, 11, 18.5). IDLBC1 type tumours (48%) harboured mainly oncogenic point mutations (predominantly PIK3CA 51%, MAP3K1 27%, NCOR1 22%, FANCD2 20%). IDLBC2 (34%) and IDLBC3 type tumours (18%) were both mutated (PIK3CA 53% vs 38%, GATA3 12% vs 30%, TP53 10% vs 37%, CDH1 20% vs 8%), 8p11-12 (IDLBC3 38% vs IDLBC2 21% or IDLBC1 5%, p value &amp;lt; 0.001) and/or 11q13-14 amplified (IDLBC3 46% vs IDLBC2 28% or IDLBC1 2%, p value &amp;lt; 0.001). Consistent with the higher DNA damage load patients with IDLBC3 type tumours had significantly shorter distant recurrence free intervals (DRFI) (HR (95% CI) 2.35 [1.99; 2.78] p-value= &amp;lt;2e-16) and significantly shorter OS compared to IDLBC1 or -2 (HR (95% CI) 2.55 [2.2; 2.96] p-value= &amp;lt;2e-16). Patients with IDLBC1 or -2 type tumours seemed to have the same survival regardless of hormonal treatment assignment. However, the IDLBC3 group derived greater magnitude of benefit from Letrozole compared to Tamoxifen (HR (95% CI): DRFI 0.85 [0.66; 1.09] vs. 0.53 [0.35; 0.79] interaction p-value=0.03, OS 0.98 [0.8; 1.21] vs 0.34 [0.25; 0.47], interaction p-value=2.5e-09). Conclusions We have validated our integrated clinical-pathologic and genomic classification method on an independent dataset of HRpos, HER2neg early stage breast cancer. Our classification also suggests differing magnitude of benefit for adjuvant Letrozole benefit. Prospective clinical studies will be required to validate and corroborate this novel classification approach.

Abstract P2-08-04: Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET)

Abstract Background: EndoPredict (EPclin) is a validated prognostic test combining expression of 12 cancer-related genes for breast cancer patients with estrogen receptor (ER) positive, HER2-negative disease who received 5 years of endocrine therapy (Buus et al., 2017; Dubsky et al. 2012) and for women who received chemotherapy (Martin et al., 2014). Here, we determine the EPclin and 10-year distant recurrence free interval (DRFI) rates for patients who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) using data from five large clinical trials. Methods: A total of 3746 women with ER-positive, HER2-negative disease were included in this analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET+C (GEICAM 2003-02/9906). EPclin incorporates tumor size and nodal status and accounts for different EPClin scores between ET+C and ET alone cohorts. The primary objective was to evaluate the 10-year DRFI rates as a continuous function of EPclin separately for patients in ET+C and ET. Secondary objectives included assessing the difference in the prognostic ability of EPclin between ET+C and ET overall (years 0-10) and for specific follow-up periods (years 0-5 and years 5-10). The primary endpoint was DRFI and the secondary endpoint was breast cancer free interval (BCFI). Cox proportional hazard models were used to estimate 10-year DRFI rates and to assess the prognostic information provided by EPclin. Results: All of the women on ET alone and 49% of those on ET+C were postmenopausal. Women who received ET+C had more node positive disease, more poorly differentiated tumours, and higher EPclin scores than those who received ET alone. Women who received ET+C had significantly smaller increases in 10-year DRFI rates with increasing EPclin score than those receiving ET alone (Table). EPclin was highly prognostic for DRFI in all women who received ET alone (HR=2.79 (2.49-3.13), P&amp;lt;0.0001) as well as in those who received ET+C (HR=2.27 (1.99-2.59), P&amp;lt;0.0001), both in the overall cohort and in postmenopausal women only (ET+C: HR=2.64 (2.07-3.37), P&amp;lt;0.0001). We observed a significant interaction between EPclin and treatment for DRFI at 10 years (Pinteraction=0.022). EPclin was highly prognostic in ET alone and ET+C in years 0-5 and in particular in years 5-10. Similar results were observed when BCFI was the endpoint. Conclusion: In our results from a non-randomized analysis, we observed significantly smaller increases in 10-year DRFI rates with increasing EPclin scores for women who received ET+C compared to those who received ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease. 10-year DRFI risks (%) (95% CI) according to EPclin score for patients who received ET+C versus ET alone. ET+CETEPclin10-year DR risk (%)10-year DR risk (%)11.1% (0.5-1.7)1.0% (0.6-1.4)22.5% (1.5-3.5)2.8% (2.1-3.5)35.7% (4.1-7.2)7.6% (6.4-8.8)412.4% (10.1-14.6)19.8% (17.6-22.0)525.8% (22.0-29.5)46.1% (40.2-51.4) Citation Format: Sestak I, Martin M, Dubsky P, Rojo F, Cuzick J, Filipits M, Ruiz A, Buus R, Hlauschek D, Rodriguez-Lescure A, Dowsett M, Gnant M. Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-04.

Abstract P2-08-07: Prognostic impact of the 21-gene recurrence score assay among young women with node-negative and node-positive ER+/HER2- breast cancer

Abstract Background: The 21-gene Recurrence Score (RS) assay is prognostic among women with early-stage estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) and is used to select patients for chemotherapy (CT). Young women (age &amp;lt;40) have represented a minority in studies evaluating gene expression assays, including TAILORx, and additional data in young women are needed. Methods: In the Young Women's Breast Cancer Study, a prospective cohort study of women diagnosed with BC at age &amp;lt;40 enrolling between 2006-2016 (N=1302), we identified those with stage I-III ER+/HER2- BC. Disease and treatment information were obtained through serial surveys and medical record review. The RS was performed on banked specimens for those not tested clinically. Distant recurrence free interval (DRFI), defined as distant recurrence or BC specific death, by risk group was assessed using Cox regression and Kaplan-Meier survival estimates. Outcomes by receipt of CT were explored in the RS 11-25 group, and due to small number of events, reported descriptively. 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 years. Median age at diagnosis was 37, most had N0 BC (300/509, 59%), and the majority had RS 11-25 (306/509, 60%). RS result was significantly associated with DRFI in N0 BC, with hazard ratio (HR) (95% CI) of 0.29 (0.07,1.30) and 0.21 (0.09,0.50) for RS&amp;lt;11 and RS 11-25, respectively, relative to RS&amp;gt;26 (and trended towards significance in N1 BC). Results were similar using conventional RS groups. Among women with N0 BC and RS 11-25, 44% received CT, with two events in the 86 receiving CT (2.3%) and 6 events in the 109 without CT (5.5%); 5/8 (63%) occurred in those with RS 20-25. Table 1 N0N1Total Cohort N%N%N% 3005916332509100Median Age37.137.537.2Tumor Stage T120869694229358T28227784817635T3103159357T4001151Grade I4716855711II16555794926652III8829754618536Not assessed 1 1 PR status by IHC Negative (&amp;lt;1%)2071710398Positive (&amp;gt;=1%)280931469047092Chemotherapy No1414712715430Yes159531519335570Ovarian Suppression No263881499145289Yes37121495711TAILORx RS Groups RS &amp;lt;1133111495411RS 11-2519565885430660RS &amp;gt;=267224613714929Conventional RS Groups RS &amp;lt;1812742543319939RS 18-3012542694221142RS &amp;gt;=31481640259919 Table 2 6-year freedom from distant recurrence or breast cancer deathDRFI HR (95% CI) N0N1N0N1TAILORx RS Groups RS &amp;lt;1194.4%92.3%0.29 (0.07,1.30)0.21 (0.03,1.61)RS 11-2596.9%85.2%0.21 (0.09, 0.50)0.55 (0.27,1.12)RS &amp;gt;=2685.1%71.3%RefRefConventional RS Groups RS &amp;lt;1897.5%85.9%0.19 (0.06,0.59)0.31 (0.13,0.74)RS 18-3093.1%87.3%0.39 (0.16,1.00)0.32 (0.14,0.73)RS &amp;gt;=3186.4%62.8%RefRef Conclusions: The RS is prognostic among young women with node-negative and node-positive BC, and is a valuable tool for risk stratification. Disease outcomes among young women with N0 disease and RS 11-25, a minority of whom received CT, are very good. Evaluation of the effect of ovarian suppression/CT-induced amenorrhea by RS/treatment strata is ongoing. Citation Format: Poorvu PD, Gelber SI, Rosenberg SM, Ruddy KJ, Tamimi RM, Collins LC, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Jakubowski DM, Russell C, Winer EP, Partridge AH. Prognostic impact of the 21-gene recurrence score assay among young women with node-negative and node-positive ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-07.

Abstract GS1-10: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE

Abstract Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p&amp;lt;0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p&amp;lt;0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-10.

Abstract OT2-04-03: Examining personalized radiation therapy (EXPERT): A randomised phase III trial of adjuvant radiotherapy vs observation in patients with molecularly characterized luminal A breast cancer

Abstract Background Radiation therapy (RT) after breast conserving surgery (BCS) is the current standard of care for patients with early stage breast cancer. However, individual absolute recurrence risks and hence benefits of RT vary substantially. A study showed significant association between local recurrence (LR) risk and PAM50-defined intrinsic subtypes and Risk of Recurrence scores (ROR).1 The objective of EXPERT, a co-lead study of Breast Cancer Trials-Australia &amp; New Zealand (BCT-ANZ), and Breast International Group (BIG), is to optimize local therapy for early breast cancer through precise individualized quantification of LR risk to identify patients for whom RT after BCS may be safely omitted. Trial design This is a randomized, non-inferiority, phase III study of women who plan to receive adjuvant endocrine therapy for Prosigna (PAM50)-defined luminal A breast cancer with ROR ≤60 resected by BCS. Women are randomized to receive adjuvant whole breast RT and endocrine therapy or endocrine therapy alone and followed-up for 10 years after randomization. Major eligibility criteria Females aged ≥50 years; histologically confirmed invasive breast carcinoma ≤2 cm, grade 1 or 2, ER and PgR ≥10%, HER2-negative and node-negative; treated by BCS with negative margins for invasive carcinoma and associated DCIS; Prosigna (PAM50)-defined Luminal A subtype and ROR ≤60; and plan to receive adjuvant endocrine therapy. Specific aims Primary: To determine if omission of RT is not inferior to RT in terms of LR-free interval after BCS. Secondary: To evaluate the impact of omission of RT on regional, local-regional and distant recurrence-free interval; disease-free survival (DFS); invasive DFS; overall survival; salvage RT or mastectomy rate; toxicity; endocrine therapy adherence; patient reported outcomes; and health economic outcomes. Statistical methods An estimated 5-year LR rate in the target population is expected to be 1% with RT. A rate of 4% is considered non-inferior as a worthwhile trade-off against RT toxicity. Using O'Brien-Fleming boundary for rejecting non-inferiority, 29 LR events are required for final analysis expected 8 years after the first patient is randomized. Two interim analyses will be conducted after 10 and 21 events. If the stratified log-rank test statistic exceeds the upper boundary at interim or final analysis, the hypothesis of non-inferiority will be rejected and it will be concluded that no RT is inferior to RT. Accrual: Target (1170), actual: 82 (June 2018) The study was activated in Australia in August 2017, with global activation planned for Q4 2018. Recruitment is expected to be completed in 4.5 years. Contact information Professor Boon Chua, UNSW Sydney and Prince of Wales Hospital, NSW, Australia; email boon.chua@health.nsw.gov.au; T +61 2 49255239. Registration: NCT02889874 References Fitzal F, Filipits M, Fesl C, et al. Predicting local recurrence using PAM50 in postmenopausal endocrine responsive breast cancer patients. JCO 2014;32(15 suppl):1008. Citation Format: Chua BH, Gray K, Krishnasamy M, Regan M, Zdenkowski N, Loi S, Mann B, Forbes JF, Wilcken N, Spillane A, Martin A, Badger H, Jafari S, Fong A, Mavin C, Corachan S, Arahmani A, Martinez J-L, Francis P. Examining personalized radiation therapy (EXPERT): A randomised phase III trial of adjuvant radiotherapy vs observation in patients with molecularly characterized luminal A breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-04-03.

Effects of adjuvant tamoxifen over three decades on breast cancer–free and distant recurrence–free interval among premenopausal women with oestrogen receptor–positive breast cancer randomised in the Swedish SBII:2pre trial

AimsThe primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)–positive tumours, regarding breast cancer–free interval (BCFi) and distant recurrence–free interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence. MethodsPremenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers. ResultsThe median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of <20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61–0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47–0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54–0.99, p = 0.043). The positive effect on BCFi was significant also for the interval >15–30 years (HR = 0.53, 95% CI 0.28–0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n = 165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35–0.96, p = 0.035), whereas no differences were observed regarding other secondary malignancies. ConclusionsWith three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancer–related events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence.

Metastatic breast cancer incidence, site and survival in Australia, 2001–2016: a population-based health record linkage study protocol

IntroductionAdvances in systemic therapy for early and metastatic breast cancer (BC) over the last two decades have improved patients’ survival, but their impact on metastatic disease outcomes at a population...

Evaluation of non-genomic, clinical risk and survival results in endocrine-sensitive, HER2-negative, lymph node negative breast cancer

Background and objectivesIn endocrine-sensitive, HER2 negative, node negative breast cancer, the presence of a low genomic risk allows treatment with adjuvant endocrine therapy alone, obtaining excellent survival rates. The justification for this study is to show that excellent survival rates are also obtained by treating with adjuvant hormone therapy alone, based on clinical risk assessment. Patients and methodsA descriptive, observational and retrospective study was performed between 2006 and 2016 with endocrine-sensitive, HER2 negative, node negative breast cancer, greater than 1cm or between 0.6 and 1cm with unfavourable features. Retrospective review of health records. Mortality data of the National Registry of Deaths. ResultsA total of 203 patients were evaluable for survival. One hundred and twenty-three (60.50%) were treated with adjuvant endocrine therapy alone, 77 (37.90%) with chemotherapy and endocrine therapy, one (0.50%) with chemotherapy alone and 2 (1%) were not treated. The overall survival rate at 5 years was 97% (95% confidence interval [CI] 94–100). Distant recurrence-free interval was 94% (95% CI 90–98). In the subgroup of patients treated with endocrine therapy alone, overall survival and distant recurrence-free interval rates at 5 years were 98% (95% CI 95–100) and 97% (95% CI 93–100), respectively. ConclusionsPatients with endocrine-sensitive, HER2-negative, node negative breast cancer treated with endocrine therapy alone according to their clinical risk have similar survival outcomes as those treated with endocrine therapy according to their genomic risk.

21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer

The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18–30, ≥31, and the TAILORx cutoffs: <11, 11–25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan–Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18–30 groups, 1.7 and 6.7% were HER2 positive. In the RS ≥ 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rank P = 0.06), but substantial benefit from chemotherapy remained in the RS ≥ 31 cohort (HR = 0.18; 95% CI: 0.07–0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12–0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx.

Prognostic Value of the Progesterone Receptor by Subtype in Patients with Estrogen Receptor-Positive, HER-2 Negative Breast Cancer.

In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER-2) negative breast cancers, the progesterone receptor (PR) is an independent prognostic marker. Little is known about the prognostic value of PR by tumor grade. We assessed this in two independent datasets. Women with primary operable, invasive ER+ HER-2 negative breast cancer diagnosed between 2000 and 2012, treated at University Hospitals Leuven, were included. We assessed the association of PR status and subtype (grade 1-2 vs. grade 3) with distant recurrence-free interval (DRFI) and breast cancer-specific survival. The interaction between PR status and subtype was investigated, and associations of PR status by subtype were calculated. The BIG 1-98 data set was used for validation. In total, 4,228 patients from Leuven and 5,419 from BIG 1-98 were analyzed. In the Leuven cohort, the adjusted hazard ratio (HR) of PR-positive versus PR-negative tumors for DRFI was 0.66 (95% confidence interval [CI], 0.50-0.89). For the interaction with subtype (p = .34), the HR of PR status was 0.79 (95% CI, 0.61-1.01) in luminal A-like and 0.59 (95% CI, 0.46-0.76) in luminal B-like tumors. In luminal A-like tumors, observed 5-year cumulative incidences of distant recurrence were 4.1% for PR-negative and 2.8% for PR-positive tumors, and in luminal B-like 18.7% and 9.2%, respectively. In the BIG 1-98 cohort, similar results were observed; for the interaction with subtype (p = .12), the adjusted HR of PR status for DRFI was 0.88 (95% CI, 0.57-1.35) in luminal A-like and 0.58 (95% CI, 0.43-0.77) in luminal B-like tumors. Observed 5-year cumulative incidences were similar. PR positivity may be more protective against metastatic relapse in luminal B-like versus luminal A-like breast cancer, but no strong conclusions can be made. In absolute risk, results suggest an absent PR is clinically more important in high compared with low proliferative ER+ HER-2 negative tumors. An absent progesterone receptor (PR) predicts a worse outcome in women treated for an estrogen receptor-positive, human epidermal growth factor receptor 2 negative breast cancer. As low proliferative tumors lacking PR are now also classified high risk, the prognostic value of PR across risk groups was studied. Despite a negative test for interaction of the prognostic value of PR by tumor grade, the magnitude of an absent PR on breast cancer relapse is much larger in high than in low proliferative breast cancers.

EarlyR: A Robust Gene Expression Signature for Predicting Outcomes of Estrogen Receptor–Positive Breast Cancer

IntroductionEarly stage estrogen receptor (ER)-positive breast cancer may be treated with chemotherapy in addition to hormone therapy. Currently available molecular signatures assess the risk of recurrence and the benefit of chemotherapy; however, these tests may have large intermediate risk groups, limiting their usefulness. MethodsThe EarlyR prognostic score was developed using integrative analysis of microarray data sets and formalin-fixed, paraffin-embedded–based quantitative real-time PCR assay and validated in Affymetrix data sets and METABRIC cohort using Cox proportional hazards models and Kaplan-Meier survival analysis. Concordance index was used to measure the probability of prognostic score agreement with outcome. ResultsThe EarlyR score and categorical risk strata (EarlyR-Low, EarlyR-Int, EarlyR-High) derived from expression of ESPL1, MKI67, SPAG5, PLK1 and PGR was prognostic of 8-year distant recurrence-free interval in Affymetrix (categorical P = 3.5 × 10−14; continuous P = 8.8 × 10−15) and METABRIC (categorical P < 2.2 × 10−16; continuous P < 10−16) data sets of ER+ breast cancer. Similar results were observed for the breast cancer–free interval end point. At most 13% of patients were intermediate risk and at least 66% patients were low risk in both ER+ cohorts. The EarlyR score was significantly prognostic (distant recurrence-free interval; P < .001) in both lymph node–negative and lymph node–positive patients and was independent from clinical factors. EarlyR and surrogates of current molecular signatures were comparable in prognostic significance by concordance index. ConclusionThe 5-gene EarlyR score is a robust prognostic assay that identified significantly fewer patients as intermediate risk and more as low risk than currently available assays. Further validation of the assay in clinical trial–derived cohorts is ongoing.

Abstract 4207: Androgen receptor expression and ER+ breast cancer prognosis in the BIG 1-98 trial

Abstract Background The androgen receptor (AR) is emerging as a potential biomarker of breast cancer prognosis and therapeutic target. AR is expressed in 60-80% of breast cancers, with higher prevalence among estrogen receptor (ER) positive tumors. Treatment with dihydrotestosterone has been found to inhibit ER signaling in ER+/AR+ breast cancer cell lines, and epidemiologic studies have shown AR expression to be associated with improved survival among women with ER+ breast cancer. However, it is unknown if AR expression modifies the efficacy of selective ER modulators or aromatase inhibitors in patients with ER+ cancers. Methods We evaluated AR expression among 3,103 postmenopausal patients with ER+ breast cancer in the Breast International Group (BIG) 1-98 trial (NCT00004205). The BIG 1-98 study was a four-armed randomized double-blind phase III clinical trial that compared 5 years of tamoxifen or letrozole monotherapy, or sequences of 2 years and 3 years treatment with one drug and then the other. Tissue microarrays were constructed from tumor tissue from trial participants. AR expression was measured by immunohistochemistry and the percentage of AR positive nuclei was digitally quantified. The association between AR expression and prognosis was evaluated through use of Cox proportional hazards models, adjusting for patient, tumor, and treatment factors. Continuous AR-by-treatment interactions were assessed by use of Subpopulation Treatment Effect Pattern Plots (STEPP). Results In the univariate Kaplan-Meier analysis, AR expression (≥1% vs. &amp;lt;1%) was associated with longer breast cancer-free interval (247 events) over a median 8.2 years (IQR: 7.3-9.1) of follow-up (p=0.029 from log-rank test). Patients with AR+ cancers were more likely to have smaller, lower-grade tumors, as well as tumors with greater ER and PR expression and lower Ki67 expression. However, upon adjustment for patient, tumor, and treatment factors, AR expression (≥1% vs. &amp;lt;1%) was not associated with breast cancer-free interval (HR=1.06, 95% CI 0.82-1.36). A 10% increase in AR expression similarly did not predict breast cancer-free interval (HR=1.02, 95% CI 0.96-1.07). The letrozole vs. tamoxifen treatment effect was non-significantly stronger among AR- tumors (HR=0.42, 95% CI 0.24-0.74) than among AR+ tumors (HR=0.65, 95% CI 0.48-0.87). STEPP analysis also suggested no heterogeneity of treatment effect across the continuum of AR expression (p=0.280). Findings were likewise null when evaluating the secondary endpoints of distant recurrence free interval, disease free survival, and overall survival. Conclusions After adjustment for tumor characteristics, AR expression did not predict prognosis among postmenopausal patients with ER+ breast cancer, nor did it modify the effect of tamoxifen or letrozole treatment. These findings suggest that AR expression may not be an informative biomarker for the treatment of postmenopausal ER+ breast cancers. Citation Format: Kevin H. Kensler, Meredith M. Regan, Yujing J. Heng, Michael E. Pyle, Stuart J. Schnitt, Beat Thürlimann, Giuseppe Viale, Marco Colleoni, Myles Brown, Rulla M. Tamimi. Androgen receptor expression and ER+ breast cancer prognosis in the BIG 1-98 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4207.

TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score.

LBA1 Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error rate 5%). The target sample size was adjusted to compensate for non-adherence to randomized treatment, and the protocol-specified final analysis was triggered after 835 iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

Association of Somatic Driver Alterations With Prognosis in Postmenopausal, Hormone Receptor–Positive, HER2-Negative Early Breast Cancer

A range of somatic driver alterations has been described in estrogen receptor-positive, HER2-negative (ER+/HER2-) early breast cancer (BC); however, the clinical relevance is unknown. To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit associated with endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole. The Breast International Group (BIG) 1-98 trial randomized 8010 postmenopausal patients with hormone receptor-positive, operable, invasive BC to monotherapy with letrozole, tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next-generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible patients with ER+/HER2- BC, with 841 distant recurrences after a median of 8.1 years of follow-up. To correct for the oversampling of distant recurrences, weighted analysis methods were used. This analysis was conducted from April 4, 2016, to November 30, 2016. The prevalence of driver alterations, associations with clinicopathologic factors, distant recurrence-free interval, and treatment interactions were analyzed. Multivariable analyses were performed to adjust for clinicopathologic factors. Of 764 samples, 538 (70.4%), including 140 distant recurrence events, were successfully sequenced. Nineteen driver alterations were observed with 5% or greater frequency, with a mean of 4 alterations (range, 0-15) per tumor. PIK3CA mutations were the most common (49%) and were significantly associated with reduction in the risk for distant recurrence (hazard ratio [HR], 0.57; 95% CI, 0.38-0.85; P = .006). TP53 mutations (HR, 1.92; 95% CI, 1.21-3.04; P = .006), amplifications on 11q13 (HR, 2.14; 95% CI, 1.36-3.37; P = .001) and 8p11 (HR, 3.02; 95% CI, 1.88-4.84; P < .001), and increasing number of driver alterations (HR per additional alteration, 1.18; 95% CI, 1.11-1.25; P < .001) were associated with significantly greater risk. Amplifications on 11q13 and 8p11 remained significant predictors in multivariable analysis, but not PIK3CA and TP53 mutations. Patients with tumors harboring kinase or helical domain PIK3CA mutations derived significantly greater benefit from letrozole over tamoxifen than patients whose tumors did not (P interaction = .002). In ER+/HER2- postmenopausal, early-stage BC, amplifications on 11q13 and 8p11 were significantly associated with increased risk for distant recurrence and PIK3CA mutations were predictive of greater magnitude of benefit from letrozole. With these findings, DNA-based classification may aid adjuvant treatment decision making in this setting. ClinicalTrials.gov Identifier: NCT00004205.