KATHERINE Trial Research Articles

Invasive disease free survival and brain metastasis rates in patients treated with neoadjuvant chemotherapy with trastuzumab and pertuzumab.

589 Background: Patients (pts) with human epidermal growth factor receptor 2 (HER2) positive (+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD) after surgery. HER2 negative (-) RD has been reported in 1/3 of pts after NAST. The KATHERINE trial suggests that pts with HER2- RD (8%) have better invasive disease-free survival (IDFS) with adjuvant (adj) trastuzumab emtansine (T-DM1) versus trastuzumab (H) alone. However, only 18% of the pts enrolled in the trial received NAST with trastuzumab and pertuzumab (HP). We aimed to analyze IDFS and brain metastasis (BM) rates in pts with HER2+ EBC in a modern population homogenously treated with NAST. We also report the incidence of pts with HER2- RD and their outcomes. Methods: Clinicopathologic data for pts with HER2+ EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. External assessment of HER2 status before NAST was allowed. HER2 status of the surgical specimens with RD were assessed internally at our center. IDFS was defined as the time from surgery until first occurrence of invasive cancer recurrence, distant recurrence, or death from any cause. Results: The total cohort was 594 pts. 456 (77%) and 138 (23%) received antracycline-taxane and taxane based chemotherapy, respectively during NAST. 587 (99%) received HP and 7 (1%) received H alone. NAST was completed by 566 (95%) of pts. pCR (ypT0/isN0) was achieved in 325 (55%) and RD was seen in 269 (45%) pts. In 269 pts with RD, 46 (17%) did not have HER2 retesting and were excluded from the final analysis. In the remaining 223 pts, 143 (64%) were HER2+ and 80 (36%) were HER2-. In the 143 pts with HER2+ RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 120 (84%), 16 (11%), 1 (1%) and 6 (4%) of pts, respectively. In the 80 pts with HER2- RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 44 (55%), 27 (34%), 3 (4%) and 6 (7%) of pts, respectively. With a median follow up of 24 months, 7 pts developed BM at initial recurrence, 3/325 (0.9%) with pCR and 4/143 (2.8%) with HER2+ RD. None of the pts who developed BM had HER2- RD. IDFS events occurred in 22/594 (3%) pts. RD pts had a higher likelihood of having an IDFS event, 14/269 (5%) in RD and 8/325 (2%) in pCR (p = 0.04). In the evaluable 223 pts with RD there was no difference in IDFS between 10/143 (7%) pts with HER2+ RD or 4/80 (5%) with HER2- RD (p = 0.10). Conclusions: At a single center, in pts who predominantly received HP with chemotherapy as NAST, pts with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2+ status; IDFS events appeared similar in those with HER2+ RD versus those with HER2- RD. The HER2 loss rate is higher than reported in KATHERINE possibly due to majority of pts receiving dual HP as NAST. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adj setting to minimize BM risk.

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study)

IntroductionTrastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. Material and methodsWe conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. ResultsA total of 114 patients were included (March–July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1–3 N0–1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. ConclusionThe KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.

Acute skin radiation toxicity seen with concurrent T-DM1: A single institutional report of 35 patients

Trastuzumab emtansine (T-DM1) is a novel therapeutic for HER2+ breast cancer patients with residual disease after neoadjuvant chemotherapy. Concurrent radiotherapy (RT) is offered to a subset of patients based on results from the KATHERINE trial which showed a favorable safety profile. With emerging therapies that necessitate concurrent RT, we must closely follow rates of skin toxicity. Our first 35 patients who underwent concurrent T-DM1 treatment with breast/chest wall (CW) ± nodal irradiation are reported. Most patients (22/35) had grade 2+ toxicity and 3 patients had grade 3 toxicities. We add our experience with radiation dermatitis and concurrent T-DM1 to contribute to existing reports.

Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.

Residual Disease Burden After Neoadjuvant Therapy Among US Patients With High-Risk HER2-positive Early-Stage Breast Cancer: A Population Effectiveness Model

BackgroundApproximately half of patients with high-risk HER2-positive early-stage breast cancer (ESBC) do not have pathologic complete response (pCR) after neoadjuvant therapy. The residual burden of disease among this population has not been previously quantified. Materials and MethodsWe used decision-modeling techniques to simulate recurrence, progression from locoregional to distant cancer, breast cancer-related mortality, and mortality from other causes over a 10-year period in a hypothetical cohort. We derived progression probabilities primarily from the KATHERINE trial of T-DM1 (ado-trastuzumab emtansine) and mortality outcomes from the published literature. Modeled outcomes included recurrences, breast cancer deaths, deaths from other causes, direct medical costs, and costs due to lost productivity. To estimate the residual disease burden, we compared outcomes from a cohort of patients treated with T-DM1 versus a hypothetical cohort with no disease recurrence. ResultsWe estimated that 9,300 people would experience incident high-risk HER2-positive ESBC in the United States in 2021 based on cancer surveillance databases, clinical trial data, and expert opinion. We estimated that, in this group, 2,118 would experience disease recurrence, including 1,576 distant recurrences, and 1,358 would experience breast cancer deaths. This residual disease burden resulted in 6,435 life-years lost versus the recurrence-free cohort, and healthcare-related costs totaling $644 million, primarily associated with treating distant cancers. ConclusionPatients with HER2-positive ESBC who do not achieve pCR after neoadjuvant therapy are at ongoing risk of recurrence despite the effectiveness of neoadjuvant treatment. There is substantial clinical and economic value in further reducing the residual disease burden in this population.

Three-year disease-free survival in randomized trials of chemotherapy and HER2-targeted therapy: A meta-analysis.

579 Background: The Katherine trial reported a 3-year invasive disease-free survival (DFS) of 77% in patients not achieving pathological complete response (pCR) and continuing on adjuvant trastuzumab. Case series suggest better outcomes and data support that some patients with residual disease have similar outcomes to those with pCR (Steenbruggen et al). The absolute benefit of adjuvant trastuzumab emtansine (T-DM1) would be smaller in patients with favourable outcomes despite residual disease. As such, a more precise estimate of 3-year DFS is needed for treatment planning. Methods: We reviewed reports of randomized trials of neoadjuvant chemotherapy and HER2-directed therapy and extracted the 3-year DFS, a validated surrogate endpoint in HER2-positive early-stage breast cancer. Data were extracted for patients with residual disease and with pCR. The mean 3-year DFS weighted by study sample size was calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was performed to explore associations between 3-year DFS and trial-level patient, disease and treatment factors and changes in 3-year DFS over time. Quantitative significance was explored using methods described by Burnand et al. Results: Eleven studies comprising 3908 patients were included in the analysis. The mean 3-year DFS for patients with pCR and for residual disease was 90.1% and 80.0%, respectively. DFS improved over time. For trials whose final year of accrual was after 2010, mean 3-year DFS for residual disease was 84.7% compared to 78.0% for trials completing accrual before that time (p<0.001). In a subgroup analysis of patients with residual disease, those receiving dual HER2-targeted therapy in the neoadjuvant setting had a 3-year DFS of 85.3% compared to 73.3% for those receiving only trastuzumab (p<0.001). Meta-regression results for residual disease are shown in the Table. Positive quantitative significance was observed for final year of accrual, ER-expression, dual anti-HER2 therapy and concurrent vs sequential anti-HER2 therapy. Negative quantitative significance was observed for larger clinical tumor size and nodal involvement. Conclusions: 3-year DFS for patients with residual disease and HER2-targeted therapy is better than reported in the Katherine trial and has improved over time, possibly due to increased use of dual HER2-targeted therapy in the neoadjuvant setting. In this context, the absolute benefit of adjuvant T-DM1 may be smaller than anticipated. [Table: see text]

Abstract P2-11-19: Estimating the long-term risk of recurrence in patients receiving HER2-targeted agents in HER2+ early-stage breast cancer (ESBC)

Abstract Background: The APHINITY, KATHERINE and ExteNET pivotal trials demonstrated the benefits of HER2-targeted agents for disease-free survival in HER2+ ESBC. However, heterogeneity in patient populations and study designs make assessment of treatment benefits challenging. The objective of this study was to project absolute treatment benefits over a standardized 10-year time horizon. Methods: An epidemiologic model was developed to simulate numbers of distant recurrences for 1000 patients with newly diagnosed HER2+ ESBC in the ExteNET, APHINITY and KATHERINE patient populations and select subgroups. ExteNET evaluated neratinib vs. placebo from 2009 to 2012. APHINITY evaluated pertuzumab + trastuzumab vs. placebo + trastuzumab + standard adjuvant chemotherapy in high-risk patients without neoadjuvant therapy treated from 2011 to 2014. KATHERINE evaluated ado-trastuzumab emtansine (T-DM1) vs. trastuzumab in patients without pathologic complete response (pCR) following neoadjuvant therapy treated from 2013 to 2016. We used disease-free survival curves from each trial as model inputs to estimate the risk of distant recurrence and extrapolated these results to a standardized 10-year follow-up period. We assumed there were no further treatment benefits to prevention of recurrence beyond the follow-up period of the trial. Survival curve trends beyond each trial’s observation period were informed by the trastuzumab arm of the long-term HERA trial follow-up data. Model outputs were distant recurrences for the control arms for each study and the number of distant recurrences avoided from treatment. Results: Over a 10-year time horizon, treatment benefits ranged from 11 to 65 distant recurrences avoided. Treatment benefit differed according to baseline risk of the trial population and treatment effect, with higher-risk populations and greater treatment effect (e.g. KATHERINE trial) tending to yield greater absolute treatment benefit, with the exception of the ExteNET ITT population as changes in the treatment effect over time (non-proportional hazards) made modeling long-term results more complex. Absolute treatment benefits were similar for the intent-to-treat (ITT) group in the KATHERINE trial and the no pCR group in the ExteNET trial; and the ITT groups in the APHINITY and ExteNET trials. Refinement of model projections and inclusion of local recurrences in a more complex modeling structure are ongoing. Conclusions: Results of our simulation suggest that patients with HER2+ ESBC experience a range of reductions in distant recurrence from HER2-targeted agents, depending on baseline risk (pCR and hormone receptor status), and treatment effect. Epidemiologic modeling may be a useful method to estimate long-term outcomes and facilitate evaluation across disparate clinical trials. Table. Modeled benefits of HER2-targeted agents in a cohort of 1000 patients with HER2+ ESBC over a standardized 10-year timeframeSource data inputsModeled outputs (n=1000)Distant recurrences at 10 yearsClinical study characteristicsHazard ratio for distant recurrence from study1Baseline risk: Events in control armTreatment effect: Distant recurrences avoided from treatmentExteNET study (ITT)0.78 (0.60-1.01) at 5 years14318APHINITY study (ITT)0.76 (0.62-0.95) at 6 years10320ExteNET study (HR+; treated within 12 months of trastuzumab receipt)0.57 (0.39-0.83) at 5 years14727APHINITY study (HR+)0.78 (0.51-1.18) at 6 years26111KATHERINE study (no pCR, ITT)0.60 (0.45-0.79) at 3 years26464KATHERINE study (no pCR, HR+)0.57 (0.42-0.75) at 3 years223941ExteNET study (no pCR, HR+; treated within 12 months of trastuzumab receipt)0.61 (0.32-1.11) at 5 years265651Values in parentheses represent 95% confidence intervals. 2Hazard ratio not reported in clinical study publication. Estimated based on reported IDFS hazard ratio and proportion of distant to all invasive recurrences in ITT population. HR = hormone receptor; ITT = intent-to-treat; pCR = pathologic complete response. Citation Format: David L Veenstra, Nathaniel Hendrix, Chantal M Dolan, Kathryn A Fisher, Deepa Lalla, Nina Oestreicher, Adam Brufsky. Estimating the long-term risk of recurrence in patients receiving HER2-targeted agents in HER2+ early-stage breast cancer (ESBC) [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 P2-11-19.

Abstract P3-16-01: Population effectiveness model of the consequences of recurrence after trastuzumab emtansine (T-DM1) treatment among U.S. patients with high-risk HER2+ early-stage breast cancer (ESBC)

Abstract Background: To estimate the long-term consequences of disease recurrence following treatment with adjuvant T-DM1 among U.S. patients with high-risk HER2+ ESBC who did not achieve pathologic complete response (pCR) after neoadjuvant therapy. Methods: A Markov model was used to simulate local/regional and distant recurrence with 10 years of follow-up. This corresponds to the estimated number of U.S. patients with incident high-risk HER2+ ESBC in 2021 (n = 10,000), which was derived from SEER population-based estimates, the NEOSPHERE trial and expert clinical opinion. The probability of recurrence was based on the T-DM1 arm in the KATHERINE trial and long-term results from the HERA trial. We assumed that 80% of patients with any recurrence experience distant recurrence, while the remainder have local/regional recurrence. SEER data and literature review were used to estimate probabilities of survival, distant recurrence secondary to local/regional recurrence, and direct medical costs. We estimated indirect costs were equal to 15% of direct medical costs. Model outcomes included: recurrences, breast cancer-related deaths, non-breast cancer-related deaths, direct medical costs, and indirect costs (all undiscounted). Results were compared to a scenario in which there was no recurrence to estimate population impact. All outcomes were also projected over 10 annual incident cohorts, each with 10 years of follow-up. Results: We estimated the 2021 U.S. patient cohort would experience 2,279 recurrences, including 1,834 distant, and 1,559 breast cancer-related deaths over 10 years, resulting in 7,744 lost years of life and $632 million in additional spending, including $549 million in direct medical costs. Projection to 10 years of incident cohorts would lead to approximately 23,000 recurrences, 16,000 deaths, 77,000 lost years of life and $6 billion in direct medical costs. Conclusions: Patients with HER2+ ESBC who do not achieve pCR after neoadjuvant therapy are at ongoing risk of recurrence despite the effectiveness of treatment with T-DM1. There is substantial clinical and economic value in further reducing the recurrence risk among this population. Findings for 2021 Cohort Projected over 10 YearsWith recurrenceNo recurrenceDifferenceLocal/regional recurrences4450445Distant recurrence1,83401,834Breast cancer deaths1,55901,559Non-breast cancer deaths416457-41Direct costs$573M$24M$549MIndirect costs$86M$3.6M$82MLife years90,24997,993-7,744Costs$659M$27M$632M Citation Format: David L Veenstra, Nathaniel Hendrix, Chantal M Dolan, Kathryn Fisher, Deepa Lalla, Nina Hill, Beverly Moy. Population effectiveness model of the consequences of recurrence after trastuzumab emtansine (T-DM1) treatment among U.S. patients with high-risk HER2+ early-stage breast cancer (ESBC) [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 P3-16-01.

Abstract P4-07-01: Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes

Abstract Background: In HER2-positive (HER2+) early breast cancer (eBC) treated with neoadjuvant therapy (NAT), HER2 loss on residual disease (RD) might be correlated with a dampen survival. Recent data from the KATHERINE trial showed a maintained benefit from post-neoadjuvant trastuzumab emtansine (T-DM1) in patients with HER2 loss on RD, even if clinicopathological variables associated with HER2 loss have not been reported. We aimed to characterize the clinicopathological variables and clinical outcomes associated with HER2 loss after NAT in patients with HER2+ eBC.Methods: We retrieved data from a prospectively collected database including all consecutive HER2+ eBC patients treated with NAT at European Institute of Oncology from September 1999 to May 2018. We collected data on age, menopausal status, NAT regimen, clinical and pathological stage, as well as histological subtype and grade, hormone receptor (HR), HER2, and Ki67 status before and after NAT. HR and HER2 status were re-assessed according to the latest ASCO/CAP guidelines. Invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate (UVA) and multivariate analyses (MVA) were performed to identify variables associated with survival outcomes. Variables considered in UVA included: clinical tumor stage (cT: 1-2 vs 3-4) and nodal status (cN: 0 vs 1-2-3), pre-and post-NAT HR status (neg vs pos), NAT (anti-HER2 agents: yes vs no; endocrine therapy: yes vs no), pathological tumor stage (ypT: is-0-1-2 vs 3-4) and nodal status (ypN: 0 vs 1-2-3). Variables with a p value<0.1 were included in the MVA. Results: Of 920 patients with HER2+ eBC who had received NAT, 106 (11.5%) had RD with HER2 loss and were included in the analysis. Median age was 49 yrs (range 29-76). 55 (51.9%), 48 (45.3%) and 3 (2.8%) patients were post-, pre- and peri-menopausal, respectively. Most patients had cT2 tumors (44.3%, vs cT1 3.8%, cT3 20.8%, cT4 31.1%) and cN+ disease (81% vs 19% N0). 84 patients (79.2%) were HR-pos at diagnosis. All patients received neoadjuvant chemotherapy; 73 patients (69.5%) received also anti-HER2 agents. Pathologic staging was: ypT0-is 9.4%, ypT1 47.2%, ypT2 24.5%, ypT3 17%, ypT4 1.9%; ypN0 42.5%, ypN1 27.4%, ypN2 14.2%, ypN3 16.0%. At a median follow-up of 80.8 months (interquartile range, 43.5-159.4), median IDFS, DRFS, and OS were 100 (95% CI, 61-NA), 183 (95% CI, 157-NA), and 197 months (95% CI, 130-NA), respectively. At UVA, pre-NAT HR status (p=0.088) along with cT (p=0.008) and ypN (p=0.016) status were significantly associated with IDFS. At MVA, only HR status retained significance (HR 0.48, 95% CI 0.24-0.94, p=0.032). Median IDFS in HR-pos and HR-neg patients was 109 (95% CI 68.8-NR) and 61 (95% CI 20.9-NR) months, respectively. None of the considered variables was significantly correlated with DRFS at MVA. cT (p=0.006) and ypN (p=0.003) status were also associated with OS at UVA, with ypN that remained independently associated with OS at MVA (HR 3.6, 95% CI, 1.18-11.3, p=0.025). Median OS in ypN0 vs ypN+ patients was 122 (95% CI, 84-NR) vs NR (95% CI, 213-NR), respectively. Conclusions: HER2 loss on RD can be found in ~10% of HER2+ eBCs treated with NAT. In this subset of patients, HR-negative tumors are associated with worse IDFS, warranting the investigation of escalation treatment strategies. Node-negative disease at surgery was instead associated with a significantly longer OS. Citation Format: Stefania Morganti, Antonio Marra, Giulia Viale, Paola Zagami, Elham Sajjadi, Chiara Corti, Giuseppe Curigliano, Nicola Fusco, Carmen Criscitiello. Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes [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 P4-07-01.

Neoadjuvant and adjuvant treatment of patients with HER2-positive early breast cancer

The availability of HER2-targeted therapy has dramatically improved patient outcome in HER2-positive (HER2+) early breast cancer (EBC) as recently demonstrated by the EBCTCTG metaanalysis on trastuzumab in HER2+ EBC: Adding trastuzumab to chemotherapy has reduced recurrence rates and breast-cancer related mortality by a third [1].Today, neoadjuvant therapy has become standard of care for women with stage II or III tumors as pathological complete response (pCR) status after surgery can be used to individualize adjuvant systemic therapy. pCR is correlated with favorable patient outcome, particularly in hormone receptor (HR) negative HER2+ EBC, as demonstrated by the FDA meta-analysis. Moreover, for patients with non-pCR, 14 cycles of adjuvant T-DM1 have become a new adjuvant therapy standard based on the results of the KATHERINE trial. Primary surgery can be offered to patients with low tumor burden (cN0 cT1). For this low-risk subgroup, 12 weeks of adjuvant paclitaxel + trastuzumab for one year are correlated with excellent outcome based on the APT trial results. A multidisciplinary team is essential right from the beginning for optimal locoregional and systemic therapy in such a complex neoadjuvant – adjuvant continuum of care.Clinical trials in HER2+ EBC are currently evaluating further therapy de-escalation in low-risk disease or patients with pCR whereas for patients with non-pCR, escalation trials are also ongoing. Newly approved drugs for HER2+ MBC like tucatinib or trastuzumab-deruxtecan or even immunotherapy combinations are being evaluated to improve upon efficacy of T-DM1 alone in the non-pCR setting. Regarding de-escalation, the WSG ADAPT trial demonstrated feasibility of avoiding overtreatment and individualizing neoadjuvant therapy without compromising outcome. Further de-escalation trials (e.g. DECRESCENDO, COMPASS-HER2) are currently ongoing.

Optimal Duration of Neoadjuvant Taxane and Carboplatin Combined With Anti-HER2 Targeted Therapy for HER2-Positive Breast Cancer.

BackgroundTaxane, carboplatin and trastuzumab (TCH) is an effective neoadjuvant regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer with high pathologic complete response (pCR) rate. The KATHERINE trial changes the outlook for high-risk HER2-positive breast cancer, which suggests that escalation treatment for patients with residual disease after neoadjuvant anti-HER2 therapy may improve survival. The major objective of this study was to investigate the fewest cycles of neoadjuvant TCH therapy needed to screen out non-pCR patients.MethodsThis retrospective study included patients with HER2-positive breast cancer who received either four or six cycles of TCH preoperatively at Fudan University Shanghai Cancer Center between 2008 and 2019. The pCR status was evaluated, and relevant factors associated with pCR were identified using univariate and multivariable analyses. The pathological results of core needle biopsy (CNB) in the breast tumor after two cycles of neoadjuvant chemotherapy were also collected. Kaplan-Meier curve was used to estimate the event-free survival (EFS).ResultsOf 758 eligible patients, 303 were included and analyzed in the four-cycle group and 455 in the six-cycle group. There was no significant difference between the two groups in terms of the pCR rate (46.5% [95% CI 40.9% - 52.2%] in the four-cycle group and 49.9% [95% CI 45.3% - 54.5%] in the six-cycle group, p = 0.365) or the four-year EFS (90.8% in four-cycle group and 93.8% in six-cycle group; p = 0.264). Multivariable analysis indicated that a negative hormone receptor status and the weekly paclitaxel were independent factors for predicting pCR. After adjusting for factors in the multivariable analysis, there was still no significant difference between four and six cycles of neoadjuvant TCH (OR = 1.252, 95% CI 0.904 - 1.733, p = 0.176). Furthermore, 17.9% patients with invasive carcinoma on CNB after two cycles of TCH ultimately achieved pCR in the breast after the completion of neoadjuvant treatment.ConclusionFour cycles of taxane/carboplatin-based neoadjuvant anti-HER2 therapy may be applied as an optimal treatment duration for screening high-risk HER2-positive breast cancer patients for escalation treatment. Further prospective study is warranted.

Projected long-term impact of adjuvant trastuzumab emtansine (T-DM1) on metastatic breast cancer occurrence in Turkey.

e12523 Background: Progression from early stage breast cancer (eBC) to metastatic breast cancer (mBC) constitutes a substantial disease burden in Turkey. At a population-level, investment in treatment with curative intent may contribute to long-term reductions or delays in mBC. Women diagnosed with human epidermal growth factor receptor 2 (HER2)-positive eBC who do not achieve pathologic complete response (pCR) after neoadjuvant taxane and trastuzumab-based treatment may be indicated for adjuvant trastuzumab emtansine (T-DM1) monotherapy. For this clinical population, the KATHERINE trial (NCT01772472) demonstrated significantly higher invasive disease-free survival among women who received adjuvant T-DM1 relative to trastuzumab (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; p<0.001). Methods: We developed epidemiology models based on data from cancer registries, observational studies, clinical trials, estimated population-level T-DM1 uptake, and extrapolations, by calendar year to predict the population-level number of women who will avoid mBC in Turkey over the next 10 years (i.e., 2022 to 2031). Weighted transitional probability averages were based on invasive disease-free and overall survival curves from the KATHERINE trial. Results: Over the next 10 years in Turkey, we projected that 22,597 women will be diagnosed with HER2-positive eBC and will not achieve pCR after neoadjuvant therapy. We projected that the total number of women who will experience mBC occurrence following adjuvant T-DM1 use from 2022-2031 will decrease annually from 0 to 249 relative to projections without introduction of T-DM1, with a cumulative total of 1,219 women not experiencing mBC occurrence, corresponding to 17% of total projected mBC occurrence over the next decade. At year 10 (2031), we projected that 29% fewer women would experience mBC occurrence in Turkey (604 with TDM-1 vs. 853 with trastuzumab). Conclusions: Population-level improvements in HER2-positive eBC to mBC disease progression are expected over the next 10 years in Turkey following adjuvant T-DM1 monotherapy. Further research will elucidate treatment-related improvements in costs to society as a result of population-level improvements in disease outcomes for women diagnosed with eBC.[Table: see text]

Managing HER2-Positive Breast Cancer Amid COVID-19

Managing HER2-Positive Breast Cancer Amid COVID-19

Abstract SP097: Local Regional Management Following Neoadjuvant Chemotherapy: Minding the Knowledge Gaps

Abstract Neoadjuvant chemotherapy is often used in managing breast cancer patients, particular those with HER2-positive (HER2+) or triple negative disease. Among the known benefits of administering chemotherapy prior to surgery is the opportunity to assess response which informs prognosis. The CTneoBC analysis, which included 12 trials enrolling over 11,950 patients, showed that patients experiencing a pathologic complete response (pCR; ypT0ypN0 or ypT0/isN0) have improved event-free and overall survival with the association between pCR and longterm outcomes being strongest in patients with triple negative breast cancer (TNBC) and in those with HER2+/hormone receptor-negative breast cancer receiving trastuzumab. In triple negative and HER2+ breast cancer, the response to neoadjuvant chemotherapy also informs the need for additional adjuvant therapy. For patients with TNBC and significant residual disease after neoadjuvant chemotherapy, the CREATE-X trial showed benefit for adjuvant xeloda. For patients with HER2+ breast cancer not experiencing a pCR to neoadjuvant chemotherapy plus HER2-targeted therapy, the KATHERINE trial showed a significant improvement in invasive disease-free survival and overall survival in patients receiving adjuvant T-DM1 versus adjuvant trastuzuamb. With respect to considerations for local regional therapy, it is known that neoadjuvant chemotherapy decreases the primary tumor size such that tumors thought to be inoperable become operable and tumors thought to require mastectomy downstage to be eligible for lumpectomy. More recently it has been shown that neoadjuvant chemotherapy can decrease the extent of axillary surgery required. While historically patients with clinically node positive disease at presentation were thought to require axillary lymph node dissection (ALND), the American College of Surgeons Oncology Group Z1071 trial demonstrated that sentinel lymph node biopsy (SLNB) was feasible in those who convert to clinically node negative disease following neoadjuvant chemotherapy. These findings were confirmed in the European SENTINA trial and Canadian SN-FNAC study. All three of these studies suggested that technical aspects of the SLNB procedure were critical to ensure a sufficiently low false negative rate. While these are the “known knowns”, there are many “known unknowns” and evolving data, particularly as it relates to local regional therapy following neoadjuvant chemotherapy. Included among the “known unknowns” are the optimal imaging modality to assess response to neoadjuvant chemotherapy thereby facilitating surgical planning, optimal technique for performing SLNB for those patients converting from clinical N1 to clinical N0 disease after neoadjuvant chemotherapy, the definition of negative margins for a lumpectomy, the role of routine use of immunohistochemistry for cytokeratins in pathologic evaluation of the sentinel lymph nodes, the optimal method for pathologic staging following neoadjuvant chemotherapy, and the role of ALND versus radiation therapy for patients with residual nodal metastases in the sentinel nodes. More recently, it has been questioned whether patients experiencing a complete radiographic response can undergo image guided biopsy in lieu of surgery; yet data from 3 prospective series demonstrate unacceptably high false negative rates with this approach. Given the significant implications of accurately assessing response to therapy and the presence of residual disease, optimizing local regional management is a critical component of the multidisciplinary care of these patients. In this lecture, the available data guiding local regional management after neoadjuvant chemotherapy will be reviewed with attention focused on areas in which there is limited data, therefore knowledge gaps. Citation Format: E Mittendorf. Local Regional Management Following Neoadjuvant Chemotherapy: Minding the Knowledge Gaps [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP097.

Leveraging Real-World Data for the Selection of Relevant Eligibility Criteria for the Implementation of Electronic Recruitment Support in Clinical Trials.

Even though clinical trials are indispensable for medical research, they are frequently impaired by delayed or incomplete patient recruitment, resulting in cost overruns or aborted studies. Study protocols based on real-world data with precisely expressed eligibility criteria and realistic cohort estimations are crucial for successful study execution. The increasing availability of routine clinical data in electronic health records (EHRs) provides the opportunity to also support patient recruitment during the prescreening phase. While solutions for electronic recruitment support have been published, to our knowledge, no method for the prioritization of eligibility criteria in this context has been explored. In the context of the Electronic Health Records for Clinical Research (EHR4CR) project, we examined the eligibility criteria of the KATHERINE trial. Criteria were extracted from the study protocol, deduplicated, and decomposed. A paper chart review and data warehouse query were executed to retrieve clinical data for the resulting set of simplified criteria separately from both sources. Criteria were scored according to disease specificity, data availability, and discriminatory power based on their content and the clinical dataset. The study protocol contained 35 eligibility criteria, which after simplification yielded 70 atomic criteria. For a cohort of 106 patients with breast cancer and neoadjuvant treatment, 47.9% of data elements were captured through paper chart review, with the data warehouse query yielding 26.9% of data elements. Score application resulted in a prioritized subset of 17 criteria, which yielded a sensitivity of 1.00 and specificity 0.57 on EHR data (paper charts, 1.00 and 0.80) compared with actual recruitment in the trial. It is possible to prioritize clinical trial eligibility criteria based on real-world data to optimize prescreening of patients on a selected subset of relevant and available criteria and reduce implementation efforts for recruitment support. The performance could be further improved by increasing EHR data coverage.

Economic evaluation of adjuvant trastuzumab emtansine in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment in Canada.

In the katherine trial, adjuvant trastuzumab emtansine [T-DM1, Kadcyla (Genentech, South San Francisco, CA, U.S.A.)], compared with trastuzumab, significantly reduced the risk of recurrence or death by 50% (unstratified hazard ratio: 0.50; 95% confidence interval: 0.39 to 0.64; p < 0.0001) in patients with her2-positive early breast cancer (ebc) and residual invasive disease after neoadjuvant systemic treatment. A cost-utility evaluation, with probabilistic analyses, was conducted to examine the incremental cost per quality-adjusted life-year (qaly) gained associated with T-DM1 relative to trastuzumab, given the higher per-cycle cost of T-DM1. A Markov model comprising a number of health states was used to examine clinical and economic outcomes over a lifetime horizon from the Canadian public payer perspective. Patients entered the model in the invasive disease-free survival (idfs) state, where they received either T-DM1 or trastuzumab. Transition probabilities between the health states were derived from the katherine trial, Canadian life tables, and published literature from other relevant clinical trials (emilia, cleopatra, and M77001). Resource use, costs, and utilities were derived from katherine, other clinical trials, published literature, provincial fee schedules, and clinical expert opinion. Sensitivity analyses were conducted for key assumptions and model parameters. Compared with trastuzumab, adjuvant T-DM1 was associated with a cost savings of $8,300 per patient and a 2.16 incremental qaly gain; thus T-DM1 dominated trastuzumab. Scenario analyses yielded similar results, with T-DM1 dominating trastuzumab or producing highly favourable incremental cost-utility ratios of less than $10,000 per qaly. Adjuvant T-DM1 monotherapy is a cost-effective strategy compared with trastuzumab alone in the treatment of patients with her2-positive ebc and residual invasive disease after neoadjuvant systemic treatment.

PCN110 Cost-Utility Analysis of Adjuvant Trastuzumab Emtansine Versus Trastuzumab in Patients with HER2+ EARLY Breast Cancer with Residual Invasive Disease after Neoadjuvant Therapy in Spain

Trastuzumab emtansine (T-DM1) in the adjuvant treatment of patients with HER2-positive early breast cancer (HER2+ eBC) with residual invasive disease (RD) after neoadjuvant taxane-based and HER2-targeted therapy demonstrated a clinically and statistically significant improvement in invasive disease-free survival (iDFS) compared to trastuzumab in the KATHERINE trial. The aim of this study is to determine the efficiency of T-DM1 versus trastuzumab as adjuvant treatment of HER2+ eBC with RD in Spain through a cost-utility analysis. A six-state Markov model (iDFS, local recurrence, iDFS after local recurrence, metastatic-relapse [1L], metastatic-relapse [2L], and death) was adapted over a lifetime horizon (specifically 38 years), considering the Spanish National Healthcare System (SNHS) perspective. KATHERINE iDFS data were fitted with a log-normal distribution to extrapolate iDFS beyond the trial follow-up. Transition probabilities and costs (list prices of medicines considered and, for the adjuvant treatment, trastuzumab biosimilar price assumed; €2019) were obtained from literature and national databases. Utilities were based mainly on the 5Q-5D outcomes from KATHERINE trial. Model inputs were validated by an expert panel. A 3% annual discount rate was applied to both effects and costs. Deterministic and probabilistic sensitivity analyses (SA) were performed to explore uncertainties. The incremental cost-utility ratio (ICUR) for T-DM1 versus trastuzumab was €6,748 per quality-adjusted life-year (QALY). Compared to trastuzumab, T-DM1 provided 1.702 additional QALYs at an additional cost of €11,485. SA confirmed the robustness of the model. In the probabilistic analysis, the probability of T-DM1 being cost-effective when considering a threshold of €30,000/QALY was >95%. T-DM1 is a more efficient therapeutic alternative than trastuzumab as adjuvant treatment of HER2+ eBC with residual invasive disease for the SNHS.

Cost-Effectiveness of Neoadjuvant-Adjuvant Treatment Strategies for Women With ERBB2 (HER2)–Positive Breast Cancer

The neoadjuvant treatment options for ERBB2-positive (also known as HER2-positive) breast cancer are associated with different rates of pathologic complete response (pCR). The KATHERINE trial showed that adjuvant trastuzumab emtansine (T-DM1) can reduce recurrence in patients with residual disease compared with patients treated with trastuzumab; however, T-DM1 and other ERBB2-targeted agents are costly, and understanding the costs and health consequences of various combinations of neoadjuvant followed by adjuvant treatments in the United States is needed. To examine the costs and disease outcomes associated with selection of various neoadjuvant followed by adjuvant treatment strategies for patients with ERBB2-positive breast cancer. In this economic evaluation, a decision-analytic model was developed to evaluate various neoadjuvant followed by adjuvant treatment strategies for women with ERBB2-positive breast cancer from a health care payer perspective in the United States. The model was informed by the KATHERINE trial, other clinical trials with different regimens from the KATHERINE trial, the Flatiron Health Database, McKesson Corporation data, and other evidence in the published literature. Starting trial median age for KATHERINE patients was 49 years (range, 24-79 years in T-DM1 arm and 23-80 years in trastuzumab arm). The model simulated patients receiving 5 different neoadjuvant followed by adjuvant treatment strategies. Data analyses were performed from March 2019 to August 2020. There were 4 neoadjuvant regimens: (1) HP: trastuzumab (H) plus pertuzumab (P), (2) THP: paclitaxel (T) plus H plus P, (3) DDAC-THP: dose-dense anthracycline/cyclophosphamide (DDAC) plus THP, (4) TCHP: docetaxel (T) plus carboplatin (C) plus HP. All patients with pCR, regardless of neoadjuvant regimen, received adjuvant H. Patients with residual disease received different adjuvant therapies depending on the neoadjuvant regimen according to the 5 following strategies: (1) neoadjuvant DDAC-THP followed by adjuvant H, (2) neoadjuvant DDAC-THP followed by adjuvant T-DM1, (3) neoadjuvant THP followed by adjuvant DDAC plus T-DM1, (4) neoadjuvant HP followed by adjuvant DDAC/THP plus T-DM1, or (5) neoadjuvant TCHP followed by adjuvant T-DM1. Lifetime costs in 2020 US dollars and quality-adjusted life-years (QALYs) were estimated for each treatment strategy, and incremental cost-effectiveness ratios were estimated. A strategy was classified as dominated if it was associated with fewer QALYs at higher costs than the alternative. In the base-case analysis, costs ranged from $415 833 (strategy 3) to $518 859 (strategy 4), and QALYs ranged from 9.67 (strategy 1) to 10.73 (strategy 3). Strategy 3 was associated with the highest health benefits (10.73 QALYs) and lowest costs ($415 833) and dominated all other strategies. Probabilistic analysis confirmed that this strategy had the highest probability of cost-effectiveness (>70% at willingness-to-pay thresholds of $0-200,000/QALY) and was associated with the highest net benefit. These results suggest that neoadjuvant THP followed by adjuvant H for patients with pCR or followed by adjuvant DDAC plus T-DM1 for patients with residual disease was associated with the highest health benefits and lowest costs for women with ERBB2-positive breast cancer compared with other treatment strategies considered.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update.

The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab. Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.Additional information can be found at www.asco.org/breast-cancer-guidelines.

Trastuzumab Emtansine: A Review of Its Adjuvant Use in Residual Invasive HER2-Positive Early Breast Cancer.

Trastuzumab emtansine (Kadcyla®), an antibody-drug conjugate of trastuzumab (Herceptin®) connected by a thioether linker to the microtubule inhibitor DM1 (a cytotoxic derivative of maytansine), provides direct intracellular delivery of the potent cytotoxin DM1 to HER2-overexpressing cells, while retaining trastuzumab activity. Its approval in metastatic/advanced breast cancer (BC) has been extended to include single-agent adjuvant treatment of HER2-positive early BC in patients with residual invasive disease in the breast and/or lymph nodes after neoadjuvant taxane-based and HER2-targeted treatment. In the pivotal KATHERINE trial in this population, significantly more trastuzumab emtansine than trastuzumab recipients were estimated to be free of invasive disease recurrence at 3years, with a 50% reduction in the risk of invasive disease recurrence or death. The tolerability of trastuzumab emtansine in early BC was consistent with its known safety profile; as expected, adverse events were more common with trastuzumab emtansine than with trastuzumab. Recently updated international and national treatment guidelines recommend trastuzumab emtansine as a preferred option in this high-risk BC population.