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OBJECTIVE: To compare overall survival of patients with a cCR undergoing active surveillance versus standard esophagectomy.SUMMARY OF BACKGROUND DATA: One-third of patients with esophageal cancer have a pathologically complete response in the resection specimen after neoadjuvant chemoradiotherapy. Active surveillance may be of benefit in patients with cCR, determined with diagnostics during response evaluations after chemoradiotherapy.METHODS: A systematic review and meta-analysis was performed comparing overall survival between patients with cCR after chemoradiotherapy undergoing active surveillance versus standard esophagectomy. Authors were contacted to supply individual patient data. Overall and progression-free survival were compared using random effects meta-analysis of randomized or propensity score matched data. Locoregional recurrence rate was assessed. The study-protocol was registered (PROSPERO: CRD42020167070).RESULTS: Seven studies were identified comprising 788 patients, of which after randomization or propensity score matching yielded 196 active surveillance and 257 standard esophagectomy patients. All authors provided individual patient data. The risk of all-cause mortality for active surveillance was 1.08 [95% confidence interval (CI): 0.62-1.87, P = 0.75] after intention-to-treat analysis and 0.93 (95% CI: 0.56-1.54, P = 0.75) after per-protocol analysis. The risk of progression or all-cause mortality for active surveillance was 1.14 (95% CI: 0.83-1.58, P = 0.36). Five-year locoregional recurrence rate during active surveillance was 40% (95% CI: 26%-59%). 95% of active surveillance patients undergoing postponed esophagectomy for locoregional recurrence had radical resection.CONCLUSIONS: Overall survival was comparable in patients with cCR after chemoradiotherapy undergoing active surveillance or standard esophagectomy. Diagnostic follow-up is mandatory in active surveillance and postponed esophagectomy should be offered to operable patients in case of locoregional recurrence.

Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab Importance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P

The World Health Organization (WHO) recently endorsed the proposal for a Decade of Healthy Ageing (2020-2030). The WHO defines "healthy aging" as "the process of developing and maintaining the functional ability that enables wellbeing in older age." Among the strategies for the Decade of Healthy Ageing, the WHO has suggested enhancing intrinsic capacity, promoting functional ability, and implementing the Integrated Care for Older People (ICOPE) package. The WHO has defined steps for ICOPE evaluation and scale-up and is performing a prospective study in 2-3 countries (low and middle income, high income) to test its feasibility in 2021-2022 and a multinational randomized study to validate its clinical efficacy and effectiveness in 2022-2024. Intrinsic capacity and frailty represent two faces of the same coin, with one indicating the reserves of the individual and the other indicating the deficits that accumulate with age. The Integrated Care of Older Patients with Frailty in Primary Care (ICOOP_Frail) study is the first integrated care program for frailty or functional decline in primary care in Korea. The results suggest that the ICOOP_Frail study can be utilized as a reference for ICOPE studies in Korea or at least to provide important findings for the forthcoming ICOPE implementation study in Korea.

Background Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here. Methods All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS. Results Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below. Conclusion Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted. Updated Results for DESTINY-Breast011 Aug 2019 datacut8 Jun 2020 datacutPatients remaining on treatment, n/N (%)79/184 (42.9%)37/184 (20.1%)Median duration of follow-up11.1 months20.5 monthsORR60.9%61.4%CR6.0%6.5%PR54.9%54.9%SD36.4%35.9%Duration of response, median (95% CI)14.8 months (13.8-16.9)20.8 months (15.0-NE)PFS, median (95% CI)16.4 months (12.7-NE)19.4 months (14.1-NE)OSMedian (95% CI)NE (NE-NE)24.6 months (23.1-NE)Point estimate at 12 mo (95% CI)86.2% (79.8-90.7)85% (79-90)Point estimate at 18 mo (95% CI)–74% (67-80)SafetyPatients with a TEAE, n (%)183 (99.5%)183 (99.5%)Grade ≥3105 (57.1%)113 (61.4%)Associated with discontinuation28 (15.2%)34 (18.5%)Associated with death10 (5.4%)10 (5.4%)Drug-related ILD per ILD adjudication committeea25 (13.6%)28 (15.2%)Grade 5 drug-related ILD per ILD adjudication committee4 (2.2%)5 (2.7%)a1 grade 1 and 1 grade 3 event are pending adjudication and are not included. Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [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 PD3-06.

Background: Two neoadjuvant anthracycline and taxane containing chemotherapy regimens have been widely used. The objective of the study was shorter duration of 6 cycles of FEC3-D3 is comparable to 8 cycles of AC4-D4 Method: Enrolled patients (pts) were diagnosed clinically stage II or III breast cancer between November 2012 and December 2015 at Asan Medical Center, Seoul, Korea. Pts were stratified according to hormone receptor and HER2 expression status and randomized 1:1 to AC4-D4 and FEC3-D3 arm. The primary endpoint was pathologic complete response (pCR) and the secondary end points were 3 year disease-free survival (3Y DFS) and toxicities.Result: Among 252 pts enrolled, 1pt ineligible for screening; 10 pts discontinued treatment due to progressive disease (7 pts in AC4-D4 arm and 3 pts in FEC3-D3), 17 pts dropped out due to withdrawal of written consent and 2 pts unable to complete study. Two hundred twenty two pts receiving surgery were included for this analysis. Baseline characteristics are well balanced between two arms- median age (47 vs 48), % of TNBC (24% vs 26%) in AC4-D4 (N=126) vs FEC3-D3 arm (N=125) respectively. Baseline median Ki-67 labeling index was 50% (range, 10%-90%). By ITT analysis, pCR was achieved in 18/126 (14.3%) pts of AC4-D4 arm and 15/125 (12.0%) pts in FEC3-D3 arm, respectively (p=0.17). According to per protocol, in AC4-D4 arm, 95/103 pts achieved clinical response (6 complete response [CR] and 89 partial response [PR]) and among them 18 pts (17.5%) achieved pCR. In FEC3-D3 arm, 97/119 pts achieved clinical response (4 CR and 93 PR) and among them 15 pts (12.6%) achieved pCR. With a median follow up of 64.1 months, 3Y DFS (77.0% in AC4-D4 vs. 74.9% in FEC3-D3) was comparable between two arms (p=0.79). The most common adverse event (AE) was Grade 3/4 neutropenia. 44/126 (34.9%) pts in AC4-D4 arm vs 39/125 (31.2%) pts in FEC3-D3 arm. The most common Grade 3/4 non-hematologic AE was hyperglycemia (3.2%). Dose modification was done in 37/126 (29.4%) pts in AC4-D4 arm and 25/125 (20.0%) pts in FEC3-D3 arm, respectively (p=0.09). Multivariate analyses showed that ≥50% of baseline Ki-67 labeling index [hazard ratio (HR) 2.1 (95% confidence interval (CI),1.20-3.72; p=0.009)], ≥40% of pre-treatment Ki-67 labeling index reduction after neoadjuvant chemotherapy(NACT) [HR 2.1 (95% CI,1.20-3.66; p=0.01)], and ≥4 lymph node metastases at surgery [HR 2.2 (95% CI,1.24-3.80; p=0.07)] were independent predictive factors for 3Y DFS. Of note, in patients with non-pCR, ≥ 40% reduction of Ki-67 after NACT was associated with better 3Y DFS in luminal type [HR 2.9 (95% CI,1.51-5.65; p=0.001)]. Conclusion: Both NACT AC4-D4 and FEC3-D3 showed comparable outcomes in terms of pCR, 3 year DFS and toxicities. ≥50% of baseline Ki-67 labeling index and ≥40% reduction of Ki-67 labeling index after NACT were independent for 3Y DFS. Shorter neo-adjuvant FEC3-D3 could be an alternative to AC4-D4 in stage II or III operable breast cancer.Keywards: Neoadjuvant, AC followed by docetaxel, FEC followed by docetaxel, operable breast cancer Citation Format: Inhwan Hwang, Jeong Eun Kim, Jae Ho Jeong, Jin-Hee Ahn, Kyung Hae Jung, Byung Ho Son, Sei-Hyun Ahn, Hee Jin Lee, Gyungyub Gong, Sung-Bae Kim. Neoadjuvant adriamycin plus cyclophosphamide followed by docetaxel (AC4-D4) vs 5-fluorouracil, epirubicin plus cyclophosphamide followed by docetaxel (FEC3-D3) in stage II or III operable breast cancer : Randomized phase III neo-shorter trial (NCT02001506) [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 PS13-07.

Background: The development of central nervous system (CNS) metastases presents a considerable challenge in metastatic breast cancer (MBC) due to the limited availability of evidence-based treatments. Up to 50% of patients with HER2-positive (HER2+) MBC develop CNS metastases during the course of their disease. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated activity against CNS metastases in HER2+ MBC in two phase 2 studies (NEfERT-T, TBCRC 022) and one phase 3 study (NALA); significant benefits for predefined CNS endpoints were reported in NEfERT-T and confirmed in NALA. Here we present an exploratory analysis of patients from NALA with CNS involvement at enrollment. Methods: NALA was an international, randomized, open-label, active-controlled, phase 3 study in patients with HER2+ MBC who had received ≥2 lines of HER2-directed therapy in the metastatic setting (ClinicalTrials.gov: NCT01808573). Patients with asymptomatic metastatic brain disease managed with stable doses of corticosteroids for ≥14 days prior to randomization were eligible, whereas patients with symptomatic or unstable brain metastases were excluded. Patients were randomized (1:1 ratio) to neratinib (N; 240 mg qd po) + capecitabine (C; 750 mg/m2 bid po) or lapatinib (L; 1250 mg qd po) + C (1000 mg/m2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Intervention for symptomatic metastatic CNS disease was a secondary endpoint. CNS disease at baseline was defined as patients with treated or untreated disease in the ‘brain’ assessed by investigator at enrollment. CNS imaging was not mandatory at screening. Results: Of the 621 patients enrolled in NALA, 101 (16%) had documented baseline CNS disease and 520 (74%) had no CNS disease at baseline. Patients with CNS disease had a lower performance status and were more likely to have hormone receptor-negative disease than those with no CNS disease; no major imbalances of baseline characteristics were noted between treatment arms. Overall, 78 (77%) patients had previously received CNS radiation [whole brain, n=59 (58%); stereotactic, n=17 (17%); unknown, n=2 (2%)], and 5 (5%) patients had undergone CNS surgery. Median treatment duration was 5.7 (IQR 2.8-8.5) months for N, and 3.5 (IQR 2.1-6.9) months for L. PFS, OS, and cumulative incidence of interventions for symptomatic CNS disease are summarized in the table. No new safety signals were detected. Conclusions: Regardless of the status of CNS metastases at baseline, patients appeared to have better outcomes in the N+C arm compared with the L+C arm. Table. Efficacy outcomes in patients with and without CNS disease at baselineIntention-to-treat (n=621)CNS metastases at baseline – Yes (n=101)CNS metastases at baseline – No (n=520)N+C (n=307)L+C (n=314)N+C (n=51)L+C (n=50)N+C (n=256)L+C (n=264)PFSaHazard ratio (95% CI)0.76 (0.63–0.93)0.66 (0.41–1.05)0.76 (0.62–0.94)P-value0.00590.07410.0099Restricted mean PFSb, months8.86.67.85.59.06.9Difference, months2.22.32.1OSHazard ratio (95% CI)0.88 (0.72–1.07)0.90 (0.59–1.38)0.85 (0.68–1.06)P-value0.20860.63520.1517Restricted mean OSb, months24.022.216.415.425.623.6Difference, months1.71.02.0Incidence of CNS interventionOverall cumulative incidencec, %22.7629.1940.1347.7919.1624.65P-value0.0430.4300.067aCentrally confirmed; bRestriction prespecified as 24 months for PFS, and 48 months for OS; c % requiring intervention for CNS disease (competing risk model) Citation Format: Cristina Saura, Larisa Ryvo, Sara Hurvitz, William Gradishar, Beverly Moy, Suzette Delaloge, Sung-Bae Kim, Mafalda Oliveira, Maureen Trudeau, Ming-Shen Dai, Barbara Haley, Ron Bose, Luciana Landeiro, Judith Bebchuk, Aimee Frazier, Kiana Keyvanjah, Richard Bryce, Adam Brufsky. Impact of neratinib on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: Findings from the phase 3 NALA trial [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 PD13-09.

Purpose In the randomised phase II LEO trial, we investigated the effect of adding everolimus (EVE) to letrozole (LET) in ovarian-suppressed premenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2–) recurrent/metastatic breast cancer. Methods Patients with progression or prior exposure to tamoxifen with or without gonadotropin-releasing hormone agonists, either sequentially or concurrently, in adjuvant or metastatic setting were randomly assigned (2:1) to the EVE arm (leuprorelin + LET + EVE) or the LET arm (leuprorelin + LET) until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS). Secondary end-points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Results Between January 2014 and October 2018, 137 patients were enrolled (median age, 44 years [range, 24–56]). Of them, 75% had endocrine-sensitive disease, and 61% had visceral metastasis. With the median follow-up of 32.4 months, the median PFS was 18.1 months in the EVE arm and 13.8 months in the LET arm (HR 0.73, P = 0.137). Among patients with visceral metastases, the median PFS was significantly longer in the EVE arm (16.4 versus 9.5 months, P = 0.048). The median OS was not reached in both arms. The CBR was significantly higher in the EVE arm (83% versus 62%, P = 0.010). The ORR was similar between the two arms. The most common grade 3/4 adverse events in the EVE arm were neutropenia, alanine aminotransferase elevation and anaemia. Conclusions EVE plus LET with ovarian-suppression resulted in longer PFS in tamoxifen-exposed HR+, HER2– metastatic breast cancer patients with visceral metastasis.

As patients receiving definitive chemoradiotherapy (dCRT) for oesophageal squamous cell carcinoma (ESCC) are heterogeneous, we aimed to identify prognostic factors and failure patterns after dCRT. From 2006 to 2015, 327 patients who received dCRT for ESCC were reviewed. Treatment response to dCRT was evaluated based on EORTC‐PET criteria with endoscopy and CT results. After dCRT, 296 patients (90.5%) achieved disease stabilisation, with 132 cases of complete response (CR) (40.4%), 158 of partial response (PR) (48.3%) and 6 of stable disease (SD) (1.8%); 31 patients (9.5%) had progressive disease (PD). Median overall survival (OS) from response evaluation was 24.0 months in the overall population. Post‐treatment clinical response was the most significant prognostic factor for OS in the multivariate analysis (median OS, 65.0 months for CR, 17.3 months for PR, 4.4 months for SD and 4.0 months for PD; p, Patients with oesophageal squamous cell carcinoma treated with definitive chemoradiotherapy show highly different prognoses after treatment, especially according to the clinical response to chemoradiotherapy.

A short tumor-to-nipple distance (TND) is reported as a strong predictor of nipple-areola complex (NAC) involvement. Eligibility for nipple-sparing mastectomy (NSM) remains controversial, especially regarding TND. In this study, we compared long-term oncologic outcomes after NSM between patients with a TND ≤ 1 cm and those with a TND > 1 cm. Overall, 1369 patients with primary breast cancer who underwent NSM with immediate reconstruction from March 2003 to December 2015 were included for analysis. After propensity score matching, 495 patients with a TND ≤ 1 cm (group A) and 495 patients with a TND > 1 cm (group B) on imaging were selected to compare long-term oncologic outcomes. After matching, the median follow-up periods for surviving patients were 109 months and 112 months for groups A and B, respectively. There were no significant differences between groups with respect to the 5-year cumulative local recurrence (8.1% vs. 6.3%; p = 0.268), NAC recurrence (5.1% vs. 2.8%; p = 0.072), regional recurrence (2.0% vs. 3.6%; p = 0.125), or distant recurrence (5.9% vs. 4.8%; p = 0.480) rates. Furthermore, no significant differences were observed between the groups with respect to the 10-year local recurrence-free survival (87.1% vs. 90.7%; p = 0.164) or disease-free survival (77.9% vs. 81.6%; p = 0.222) rates. A preoperative TND ≤ 1 cm on imaging should not be contraindicated to NSM as long as there is no involvement of NAC clinically or on imaging and if retroareolar margins are confirmed to be negative for tumor cells.

The interest in HER2-low breast cancer (BC) has increased in recent years with the development of novel anti-HER2 antibody-drug conjugates. Here, we investigated the clinical outcomes and relapse patterns of patients with HER2-low or -zero BCs in an Asian population.We retrospectively identified HER2-low or -zero BC patients with stage I-III tumours who were treated with neoadjuvant chemotherapy and underwent curative surgery, between 2014 and 2018 at Asan Medical Center, Seoul, Korea.A total of 818 and 754 HER2-zero and HER2-low BC patients, respectively, were consecutively included in this analysis. The HER2-low group had more hormone receptor [HR]-positive patients (81% versus 56%, P 0.001). The HER2-zero group had a higher proportion of patients who achieved pathological complete response (pCR) (14.7% versus 9.8%, P = 0.003); however, no significant differences of pCR rate by HER2 status were identified in the HR-positive (P = 0.4) and HR-negative groups (P = 0.3) when analysed separately. The HER2-low BC cases had higher 5-year overall survival (OS) and disease-free survival (DFS) rates (P 0.001 for OS; P = 0.002 for DFS); however, no differences were observed in terms of OS and DFS by HER2 status in the HR-positive group (P = 0.21 for OS and P = 0.66 for DFS).Our current findings do not support that HER2-low BC had different biology and clinical features compared to HER2-zero BC in patients who treated with neoadjuvant chemotherapy. However, the prognostic impact of HER2-low status in BC remains controversial; thus warranting further research.

Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P

Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients.To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC.The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020.Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation.Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method.Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery.In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment.ClinicalTrials.gov Identifier: NCT03155997.

BackgroundNeutrophils kill antibody-opsonized tumor cells using trogocytosis, a unique mechanism of destruction of the target plasma. This previously unknown cytotoxic process of neutrophils is dependent on antibody opsonization, Fcγ receptors and CD11b/CD18 integrins. Here, we demonstrate that tumor cells can escape neutrophil-mediated cytotoxicity by calcium (Ca2+)-dependent and exocyst complex-dependent plasma membrane repair.MethodsWe knocked down EXOC7 or EXOC4, two exocyst components, to evaluate their involvement in tumor cell membrane repair after neutrophil-induced trogocytosis. We used live cell microscopy and flow cytometry for visualization of the host and tumor cell interaction and tumor cell membrane repair. Last, we reported the mRNA levels of exocyst in breast cancer tumors in correlation to the response in trastuzumab-treated patients.ResultsWe found that tumor cells can evade neutrophil antibody-dependent cellular cytotoxicity (ADCC) by Ca2+-dependent cell membrane repair, a process induced upon neutrophil trogocytosis. Absence of exocyst components EXOC7 or EXOC4 rendered tumor cells vulnerable to neutrophil-mediated ADCC (but not natural killer cell-mediated killing), while neutrophil trogocytosis remained unaltered. Finally, mRNA levels of exocyst components in trastuzumab-treated patients were inversely correlated to complete response to therapy.ConclusionsOur results support that neutrophil attack towards antibody-opsonized cancer cells by trogocytosis induces an active repair process by the exocyst complex in vitro. Our findings provide insight to the possible contribution of neutrophils in current antibody therapies and the tolerance mechanism of tumor cells and support further studies for potential use of the exocyst components as clinical biomarkers.

PURPOSE Patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have poor prognosis. For these patients, treatment options are limited after first-line systemic therapy. PATIENTS AND METHODS In this open-label phase III clinical study, patients with advanced or metastatic ESCC, whose tumor progressed after first-line systemic treatment, were randomly assigned (1:1) to receive intravenous tislelizumab, an anti–programmed cell death protein 1 antibody, 200 mg every 3 weeks or chemotherapy (investigator's choice of paclitaxel, docetaxel, or irinotecan). The primary end point was overall survival (OS) in all patients. The key secondary end point was OS in patients with programmed death-ligand 1 tumor area positivity (TAP) score ≥ 10%. RESULTS In total, 512 patients across 11 countries/regions were randomly assigned. At final analysis, conducted after 410 death events occurred, OS was significantly longer with tislelizumab versus chemotherapy in all patients (median, 8.6 v 6.3 months; hazard ratio [HR], 0.70 [95% CI, 0.57 to 0.85]; one-sided P = .0001), and in patients with TAP ≥ 10% (median, 10.3 months v 6.8 months; HR, 0.54 [95% CI, 0.36 to 0.79]; one-sided P = .0006). Survival benefit was consistently observed across all predefined subgroups, including those defined by baseline TAP score, region, and race. Treatment with tislelizumab was associated with higher objective response rate (20.3% v 9.8%) and a more durable antitumor response (median, 7.1 months v 4.0 months) versus chemotherapy in all patients. Fewer patients experienced ≥ grade 3 treatment-related adverse events (18.8% v 55.8%) with tislelizumab versus chemotherapy. CONCLUSION Tislelizumab significantly improved OS compared with chemotherapy as second-line therapy in patients with advanced or metastatic ESCC, with a tolerable safety profile. Patients with programmed death-ligand 1 TAP ≥ 10% also demonstrated statistically significant survival benefit with tislelizumab versus chemotherapy.

The American Joint Committee on Cancer 8th edition staging system presents separate classifications for pTNM and post-neoadjuvant ypTNM (ypTNM-8th) to enhance prognostic prediction after neoadjuvant therapy and surgery. We aimed to validate the ypTNM-8th staging system and to compare the prognostication performance of ypTNM-8th with that of pTNM-7th and pTNM-8th in esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (nCRT).We reviewed 207 ESCC patients treated with nCRT between January 2007 and December 2014 and compared the Akaike information criterion (AIC) and Harrell's C-index to determine the prognostic performance of each TNM system.Survival curve analysis of pTNM-7th and -8th showed a stepwise drop in survival from ypT0N0 to advanced stages, whereas the survival outcome of ypStage III showed a better prognosis than that of ypStage II according to ypTNM-8th. Lymphovascular invasion, perineural invasion, and tumor regression grade were significantly associated with overall survival on univariate analysis. Each TNM system showed significant p-values for trend (p 0.0001 each), but after adjusting for prognostic factors, ypTNM-8th did not significantly predict survival (p = 0.15), whereas pTNM-7th remained significant (p 0.001). pTNM-7th incorporating ypT0N0M0 and ypT0 (is)N + M0 as separate groups was superior in prognostication as its AIC was smaller and its C-index was higher than those of pTNM-8th and ypTNM-8th, respectively.Because ypTNM-8th did not provide sufficient prognostication for patients with ESCC treated with nCRT followed by esophagectomy, more sophisticated prognostic classification should be developed for the ypTNM staging system in these patients.

Purpose This study was conducted to determine the effectiveness of immune checkpoint inhibitors (ICIs) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum-containing chemotherapy. We also identified clinical biomarkers which may be predictive of patient prognosis.Materials and Methods We analyzed 125 patients with R/M HNSCC who received ICIs, retrospectively. Overall response rate (ORR) was the primary study outcome. Overall survival (OS) and progression-free survival (PFS) were the secondary study outcomes.Results The patients received anti–programmed cell death protein-1 (PD-1) (n=73, 58%), anti–programmed death-ligand 1 (PD-L1) (n=24, 19%), or a combination of anti–PD-1/PD-L1 and anti–cytotoxic T-lymphocyte antigen 4 (n=28, 22%). The median age was 57 years (range, 37 to 87). The location of the primary tumor was in the oral cavity in 28% of the cases, followed by oropharynx (27%), hypopharynx (20%), and larynx (12%). The ORR was 15% (19/125). With 12.3 months of median follow-up, median PFS was 2.7 months. Median OS was 10.8 months. A neutrophil-to-lymphocyte ratio (NLR) > 4 was significantly associated with poor response to ICIs (odds ratio, 0.30; p=0.022). A sum of the target lesions > 40 mm (hazard ratio [HR], 1.53; p=0.046] and a NLR > 4 (HR, 1.75; p=0.009) were considered to be predictive markers of short PFS. A poor performance status (HR, 4.79; p < 0.001), a sum of target lesions > 40 mm (HR, 1.93; p=0.025), and an NLR > 4 (HR, 3.36; p < 0.001) were the significant predictors for poor survival.Conclusion ICIs exhibited favorable antitumor activity in R/M HNSCC. Clinically, our findings can be used to recognize patients benefit from receiving ICI.

Objectives To compare the long-term oncologic outcomes of nipple-sparing mastectomy (NSM) with those of conventional mastectomy (CM) in patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NACT). Summary of background data NSM has been increasingly implemented in patients with breast cancer. However, oncologic efficacy of NSM in patients with LABC has not been sufficiently demonstrated. Methods The study group comprised 850 patients with clinical stage IIB to IIIC breast cancer who underwent NACT followed by either NSM and immediate breast reconstruction or CM alone. After propensity score-matching, 418 patients were included in the analysis. Local recurrence-free survival, disease-free survival (DFS), distant metastasis-free survival, and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using log-rank tests between the NSM and CM groups. Results After matching, the mean follow-up period was 70 ± 25 months for the NSM group and 74 ± 27 months for the CM group (P = 0.181). There were no significant differences between the groups in terms of 6-year local recurrence-free survival (91.6% vs. 95.8%; P = 0.239), DFS (70.5% vs. 73.4%; P = 0.583), distant metastasis-free survival (79.8% vs. 77.4%; P = 0.320), or OS (87.6% vs. 84.8%; P = 0.465) rates. Additionally, we identified 30 patients in the NSM group who initially presented with tumor extension in the subareolar area; the nipple-areola complex was successfully preserved after NACT, and no recurrence at the nipple was observed in these patients. Conclusions In this matched control study, we demonstrated comparable long-term oncologic outcomes between NSM with immediate reconstruction and CM alone after NACT for LABC. In patients who had tumors extending to the subareolar area before NACT, NSM can be tried if tumor involvement of the nipple-areola complex appears resolved on imaging studies after chemotherapy.

Aim This study was undertaken to investigate the role of postoperative radiotherapy (PORT) including post-breast conserving radiotherapy (PBCRT) and post-mastectomy radiotherapy (PMRT) in stage IV breast cancer patients who underwent planned primary tumor resection (PTR). Methods This study enrolled 112 patients diagnosed with de novo stage IV breast cancer who were treated with potentially curative PTR with or without PORT. The primary outcome was overall survival (OS), and the secondary outcomes were locoregional recurrence-free survival (LRRFS) and distant progression-free survival (DPFS). Results At a median follow-up of 48.9 months (range, 3.5-183.4 months), the median OS was 54.9 months (range, 5.3-185.9 months) with a 5 year OS rate of 59.6%. Lower clinical T stage, Luminal A or B type tumors and PBCRT were significantly predictive of longer OS. The 5 year LRRFS and DMFS rates were 79.0% and 34.3%, respectively. In multivariate analysis for LRRFS, the PBCRT arm demonstrated significant superiority compared to the No PORT arm. A comparison of patients who did and did not receive PORT showed that patients with disseminated metastasis more likely did not receive PORT and were excluded from the analysis. PBCRT arm demonstrated significantly superior LRRFS of 100% while PMRT and No PORT arm demonstrated 81.5% and 84.0%, respectively CONCLUSIONS: De novo stage IV breast cancer patients who received planned PTR showed favorable survival outcomes compared with historical cohorts. PTR may be predictive of a good prognosis, especially in patients with luminal A or B type tumors. PORT, especially PBCRT was predictive of LRRFS, suggesting that patients may benefit from this treatment.

PURPOSE Combining the oral AKT inhibitor ipatasertib with paclitaxel as first-line therapy for metastatic triple-negative breast cancer significantly improved progression-free survival (PFS) in the placebo-controlled, randomized, phase II LOTUS trial, with a more pronounced effect in patients with PIK3CA/AKT1/PTEN-altered tumors. We report findings from the extensive translational research program. PATIENTS AND METHODS Pretreatment plasma and tumor samples were evaluated for genetic alterations using FoundationACT and FoundationOne (Foundation Medicine, Cambridge, MA) hybrid capture next-generation sequencing assays, respectively. Prevalences of the most common mutations and PIK3CA/AKT1 mutation status were determined using both assays, and concordance was assessed. In longitudinal analyses, circulating tumor DNA (ctDNA) mutations were quantified in baseline and on-treatment (cycle 3, day 1 [C3D1]) samples. The relationship between outcomes and ctDNA fraction (CTF; highest variant allele frequency) and CTF ratio (C3D1 CTF to baseline CTF) was explored. RESULTS Among 89 patients evaluable for ctDNA sequencing, 81 patients (91%) had 149 detectable mutations. There was high agreement between plasma- and tissue-based sequencing for known or likely short variant mutations but not amplifications. There was 100% concordance between ctDNA and tissue sequencing in patients with activating PIK3CA or AKT1 mutations. High baseline CTF was associated with shorter PFS in both treatment arms. Longitudinal analyses showed more favorable outcomes with lower absolute CTF at C3D1 and, to a lesser extent, greater CTF decreases. CONCLUSION These results suggest that plasma ctDNA sequencing may allow reliable and convenient assessment of prognosis and identification of genetic markers associated with increased benefit from ipatasertib. On-treatment CTF showed a meaningful association with objective response and PFS.

We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80–63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26–155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.

Background/aim Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. Patients and methods We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). Results TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. Conclusion Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.

Bioluminescence (BL) is an excellent optical readout platform that has great potential to be utilized in various bioassays and molecular imaging. The advantages of BL-based bioassays include the long dynamic range, minimal background, high signal-to-noise ratios, biocompatibility for use in cell-based assays, no need of external light source for excitation, simplicity in the measurement system, and versatility in the assay design. The recent intensive research in BL has greatly diversified the available luciferase-luciferin systems in the bioassay toolbox. However, the wide variety does not promise their successful utilization in various bioassays as new tools. This is mainly due to complexity and confusion with the diversity, and the unavailability of defined standards. This review is intended to provide an overview of recent basic developments and applications in BL studies, and showcases the bioanalytical utilities. We hope that this review can be used as an instant reference on BL and provides useful guidance for readers in narrowing down their potential options in their own assay designs.

Background By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. Methods This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. Results A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24–89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). Conclusions In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Although immune-checkpoint inhibitors (ICIs) have emerged as therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), concerns have been raised on exceptional acceleration of tumor growth during treatment with ICIs, a condition described as hyperprogressive disease (HPD). This study examined the incidence, potential predictors, and clinical impact of HPD in R/M-HNSCC.We retrospectively collected data of patients with R/M-HNSCC treated with ICIs between January 2013 and June 2018 from 11 medical centers in Korea. HPD was defined as tumor growth kinetics ratio (TGKr) 2, which was calculated by comparing TGK on ICIs with that before treatment with ICIs.Of 125 patients, 68 (54.4%) obtained progressive disease as their best responses (progressors). HPD was identified in 18 (26.5% of progressors, 14.4% of total) patients. Relatively younger age, primary tumor of oral cavity, and previous locoregional irradiation were significant predictors of HPD according to multivariable analysis (p = 0.040, 0.027, and 0.015, respectively). Compared to patients without HPD, patients with HPD had significantly shorter median progression-free survival (PFS) (1.2 vs. 3.4 months, p 0.001) and overall survival (OS) (3.4 vs. 10.7 months, p = 0.047). However, interestingly, HPD did not significantly affect the therapeutic benefit of post-ICIs chemotherapy.Younger patients with oral cavity cancer or prior treatment with locoregional radiotherapy could be regarded potential risk groups for HPD in patients with R/M-HNSCC treated with ICIs. Although HPD could consistently predict poorer survival outcomes, patients who experienced HPD with ICIs should not be excluded from the subsequent salvage chemotherapy treatments.

Steel elements exhibit varying characteristics during site installation after shop manufacturing. There may be a mix-up owing to unclear management methods for transport, and deformation might occur during field installation. Moreover, the technical basis for evaluating repair methods is narrow. In this study, variations in material properties after performing mechanical calibration were determined for widely used steel types, such as SS400 and SM490, in which thicknesses of 30 mm and less are frequently used on sites. The test results showed that the mechanical calibration in unheated and thermal heating cases increased the yield strength and tensile strength of steel, and the Korea Standard value was satisfied. A yield ratio of approximately 85% or less was obtained, indicating sufficient toughness. In addition, variations owing to thermal heating did not occur when temperatures below 650 °C were applied.

Background/Aims: A considerable number of patients with Crohn’s disease still need intestinal resection surgery. Postoperative recurrence is an important issue in Crohn’s disease management, including the selection of high-risk patients. Eastern Asian patients showed several differences from Caucasian patients. Therefore, we investigated the postoperative surgical recurrence outcome and identified risk factors in Korean patients. Methods: Clinical data of 372 patients with Crohn’s disease who underwent first intestinal resection between January 2004 and August 2014 at 14 hospitals in Korea were retrospectively reviewed. Results: Over the follow-up period, 50 patients (17.1%) showed surgi cal recurrence. The cumulative surgical recurrence rate was 6.5% at 1 year and 15.4% at 7 years. Age under 16 (p=0.011; hazard ratio [HR], 5.136; 95% confidence interval [CI], 1.576 to 16.731), colonic involvement (p=0.023; HR , 2.011; 95% CI, 1.102 to 3.670), and the presence of perianal disease at surgery (p=0.008; HR, 2.239; 95% CI, 1.236 to 4.059) were independent risk factors associated with surgical recurrence. Postoperative thiopurine treatment (p=0.002; HR, 0.393; 95% CI, 0.218 to 0.710) was a protective factor for surgical recurrence. Conclusions: Among the disease characteristics at surgery, younger age, colonic location, and perianal le sions were independent risk factors for surgical recurrence. Postoperative thiopurine treatment significantly reduced the incidence of surgical recurrence. (Gut Liver 2020;14:331-337)

We demonstrate the potential of an eight-channel light sensing platform system, named Black Box I (BBI), for rapid and highly sensitive measurement of low-level light using a nonradioactive optical readout. We developed, normalized, and characterized the photon sensitivities of the eight channels of the BBI using placental alkaline phosphatase (PLAP) as a model imaging reporter. We found that the BBI system had a statistically strong linear correlation with the reference IVIS Lumina II system. When we applied normalization constants, we were able to optimize the photomultiplier tubes (PMT) of all eight channels of the BBI (up to r2 = 0.998). We investigated the biomedical utilities of BBI by: (i) determining alkaline phosphatase activities in mouse plasma samples as a diagnostic secretory biomarker of cancer, and (ii) diagnosing cancer metastases in the organs of mice bearing triple negative breast cancer. We provide an important new addition to low-cost biomedical instruments intended for pre-clinical diagnostic imaging with high sensitivity, high sample throughput, portability, and rapid on-site analysis of low-level light.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-08.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA 2 investigates tesetaxel plus a reduced dose of capecitabine as an all-oral regimen in taxane-naïve patients with HER2-, HR+ MBC. Trial design: CONTESSA 2 is a 125-patient, multinational, multicenter, single-arm, Phase 2 study of tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day for 14 days of each 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have not previously been treated with a taxane in any setting. Patients with CNS metastases are eligible. The primary endpoint is confirmed ORR assessed by an Independent Radiologic Review Committee (IRC). A sample size of 125 will allow the ORR to be estimated with a maximum standard error of < 5%. Secondary endpoints include duration of response, pharmacokinetics (PK) of tesetaxel and potential for a PK interaction between tesetaxel and capecitabine. Enrollment was initiated in January 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03858972). Citation Format: Lee Schwartzberg, Jamil Asselah, Igor Bondarenko, YeeSoo Chae, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Julie Lemieux, Mei-Ching Liu, Gavin Marx, Joyce O'Shaughnessy, Mafalda Oliveira, Hope Rugo, Andrew Seidman, Gail Wright, Joseph O'Connell, Thomas Wei, Sung-Bae Kim. CONTESSA 2: A multinational, multicenter, phase 2 study of tesetaxel plus a reduced dose of capecitabine in patients with HER2-, HR+ metastatic breast cancer (MBC) who have not previously received a taxane [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-07.

Background: Adagloxad simolenin (AS) is an investigational immune stimulant comprising the Globo H hexasaccharide epitope linked to the carrier protein keyhole limpet hemocyanin (KLH). KLH facilitates a more vigorous immune response given the weak antigen, Globo H. Furthermore, AS is co-administered with the potent saponin-based adjuvant OBI-821 to induce a humoral response. A phase 2 trial examining the correlation between Globo H expression and clinical outcomes showed that patients with metastatic breast cancer whose tumors had an H-score of ≥15 (validated immunohistochemical [IHC] assay to determine Globo H expression; range 0-300) treated with AS/OBI-821 had a trend for superior progression-free survival vs placebo. As previously reported, Globo H is expressed similarly among both hormone receptor-positive and triple-negative breast cancer tumor subtypes. In an effort to improve outcomes in TNBC, we are conducting a randomized phase 3 trial in this high-risk population. Study Aim: The primary objective is to determine the effect of AS/OBI-821 on invasive disease recurrence and disease-free survival in patients with TNBC at high risk for recurrence. Secondary objectives are to determine the impact of AS/OBI-821 on overall survival, quality of life (QoL), breast cancer-free interval, distant disease recurrence and disease-free survival, safety, and tolerability. Methods. Eligible patients will have TNBC (estrogen receptor/progesterone receptor Patients will be followed every 26 weeks for disease recurrence during the follow-up period until a total of 187 endpoint events (either disease recurrence or death) are reached or the last patient has been followed for 3 years after randomization. Enrolled patients will undergo imaging (baseline, weeks 28, 52, 76, 104, 130, 156, 208, 260) and clinical examination every 3 months for 2 years and every 6 months thereafter. QOL will be assessed (weeks 1, 28, 52, 76, 104, 130, 156, 208, 260) using the EORTC QLQ-C30 plus additional EORTC QLQ-BR23 for breast cancer and European Quality of Life 5 Dimensions 5 Levels questionnaire. Adverse events will be graded/recorded by investigators as per National Cancer Institute CTCAE v5.0. Blood/tumor tissue samples will be collected for exploratory assessments during/after end of trial. Present and target accrual: Approximately 110 study centers across Europe, North America, and Asia-Pacific will enroll an estimated 668 patients. Patients will be treated for up to 2 years and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last patient randomized. Survival follow-up is for 5 years from randomization of last patient. Citation Format: Hope S Rugo, Louis WC Chow, Javier Cortes, Peter A Fasching, Binghe Xu, Chiun-Sheng Huang, Sung-Bae Kim, Yen-Shen Lu, Rita Nanda, Priyanka Sharma, Richard B Schwab, Chen-En Tsai. Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adagloxad simolenin (OBI-822) and OBI-821 treatment in patients with early-stage triple-negative breast cancer (TNBC) at high risk for recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-03.

Background: Abemaciclib is an oral selective inhibitor of cyclin-dependent kinases 4 and 6 approved for hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer. In the randomized, 3-arm, phase 2 study monarcHER (NCT02675231) for HR+, HER2+ advanced breast cancer (ABC), abemaciclib in combination with trastuzumab (T) and fulvestrant (F) significantly improved investigator-assessed progression-free survival (whereas abemaciclib + T did not) versus (vs) T + physician’s choice of chemotherapy and demonstrated a tolerable safety profile. Here, patient-reported HRQoL, functioning, and symptoms are reported. Methods: In monarcHER, 237 postmenopausal (surgical, natural, or chemical ovarian suppression) women with ABC and ≥2 prior HER2+ directed therapies in the advanced setting were randomized 1:1:1 to abemaciclib (150 mg PO Q12H every 21 days) + T (IV infusion on D1 every 21 days) with F (500 mg IM on Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W; Arm A) or without F (Arm B) vs T + physician’s choice of chemotherapy (per label every 21 days; Arm C). Supportive measures to manage diarrhea were permitted. Patient-reported outcomes were measured at baseline and at each cycle using the modified Brief Pain Inventory-short form (mBPI-sf) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EuroQol 5-Dimension 5 Level (EQ-5D 5L) questionnaire was also collected. Higher scores on EORTC QLQ-C30 functional and health status/QoL scales indicate improvement whereas higher scores on EORTC QLQ-C30 symptom scales and mBPI-sf indicate worsening of symptoms/pain. The EQ-5D 5L index score was calculated from a set of item weights to derive a score of 0-1, with 1 representing the best health status. Treatment arm comparisons of change from baseline (all post-baseline visits) were conducted using a mixed model repeated measure, with .05 considered statistically significant. Clinical meaningfulness was defined as a ≥10-point score change from baseline (on a 0-100 scale) for EORTC QLQ-C30 and a 2-point score change from baseline for mBPI-sf. Results: Patient-reported outcome compliance rates were ≥90% through Cycle 15; the range for median duration of each treatment component of each arm was 7.5-10.0 cycles. Overall, no statistically significant or clinically meaningful changes from baseline differences were observed between treatment arms for mBPI-sf pain scores or EORTC QLQ-C30 global health score, function scales, or for symptoms of fatigue, dyspnea, appetite loss, or financial difficulties. Least square (LS) mean change from baseline differences showed statistically significant improvements in Arm A vs C for EORTC QLQ-C30 symptoms of pain (-6.81; p=.026) and insomnia (-6.39; p=.041). Worsening for the symptom of nausea/vomiting was statistically significant but not clinically meaningful in Arm A vs C (4.08; p=.043). Diarrhea showed a statistically significant and clinically meaningful worsening in Arm A vs C (19.27; p Conclusions: Quality of life was maintained for patient-reported pain, global health, functioning, and most symptoms when abemaciclib was added to T + F compared with physician’s choice of chemotherapy in patients with HR+, HER2+ ABC. Gastrointestinal-related symptoms were transient and consistent with the manageable, reversible adverse event profile. Citation Format: Sara M Tolaney, Andrew M Wardley, Stefania Zambelli, John F. Hilton, Tiffany A Troso-Sandoval, Francesco Ricci, Seock-Ah Im, Sung-Bae Kim, Stephen RD Johnston, Arlene Chan, Shom Goel, Kristen Catron, Zhengyu Yang, M. Corona Gianford, Gregory L Price, Fabrice André. Health-related quality of life (HRQoL) in monarcHER: Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in HR+, HER2+ advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-10.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.)

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.

In DESTINY-Breast01 (NCT03248492) and DESTINY-Breast03 (NCT03529110), trastuzumab deruxtecan (T-DXd) demonstrated unprecedented activity in patients (pts) with HER2+ (immunohistochemistry 3+; immunohistochemistry 2+/in situ hybridization+) advanced metastatic breast cancer (mBC), leading to regulatory approvals in several countries for HER2+ unresectable/mBC after a prior anti–HER2-based regimen. DESTINY-Breast02 (NCT03523585) is a phase 3 trial of T-DXd vs treatment of physician’s choice (TPC) in patients with centrally confirmed HER2+ mBC previously treated with trastuzumab emtansine (T-DM1). It acts as a confirmatory study for the pivotal phase 2 DESTINY-Breast01 trial. Here we report the primary results of DESTINY-Breast02. Methods: Pts with HER2+ mBC were randomized 2:1 to receive T-DXd or TPC (trastuzumab + capecitabine or lapatinib + capecitabine) and stratified by hormone receptor (HR) status (HR+/HR-), prior pertuzumab treatment, and history of visceral disease. The primary endpoint of this time-driven primary analysis was progression-free survival (PFS) as determined by blinded independent central review (BICR). The powered secondary endpoint was overall survival (OS). Other secondary endpoints included confirmed objective response rate (ORR) by BICR, duration of response (DoR) by BICR, PFS by investigator assessment, safety, and others. Results: 608 pts were randomized to receive T-DXd (n = 406) or TPC (n = 202). Pts receiving T-DXd and TPC had a median age of 54.2 years (range, 22.4-88.5 years) and 54.7 years (range, 24.7-86.5 years), respectively, with a median of 2 (range, 0-10 and range,1-8) prior lines of systemic therapy (excluding hormone therapy) in the metastatic setting. Median treatment duration was 11.3 mo in the T-DXd arm and ~4.5 mo in the TPC arm. Efficacy and safety results are shown in the table below. T-DXd significantly improved PFS (HR, 0.36; 95% CI, 0.28-0.45; P Conclusions: Results from DESTINY-Breast02 confirmed the clinical benefit and superiority of T-DXd over conventional chemotherapy-based regimens in pts with HER2+ mBC previously treated with T-DM1, as evidenced by significant and clinically meaningful improvements in PFS and OS. These data, together with earlier reported results from the DESTINY-Breast03 study of T-DXd vs T-DM1 solidify T-DXd as an optimal treatment option in pts with progressive HER2+ mBC across broad settings. Editorial Acknowledgment Under guidance of the authors, assistance in medical writing and editorial support was provided by Caylin Bosch, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy and Safety Results for T-DXd and TPC in Patients With HER2+ mBC Previously Treated With T-DM1 Citation Format: Ian Krop, Yeon H. Park, Sung-Bae Kim, Giuliano Borges, Sercan Aksoy, Joaquin Gavila Gregori, Rebecca Roylance, Elgene Lim, Rinat Yerushalmi, Flora Zagouri, Francois P. Duhoux, Tanja Fehm, Toshimi Takano, Anton Egorov, Iris Wu, Jillian Cathcart, Changan Chu, Fabrice Andre. GS2-01 Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-01.

Background: The prognostic value of stromal tumor-infiltrating lymphocytes (TILs) as a biomarker for triple-negative breast cancer (TNBC) has been extensively demonstrated in patients (pts) receiving (neo)adjuvant systemic therapy. In addition, several small studies suggest that a subset of pts with early-stage TNBC and high TILs have excellent long-term outcomes, even in the absence of systemic therapy [1-3]. However, data on the absolute risk of TNBC recurrence according to TIL levels in the absence of systemic therapy are limited and critical to inform the design of future systemic therapy de-escalation clinical trials. Methods: We conducted an individual patient data pooled analysis of 12 international cohorts of pts with TNBC treated with locoregional therapy but no systemic therapy. TNBC was defined as tumors with estrogen and progesterone receptor of < 1% and HER2 negative (IHC 0, 1+ or IHC 2+ and FISH negative) per local evaluation. TILs were locally assessed in hematoxylin & eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group guidelines (www.tilsinbreastcancer.org). We used the Kaplan-Meier method to assess survival outcomes according to prespecified TIL thresholds: 30% and 50%. Confidence intervals (CI) for survival probabilities were calculated using a percentile bootstrap method. The primary endpoint was invasive disease-free survival (iDFS, STEEP 2.0 definition). Key secondary outcomes included recurrence-free survival (RFS), distant disease-free survival (DDFS) and overall survival (OS). Results: 1,835 pts diagnosed with TNBC between 1982 and 2017 who did not receive systemic therapy were included. The median age at diagnosis was 56 (IQR 38-71). Menopausal status was known in 1,184 women, of whom 78% were post-menopausal. The median tumor size was 2.0 cm (IQR 1.2-2.6). Most pts (87%) had no axillary lymph node involvement (N0). Most tumors were invasive ductal carcinoma (74%) and grade 3 (70%). The median level of TILs was 15% (IQR 5-40). The median duration of follow-up was 30.4 years (95% CI 29.9, 31.1). A total of 950 (52%) iDFS, 828 (45%) RFS, 767 (42%) DDFS events, and 604 (33%) deaths were observed. In multivariable analyses, higher TILs were independently associated with improved iDFS, RFS, DDFS, and OS beyond clinicopathological factors (likelihood ratio p< 10e-6). Each 10% increment in stromal TILs was associated with an 8% (95% CI: 6-11), 10% (95% CI: 7-13), and 13% (95% CI: 10-15) reduction in the risk of experiencing an iDFS, RFS or DDFS event, and with a 12% (95% CI: 9-15) reduction in the risk of death. iDFS, RFS, DDFS and OS rates according to different TIL thresholds and nodal status are shown in the Table. Of note, the RFS estimates (which exclude second non-breast primaries and contralateral breast cancers) were consistently higher than the iDFS counterparts (which include both), consistent with a high rate of contralateral breast cancers and second primary tumors in this cohort. Notably, patients with node-negative—and especially stage I—TNBC with high TILs had excellent survival rates at 10-year follow-up. Conclusion: TILs are highly prognostic in pts with systemically untreated early-stage TNBC. Pts with pN0 (and especially stage I) TNBC with high TILs exhibited very favorable long-term outcomes even in the absence of systemic therapy. These data define the natural history of TIL-rich TNBC pts and are crucial to identifying the optimal patient population for future chemotherapy and immunotherapy de-escalation clinical trials. References: [1] Leon-Ferre et al, 2017, PMID: 28913760 [2] Park et al, 2019, PMID: 31566659 [3] de Jong et al, 2022, PMID: 35353548 Table 5 and 10-year survival endpoints according TIL level, nodal status, and stage Citation Format: Roberto A. Leon-Ferre, Sarah Flora Jonas, Roberto Salgado, Sherene Loi, Vincent De Jong, Jodi M. Carter, Torsten Nielson, Samuel Leung, Nazia Riaz, Giuseppe Curigliano, Carmen Criscitiello, Vincent Cockenpot, Matteo Lambertini, Vera Suman, Barbro Linderholm, John WM Martens, Carolien HM van Deurzen, Mieke Timmermans, Tatsunori Shimoi, Shu Yazaki, Masayuki Yoshida, Sung-Bae Kim, Hee Jin Lee, Maria Vittoria Dieci, Guillaume Bataillon, Anne Salomon, Fabrice Andre, Marleen Kok, Sabine Linn, Matthew P. Goetz, Stefan Michiels. Stromal tumor-infiltrating lymphocytes identify early-stage triple-negative breast cancer patients with favorable outcomes at 10-year follow-up in the absence of systemic therapy: a pooled analysis of 1835 patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD9-05.

Background: The Penelope-B trial did not show improvement in invasive disease-free survival (iDFS) with the addition of palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) after neoadjuvant chemotherapy (NACT). Biomarkers may be able to identify subgroups of patients deriving benefit from Palbociclib and guide future studies. Estrogen-receptor (ER), progesterone-receptor (PgR) and Ki-67 might be helpful in identifying patients benefiting from palbociclib. Concordantly, tumors with elevated expression of Cyclin D1 and phosphorylated retinoblastoma protein (phospho-RB) may harbor more dependency on CDK4/6 and thus higher sensitivity to palbociclib. Methods: The percentage of positive ER and PgR cells and Ki-67 assessed in surgical specimens after NACT were combined to obtain the immunohistochemical score 3 (IHC3, Cuzick et al JCO 2011, low vs high based on the median IHC3 value). Cyclin D1 and phospho-RB Ser 807/811 immunoreactive (phospho-RB) scores were analyzed in residual tumors after NACT (range 0-12 each). Proportional hazard regression model was used to assess the predictive and prognostic value of IHC3 and treatment on iDFS. Subgroup analysis was performed according to BC intrinsic subtypes (luminal-A/normal-like, luminal-B/HER2-enriched/basal) and HER2-status (HER2 0, HER2 low). Cox/Fine-Gray regression was used to define the predictive and prognostic value of CyclinD1 (≤1, >1), phospho-RB (≤2, >2) as dichotomized and continuous variables on iDFS, distant DFS (DDFS), locoregional invasive recurrence-free interval (LRRFI) and overall survival (OS). Multivariate analyses (MVA) were adjusted for age (≤50 vs >50), Ki-67 (≤15 vs >15), region (non-Asian vs Asian), ypN (ypN0-1 vs ypN2-3), risk status (CPS-EG=2 ypN+ vs ≥3), cT (cT1-2 vs cT3-4), ypT (ypT0-2 vs ypT3-4), and grade (G1-2 vs G3). The MVA for IHC3 includes all the covariates above except Ki-67. p< 0.05 was defined as statistically significant. Results: Data for ER, PgR, Ki-67, HER2, Cyclin D1 and phospho-RB were available for 1250 patients. Overall, 98.9% of the patients had ER+ tumors, 75.0% PgR+, 52.2% had HER2 low, 25.5% Ki-67>15, 50% had IHC3 score higher than median, 93.9% had Cyclin D1 >1, 57.8% had phospho-RB >2. Patients with IHC3 score high had a worse iDFS compared to patients with IHC3 score low (MVA HR 2.28 95%CI (1.78-2.91), p< 0.0001). Patients with luminal-A/normal-like tumors and IHC3 low had an improved iDFS with the addition of palbociclib to ET (MVA HR 0.35 95%CI (0.14-0.90), test for interaction p=0.01). No difference was observed according to HER2 status. Cyclin D1>1 has no predictive value but is prognostic for better iDFS (MVA HR 0.62 95%CI (0.41-0.94), p=0.023), LRRFI (MVA HR 0.30 95%CI (0.15-0.63), p=0.001) and OS (MVA HR 0.50 95%CI (0.28-0.89), p=0.019). Similar results were obtained when Cyclin D1 was analysed as a continuous variable. Phospho-RB had neither predictive nor prognostic value. Phospho-RB highly correlates with Ki-67 (p< 0.001, Spearman correlation 0.248). Conclusions: Patients with high Cyclin D1 expression had a favorable prognosis independent of treatment arm, but patients with luminal-A/normal-like tumors and IHC3 low after NACT had an improved outcome when receiving palbociclib in addition to adjuvant ET. Theses exploratory studies suggest specific signatures/phenotypes could predict benefit from Palbociclib in high-risk early breast cancer. Citation Format: Erik S. Knudsen, Sivaramakrishna Rachakonda, Frederik Marmé, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Wolfgang D. Schmitt, Sung-Bae Kim, Harry D. Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Bruno V. Sinn, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Nicholas Turner, Federico Rojo, Martin Filipits, Peter A. Fasching, Christian Schem, Lesley-Ann Martin, Yuan Liu, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Jenny Furlanetto, Karsten Weber, Carsten Denkert, Sibylle Loibl. Immunohistochemical markers and determinants of clinical response in the Penelope-B trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-06.

Background: CD166 is broadly expressed in normal epithelium and overexpressed in many types of malignancies, including breast cancer. Probody® therapeutic candidates are masked antibodies, conditionally activated by tumor-associated proteases, which restricts their activity to the tumor microenvironment and minimizes ‘off-tumor’ toxicity. CX-2009 is a conditionally activated humanized anti-CD166 monoclonal antibody conjugated to DM4 that showed clinical activity in ABC patients in a phase 1 study (Boni et al. Clin Cancer Res. 2022). This phase 2 study (NCT04596150) evaluates CX-2009 as monotherapy in patients with advanced HR+/HER2− BC (Arm A) and TNBC (Arm B), and in combination with pacmilimab (a conditionally activated PD-L1) in TNBC (Arm C). Methods: Key eligibility criteria for all cohorts include: ECOG 0-1, acceptable end-organ function, measurable disease, willingness to receive ocular prophylaxis for DM-4 related toxicity, and available tumor tissue for CD166 evaluation. Eligibility criteria for HR+ BC include: 2-4 prior regimens (excluding single-agent hormonal therapy with up to 2 prior cytotoxic regimens) and a prior CDK 4/6 inhibitor in the metastatic setting; eligibility criteria for TNBC include CD166 by IHC >1% by central assessment, 1-3 prior regimens in the metastatic setting and prior taxane. All patients initially received 7 mg/kg Q3W; the protocol was subsequently amended to enroll patients at 6 mg/kg Q3W. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by central review. Other key endpoints include ORR by investigator assessment, clinical benefit rate at 24 weeks (CBR24; defined as any response, confirmed or unconfirmed, or SD for 24 weeks), duration of response, and progression-free survival by investigator. Archival tumor specimens and blood samples were collected for correlative research including genomic analyses. Results: As of 13 May 2022, 60 patients were enrolled in Arm A (all patients started at 7 mg/kg); 52 were evaluable for efficacy by investigator. Median duration of follow-up was 29.1 weeks (range: 3.6-60.7). Median age was 60.5 years (36, 83); pts received a median of 3.5 (1, 6) prior treatments for ABC. CD166 H-Score > 200 was reported in 53.3% of patients. Arm A met the primary efficacy endpoint with a confirmed ORR by central radiology of 14.9% (n=47); by investigator, ORR was similar at 15.4% (n=52); an additional 9 patients (17.3%) had an unconfirmed response. CBR24 was 40.4%; using only confirmed responses, CBR24 was 23.1%. Median PFS was 11.4 weeks (95% CI 9.0, 13.9). Common treatment-related all-grade adverse events (TRAEs) included blurred vision (42%), nausea (35%), fatigue (35%), diarrhea (25%), peripheral neuropathy (27%), infusion-related reaction (23%) and decreased appetite (20%). Grade ≥3 ocular and neuropathic TRAEs were 15% and 10%, respectively. AEs resulting in treatment discontinuation (AEDC) were 25%. For Arm B and C, 55 and 10 patients were enrolled (the majority received a starting dose of 6 mg/kg). For Arm B, the futility boundary was crossed (ORR < 10%). Grade ≥3 ocular and neuropathic TRAEs and AEDC at 7 mg/kg in Arm B were similar to Arm A (11%, 11% and 21% respectively); whereas at 6 mg/kg, they were reduced at 3%, 0% and 0%, respectively. Biomarker data and correlation with outcomes will be presented. Conclusions: Praluzatamab ravtansine demonstrated single-agent activity in unselected heavily pretreated patients with HR+/HER2- ABC. Time to event analyses, such as PFS, were confounded by higher-than-expected toxicity at a starting dose of 7 mg/kg. The toxicity profile was generally consistent with a DM4 payload. The lower dose of 6 mg/kg appears to be better tolerated. Additional clinical studies in HR+ABC, incorporating a starting dose of 6 mg/kg and potentially including a biomarker strategy, are warranted. Citation Format: Kathy Miller, Sara Tolaney, Leisha A. Emens, Sung-Bae Kim, Erika Hamilton, Cristina Saura, Lucia Sanz, Valentina Boni, Filipa Lynce, Juan Miguel Cejalvo, Jennifer Crozier, Shirley Wang, Hirdesh Uppal, Alison L. Hannah, Sara Hurvitz. Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-15.

We examined whether

BackgroundIn the phase 3 KEYNOTE-522 trial, neoadjuvant pembrolizumab+chemotherapy followed by adjuvant pembrolizumab monotherapy resulted in a statistically significant improvement in pathologic complete response (pCR) and event-free survival, compared with neoadjuvant chemotherapy alone, in patients with early-stage TNBC. In the phase 1b KEYNOTE-173 (NCT02622074) trial—another neoadjuvant pembrolizumab+chemotherapy trial—we evaluated TNBC biopsy samples at baseline and collected after one cycle of neoadjuvant pembrolizumab, before the initiation of chemotherapy, to explore the features within the TME at both timepoints that might be potentially predictive of clinical response and the effects of a single cycle of pembrolizumab on cell populations within the TME.MethodsTwenty paired samples (baseline and obtained following one cycle of pembrolizumab before the initiation of chemotherapy) were included. Multiplex immunohistochemistry analyzed deconvoluted cell fractions by spatial localization (tumor compartment, stromal compartment, or total tumor) using three 6-plex panels: T cell (CD3/CD8/FoxP3/Ki67/granzyme B/PD-1), myeloid cell (CD68/CD163/MHCII/arginase/CD33/CD11c), and natural killer cell (CD16/CD56/CD11b/CD20/CD3/CD45). Area under the receiver operating characteristic (AUROC) was used to assess associations between immune subsets and pCR. Analyses were descriptive, with top-ranked findings reported, and were deemed hypothesis generating; no claims of statistical significance are made.ResultsAt baseline, 6 of 75 evaluated immune subsets (counting different compartments) showed 95% CIs of AUROC not crossing 0.5 with pCR. These include some myeloid cell populations within the tumor compartment (AUROC, 95% CI), specifically CD11c+ (macrophage and dendritic cell [DC]: 0.85, 0.63–1.00), CD11c+/MHCII+/CD163–/CD68– (DC: 0.76, 0.53–0.99), CD11c+/MHCII–/CD163–/CD68– (nonactivated/immature DC: 0.8, 0.54-1.00), and CD11c+/CD163+ (M2 macrophage: 0.77, 0.55–0.99). Other associations with pCR included baseline CD11c+/MHCII–/CD163–/CD68– (nonactivated/immature DC) within the total tumor (AUROC, 0.76; 95% CI, 0.51–1.00) and the baseline ratio of CD11c/CD3 within the tumor compartment (AUROC, 0.75; 95% CI, 0.52–0.98). Although T-cell associations were relatively weak, specific CD8 subsets, especially CD8+/granzyme B+/Ki67+, showed a trend toward association. Negative correlations between change from baseline and baseline values were observed; therefore, baseline detrending was applied to change from baseline values. One immune subset showed a negative association trend between change from baseline and pCR after baseline detrending: CD163+/MHCII+ (DC3) within the stroma (AUROC, 0.2; 95% CI, 0.0–0.42).ConclusionsAlthough the sample size in this exploratory analysis was small (n=20), myeloid cell populations within the tumor compartment at baseline show a promising association trend, as evaluated by AUROC, with pCR after neoadjuvant pembrolizumab+chemotherapy in early-stage TNBC. Changes in immune subsets following one cycle of pembrolizumab were not strongly associated with pCR.Trial RegistrationClinicalTrialsgov, NCT02622074Ethics ApprovalThe study protocol and all amendments were approved by the relevant institutional review board or ethics committee at each study site.ConsentAll patients provided written informed consent to participate in the clinical trial.