Early Triple-negative Breast Cancer Research Articles

Systemic treatment of patients with early breast cancer: recent updates and state of the art

This review is focused on trials generating results that potentially impacted clinical practice since the 2017 St. Gallen Consensus; the most impactful trial was KATHERINE, which revealed a 11.3% absolute iDFS improvement with T-DM1 (compared to trastuzumab) in HER2-positive breast cancer patients who presented invasive residual disease following neoadjuvant treatment. These results, if reinforced by a subsequent overall survival benefit, will consolidate neoadjuvant treatment as the standard-of-care for most HER2-positive breast cancer patients. The addition of pertuzumab to adjuvant trastuzumab (APHINITY) or extending anti-HER2 therapy with 1 year of neratinib (ExteNET) also improved outcomes, but in a more modest way. In triple-negative early breast cancer patients presenting invasive residual disease after neoadjuvant chemotherapy, the CREATE-X trial demonstrated the benefit of post-neoadjuvant capecitabine. In patients with luminal tumours, updated results of the SOFT/TEXT trials confirmed the benefit of aromatase inhibitors plus ovarian suppression in high-risk premenopausal patients, and the 12-year results of the BIG1–98 trial demonstrated a sustained trend in favour of letrozole compared to tamoxifen in the adjuvant treatment of postmenopausal patients. The TAILOR-X study showed that, overall, patients with an intermediate recurrence risk score (11–25) in the OncotypeDX 21-gene assay did not benefit from adjuvant chemotherapy. A meta-analysis performed by the EBCTCG demonstrated that extended adjuvant aromatase inhibitors modestly reduced breast cancer recurrence risks, with a more pronounced benefit in patients previously treated with tamoxifen. Finally, an EBCTCG meta-analysis including patients with all breast cancer subtypes showed that dose-dense chemotherapy improved survival when compared to conventionally-timed chemotherapy.

Dose-Dense Paclitaxel Plus Carboplatin (PCdd) versus Epirubicin and Cyclophosphamide (ECdd) Followed by Paclitaxel (P) As Adjuvant Chemotherapy in Early Triple-Negative Breast Cancer at High Risk of Recurrence, A Randomised, Open-Label, Phase 3 Trial

Background: Triple-negative breast cancer (TNBC) may be more sensitive to platinum-based regimens. This open-label, randomized phase III trial aimed to compare dose dense paclitaxel plus carboplatin (PCdd) with dose-dense epirubicin and cyclophosphamide followed by paclitaxel (ECdd-P) regimen as adjuvant chemotherapy (AC) for high-risk early TNBC. Methods: We included Chinese patients with high recurrence risk TNBC who underwent primary breast surgery. They were randomly assigned in a 1:1 ratio to receive PCdd (paclitaxel 150 mg/m2 on day 1 and carboplatin AUC=3 on day 2 for 8 cycles) or ECdd-P (epirubicin 80 mg/m2 divided in 2 days and cyclophosphamide 600 mg/m2 on day 1 for 4 cycles followed by paclitaxel 175 mg/m2 on day 1 for 4 cycles) every 2 weeks, with granulocyte colony-stimulating factor (G-CSF) support. The primary endpoint was 3-year disease-free survival (DFS); the secondary endpoints were overall survival (OS) and safety. Findings: The intent-to-treat population included 143 patients (70 in the PCdd arm and 73 in the ECdd-P arm). Compared with the ECdd-P arm, the PCdd arm had significantly higher 3-year DFS (93⋅9% vs.79⋅1%, hazard ratio[HR]=3⋅224, 95% confidence interval [CI] =1⋅420-7⋅321, log-rank p=0⋅0051) and OS (98⋅5% vs.92⋅9% [HR] =7⋅092, 95% CI=1⋅212-16⋅630, log-rank p=0⋅0281). The 3-year DFS in the PCdd arm was significantly higher (p 40 years, Ki-67>30, and clinically evaluated lymph nodes. Both regimens were well tolerated. Worse neutropenia (grade 3/4) was found in the ECdd-P arm (47⋅9% vs. 21⋅4%, p=0⋅001). Interpretation: PCdd was superior to ECdd-P as AC for early TNBC with respect to improving the 3-year DFS and OS. PCdd also yields lower hematological toxicity.Thus, PCdd might be a preferred AC regimen for early TNBC patients with high recurrence risk. Trial Registration: This trial is registered at ClinicalTrials. gov (number NCT01378533). Funding Statement: This study was supported by National Key Research and Development Program of China (2018YFC1312101); and Chinese Academy of Medical Science Initiative funded this study for Innovative Medicine (CAMS-12M-1-010). Declaration of Interests: All authors declare no conflicts of interest. Ethics Approval Statement: All interventions were performed in accordance with Chinese laws and regulations and the Helsinki declaration. The study protocol was approved by the independent ethics board committee at the National Cancer Center, Chinese Academy of Medical Sciences (Approval number: CH-BC-012).

LBA8_PR - KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)

LBA8_PR - KEYNOTE-522: Phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)

236P - Clinical decision making and multidisciplinary team meetings (MDMs) in early breast cancer. Is the agreement between planned and applied therapeutic program?

BackgroundCancer multidisciplinary team meetings (MDMs) are commonly acknowledged as a good clinical practice. One of the roles of MDMs is to identify the best diagnostic and therapeutic strategies for patients (pts) with new diagnosis of early breast cancer (EBC). In this setting, the purpose of the study was to define whether there was agreement between the planned program (i.e. MDMs-based decision) and that actually applied (i.e. actual therapeutic choice, ATC). In addition, the study explored factors associated with discordance. MethodsWe conducted a monocentric retrospective study of a consecutive series of 291 pts with new diagnosis of EBC, discussed at MDMs at the University Hospital of Udine (Italy), from January 2017 to June 2018. ResultsMedian age was 62 years (range 27-88 years). Among invasive EBC patients, the most frequent phenotype was luminal-A (38%), followed by luminal-B (33%), HER2-positive (12%) and triple negative (5%). Thirty-four pts (12%) had diagnosis of in situ carcinoma (DCIS). Median time from MDMs discussion to first oncological examination was two weeks. Rate of discordance between MDMs-based decision and final choice, during face to face consultation with the oncologist, was 15.8% (46/291). Among cases with discordance, 19 pts (41.3%) had age > 70 years; 8 pts (17%) had a diagnosis of DCIS, 13 pts (28%) luminal-B carcinoma, 12 pts (26%) luminal-A, 9 pts (20%) HER2-positive and 4 pts (9%) triple negative EBC. The most frequent reason for changing the MDMs-based program was clinical decision by the oncologist at the first evaluation (87%). Follow-up was preferred to the chemotherapy proposed within the MDMs by 15% of pts, and to the endocrine therapy in 39% cases (among these, 44.5% had diagnosis of DCIS). In our study 16/46 pts (35%) had a therapeutic change from chemotherapy to endocrine therapy: among these pts, 7/16 had a luminal-B and 6/16 had a HER2-positive disease. Further analysis aiming at evaluating variables which could predict discordance between MDMs proposal and face to face oncological consultation are ongoing. ConclusionsThe results of our study could be useful for enhance the role of MTD and identify unmet needs in decision making process in EBC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

289TiP - ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early stage triple negative breast cancer

BackgroundEarly stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer. On March 8th 2019, the Food and Drug Administration approved anti–PD-L1 antibody, atezolizumab, in combination with chemotherapy for the treatment of PD-L1-positive unresectable locally advanced or metastatic TNBC based on the results of the randomized phase 3 IMpassion130 trial. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial currently investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane adjuvant chemotherapy versus chemotherapy alone in early stage TNBC. Trial designALEXANDRA/IMpassion030 will randomize 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant chemotherapy consist of weekly paclitaxel 80mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90mg/m2 or doxorubicin 60mg/m2) and cyclophosphamide 600mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840mg every 2 weeks followed by maintenance atezolizumab 1200mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first site was activated May 4th 2018, and approximately 430 sites are expected to open globally in 30 countries. This trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinical trial identificationNCT03498716. Legal entity responsible for the studyThis trial is sponsored by Roche and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. FundingRoche. DisclosureM. Ignatiadis: Advisory / Consultancy: Celgene, Novartis, Pfizer, Seattle Genetics, Tesaro; Research grant / Funding (institution): Roche, Menarini Silicon Biosystems, Janssen Diagnostics, Pfizer; Travel / Accommodation / Expenses: Pfizer,Bayer. H.L. McArthur: Advisory / Consultancy: LIlly, Amgen, Immunomedics, Pfizer, Genentech, BMS, Genomic Health, Merck, spectrum pharmaceuticals; Research grant / Funding (institution): BMS, Lilly, Merck, Ziopharm Oncology. J. Martinez: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.. C. Lai: Full / Part-time employment: Roche/Genentech; Shareholder / Stockholder / Stock options: Roche/Genentech. T. Goulioti: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.; Shareholder / Stockholder / Stock options: GlaxoSmithKline; Spouse / Financial dependant: GlaxoSmithKline, UCB. A. Bouhlel: Full / Part-time employment: Roche. V. Balta: Research grant / Funding (institution): AstraZeneca, Roche/Genentech, Pfizer, Novartis, Tesaro, Servier, GlaxoSmithKline.. G. Viale: Honoraria (self): MSD Oncology; Advisory / Consultancy: Dako, Roche/genentech, Astellas Pharma, Novartis; Research grant / Funding (self): Roche/genentech; Research grant / Funding (institution): Ventana Medical Systems, Dako/Agilent Technologies; Travel / Accommodation / Expenses: Roche, Celgene. D.A. Nguyen: Shareholder / Stockholder / Stock options: Roche/Genentech; Full / Part-time employment: Roche/Genentech. R.D. Gelber: Research grant / Funding (institution): Roche, Novartis, Pfizer, Merck, Celgene, Ferring, Ipsen, AstraZeneca. M. Piccart: Officer / Board of Directors: Radius; Advisory / Consultancy: AstraZeneca, Lilly, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Camel-IDS, Crescendo Biologics, Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics, Menarini, Seattle Genetics, Immunomedics, Oncolytics; Research grant / Funding (institution): AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech, Synthon, Radius, Servier. E.P. Winer: Honoraria (self): Genentech, Leap, Carrick Therapeutics, Lilly, Seattle Genetics, GSK. All other authors have declared no conflicts of interest.

175O - Prognostic value of tumour infiltrating lymphocytes (TILs) in patients with early-stage triple negative breast cancers (TNBC) in the absence of chemotherapy

BackgroundStromal tumor-infiltrating lymphocytes (sTILs) have been shown to be a strong prognostic factor in early-stage triple negative breast cancer (TNBC). There is limited data on their prognostic value in TNBC patients in the absence of adjuvant chemotherapy. MethodsWe performed a pooled analysis of TNBC patient series not treated with chemotherapy. The percentage infiltration of sTILs was retrospectively evaluated in the most representative tumoral block of surgical specimens. Cox proportional hazards regression models stratified by series were used for invasive disease-free survival (iDFS), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors. ResultsWe collected individual data from 518 patients from four series. Average age was 64 years (range, 24 to 96 years), and 83% of patients were node-negative. The median size was 1.6cm (Q1-Q3: 1.6-2.5), and 82.7% of the cases were node-negative. Tumours were grade 1, 2 and 3 in 12%, 38% and 50% of the cases. The median level of sTILs was 10% (Q1-Q3, 4-30%). Higher grade was associated with larger amount of sTILs (p<10-3). During follow-up, a total of 173 iDFS, 118 D-DFS events and 107 deaths were observed. In the multivariable model which included the number of lymph nodes, tumour size, age, tumour grade and radiotherapy treatment, sTILs added significant independent prognostic information for all endpoints (likelihood ratio chi2= 7.14 for iDFS; p<10-2; chi2= 9.63 for D-DFS, p<10-2; chi2= 5.96 for OS, p=0.015). Each 10% increment in sTILs corresponded to a hazard ratio of 0.90 (95% CI, 0.82 to 0.97) for iDFS, 0.86 (95% CI, 0.77 to 0.95) for D-DFS, and 0.88 (95% CI, 0.79 to 0.98) for OS. In patients with stage I tumors with sTILs≥30% (n=74), 5-year iDFS was 91% (95% CI, 84% to 98%), D-DFS was 97% (95% CI, 93% to 100%), and OS was 98% (95% CI, 95% to 100%). ConclusionssTILs provide important prognostic information in systemically untreated early stage TNBC patients. sTILs may be used to identify stage I TNBC patients with excellent prognosis in whom chemotherapy may be withheld. Legal entity responsible for the studyThe authors. FundingANR and CGI (RHU MyPROBE, ANR-17-RHUS-0008). DisclosureM.V. Dieci: Advisory / Consultancy: Lily, Celgene, Genomic Health. C. Criscitiello: Honoraria (self), for speaker engagements and consultancy roles: Pfizer; Honoraria (self), for speaker engagements and consultancy roles: Roche; Honoraria (self), for speaker engagements and consultancy roles: Lily; Honoraria (self), for speaker engagements and consultancy roles: Novartis. R.F. Salgado: Travel / Accommodation / Expenses, travel support: Roche, Merck, AstraZeneca; Travel / Accommodation / Expenses, congress support: Roche, Merck; Research grant / Funding (self), Data and safety monitoring member: Roche, Merk, Puma; Advisory / Consultancy, Advisory board: Roche, BMS. S. Loi: Research grant / Funding (institution): Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology ,Pfizer and Eli Lilly; Advisory / Consultancy, but not compensated: Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech. S. Kim: Research grant / Funding (institution): Novartis, Sanofi-Genzyme, Dongkook Inc. G. Curigliano: Honoraria (institution), institutional fees from them: Merck, Roche, SEAGEN, Daichi Sankyo, Novartis, Pfizer. F. André: Research grant / Funding (institution): Pfizer, AstraZeneca, Novartis, Lilly, Roche, daiichi; Advisory / Consultancy: Pfizer, AstraZeneca, Novartis, Lilly, Roche, daiichi. S. Michiels: Advisory / Consultancy, punctual statistical advice: IDDI, Belgium; Advisory / Consultancy, advice on surrogacy: Janssen Cilag France; Advisory / Consultancy, Data and safety monitoring member: Hexal, J&J, Ipsen, Neovacs, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis. All other authors have declared no conflicts of interest.

213P - Response to neoadjuvant chemotherapy in HER2 non-overexpressing breast cancer subtypes

BackgroundPathologic complete response (pCR) is a surrogate marker of a better relapse-free (RFS) and overall survival (OS), particularly in HER2 overexpressing and triple-negative breast cancer (TNBC) subtypes. Our aim is to assess the impact of HER2 expression level on pCR, in patients with luminal or TNBC treated with neoadjuvant chemotherapy (NAC). MethodsWe conducted a retrospective analysis in luminal and TN non-metastatic breast cancer patients, addressed to cancer center Georges François Leclerc in Dijon for NAC. Hormone receptor and HER2 expression were centrally assessed according to CAP/ASCO criteria. The pathologic response was dichotomized in pCR and non-pCR and evaluated according to Chevalier classification. ResultsBetween 2007 and 2018, 761 patients (pts) were recorded, of which 263 (34.5%) had TNBC and 498 (65.5%) luminal-HER2 negative BC. Among TNBC, 189 pts (70.8%), 54 pts (20.2%) and 24 pts (8.9%) had respectively score 0, 1 and 2, and negative FISH. In luminal tumors these results were respectively 246 (49.3%), 181 (36.3%) and 21 (4.2%). Median age, size of primary tumour and lymph node involvement were similar in both subpopulations. Regarding NAC, 20.9% received only taxanes, 22.1% only anthracyclines and 55.1% both agents. The combination was more often recommended in TNBC 74.2% vs 59.3% (p=0.03). pCR rate in the primary tumour and lymph nodes was 29% (157 pts) in the whole cohort. This rate varied according to HER2 expression (0, 1+, 2+) from respectively 48.6% (51pts), 36.4% (8pts) and 28.6% (4pts) (p=0.256) in TNBC and from 8.5% (7pts), 5.3% (5pts) and 4.1% (2pts) (p=0.532) among luminal tumors. Both OS and RFS were associated with a good Chevalier pathologic response (p<0.001) in TNBC but not in luminal tumours (p=0.5257 and p=0.9845). Neither pCR, nor the Chevalier response was statistically correlated with HER2 score. ConclusionsNo correlation between pCR and the level of HER 2 expression was found neither in luminal nor in TNBC patients. In TNBC patients, differences in terms of pCR were noticed between the 3 HER expression groups. The predictive role of HER2 expression should be further explored in early localized TNBC in a larger population. Editorial acknowledgementIsabel Gregoire, medical writer, Department of Biostatistics Georges Francois Leclerc Cancer Center, Dijon, France. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Precision Medicine in Triple Negative Breast Cancer: The Future is Coming

Abstract Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, with high recurrence rate and short survival after metastasis. However, TNBC is a pathologically and clinically heterogenous disease. Chemotherapy is currently the main treatment choice for TNBC. Tremendous effort has been devoted to identifying new treatment regimen in high-risk or metastatic TNBC patients. Recent studies have classified TNBC into several distinct molecular subtypes and proposed new treatment regimen. In this presentation, the strategies to identify high-risk and decrease relapse in early TNBC patients will be discussed. Furthermore, new treatment strategies in specific subtypes of TNBC patients will be presented, including anti-androgen in androgen receptor-positive TNBC patients, PARP inhibitors in BRCA mutant or High HRD patients, combination immunotherapy, and other approaches. There has never been a better time for precise treatment in TNBC patients.

Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer

Chemokine Modulation Therapy and Standard Chemotherapy Before Surgery for the Treatment of Early Stage Triple Negative Breast Cancer

Contemplations on MDMX (MDM4) driving triple negative breast cancer circulating tumor cells and metastasis.

MDMX (MDM4) is emerging as an important breast cancer (BC) biomarker, and oncoprotein, that can be targeted in combination with its well-known family member MDM2. While MDM2 has previously been implicated in driving BC metastasis, information about the role of MDMX in driving circulating tumor cells (CTCs) and BC metastasis is lacking. BCs often have alterations of MDM2, MDMX, and mutant p53 (mtp53). Therefore, the role of MDM2 and MDMX in the context of mtp53 in BCs requires further clarification. Our group has recently reported that triple negative breast cancer (TNBC) metastasis is dependent on both MDM2 and MDMX, and depleting MDM2 results in increased MDMX, but depleting MDMX does not cause an increase in MDM2. In the context of human TNBC expressing mtp53 in an orthotopic mouse model the down-regulation of MDMX virtually cleared CTCs from the blood. Contemplations, using the available literature, suggest that disrupting the stability and/or function of MDMX protein (and its downstream targets), in the context of mtp53 expressing BCs, might be beneficial for patient survival. It remains to be determined if blocking mtp53-MDMX pathways can inhibit early stage TNBC and eliminate CTCs that have the potential to form metastatic lesions.

Radiation treatment in early stage triple‐negative breast cancer in New Zealand: A national database study

We aimed to investigate the impact of radiation treatment in early-stage triple negative breast cancer (TNBC). Patients with early stage (T1-3, N0-2, M0) TNBC were identified using the New Zealand breast cancer register. The outcomes of local recurrence (LRFR), local recurrence free survival (LRFS), loco-regional recurrence free rate (LRRFR), loco-regional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), metastasis free (MFS) and overall survival (OS) were determined. Predefined univariate and multivariate cox regression analyses were used to explore associations between known prognostic and treatment factors. 1209 patients were identified with a median follow-up of 3.88years. The majority were post- menopausal. The mean tumour size was 26mm, the majority had grade III disease and a third were node positive. 625 patients had mastectomy and 584 had breast conservation surgery (BCS). 92% of BCS and 38% of mastectomy patients received radiation. 67% received adjuvant chemotherapy. The 5year OS was 77.6% (95% CI 74.6-80.2), 5year BSS was 82.1% (95%CI 79.1-84.7), 5year LRRFS was 73.9% (95% CI 73.87-73.93), 5year LRFS was 75.4 (75.37-75.43) and the 5year LRFR was 92.4% (95% CI 90.6-94.2). The significant prognostic/predictive factors for OS were adjuvant radiation treatment, chemotherapy, T stage, lymph node involvement and lympho-vascular space invasion. Results were similar for BSS, DMFS, LRFS and LRRFS except that LVSI was not significantly associated with BCSS, LRFS or LRRFS. When analysed by surgical type, in the WLE group, radiation was found to be significantly associated with improvement in all outcomes. In mastectomy group, radiation was not found to be significant for BCSS, LRFS, LRRFS or OS. Radiation treatment is significantly associated with improved outcomes in early stage TNBC. This argues against the hypothesis that TNBC has inherent radiation resistance.

Early triple negative breast cancer: Are we getting better outcomes? A retrospective analysis from a single institution.

Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10years OS, DFS, and DRFI were 77% and 65%; 60% and 46%; and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77%; 68% and 54%, 77% both at 5 and 10years. Prognosis is better than previously described; adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.

Abstract 3353: Four vs six cycles of docetaxel and cyclophosphamide (TC) in early stage triple-negative breast cancer

Abstract Background: ABC trials established the use of non-anthracycline containing regimen, docetaxel and cyclophosphamide (TC) in the adjuvant setting in early stage breast cancer. In clinical practice, TC is commonly used in Stage I Triple-Negative Breast Cancer (TNBC). However, no specific recommendations exist in literature, regarding the number of cycles that can be used. i.e. TC4 vs TC6. Our aim, was to determine if TC4 is non-inferior to TC6 when used as adjuvant therapy in early stage TNBC. Methods: We retrospectively reviewed 77 patients who were diagnosed with early stage TNBC between 2007 to 2017, at our institution who had received either TC4 or TC6 as adjuvant therapy. The number of cycles the patients received were based on provider preference. The two groups (TC4, TC6) were compared in regard to stage of cancer at diagnosis based on AJCC 7thedition, grade of adverse events, recurrence and death from breast cancer recurrence. Results: Out of 77 patients, based on T stage, 25 (32.5%) were T1b, 38(49.4%) were T1c, 13(16.9%) were T2 and 1(1.3%) was T3. All patients were node negative. 53(68.8%) received TC4 and 24(31.2%) received TC6. Regarding side effects, adverse of any grade were seen in 42(79.2%) patients who received TC4 and 23(95.8%) in patients who received TC6(p=0.091). Adverse events which were grade 3 or higher were seen in 7(15.9%) in TC4 group and 3(13%) in the TC6 group (p=1.000). Recurrence in the TC4 group was seen in 4 patients (7.5%) and 3(12.5%) patient in the TC6 group (p=0.259). Death due to breast cancer recurrence was seen in 1 patient (1.9%) in the TC4 group and 1(4.1%) patient in the TC6 group. Conclusions: In this limited series, TC4 appears to be equally effective to TC6, with fewer adverse events of any grade. However, a longer follow up and a larger patient base is required to be studied for a more definitive conclusion. Citation Format: Aparna Basu, Hadi A. Mohammed, Sharmeen Mahmood, Vrushali Dabak, Randa Loutfi. Four vs six cycles of docetaxel and cyclophosphamide (TC) in early stage triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3353.

Abstract 4891: Gene expression analysis of paired baseline (BL) and on-treatment tumor samples from FAIRLANE, a double-blind placebo (PBO)-controlled randomized phase II trial of neoadjuvant ipatasertib (IPAT) plus paclitaxel (PAC) in early triple-negative breast cancer (eTNBC)

Abstract Purpose: In the FAIRLANE trial (NCT02301988) in eTNBC, adding the oral AKT inhibitor IPAT to neoadjuvant PAC led to numerical increases in rates of pathologic complete response (pCR; primary endpoint) and complete response (CR) by MRI in unselected patients (pts), with a numerically greater treatment effect in pts with PIK3CA/AKT1/PTEN-altered tumors [Oliveira et al., AACR 2018]. There was no association between PIK3CA/AKT1/PTEN alterations and response in the PBO arm. Gene expression analysis was performed to evaluate on-treatment changes in the tumor microenvironment and association with response in both treatment arms. Methods: Gene expression at BL and cycle 1 day 8 (C1D8) was evaluated by RNA sequencing using TruSeq RNA Access (Illumina, Inc., San Diego, CA, USA) at Expression Analysis (Morrisville, NC, USA). Paired samples (pts with RNA-seq at both BL and C1D8) were compared to assess on-treatment changes in gene expression. Using RNA-seq data, in silico cell-type enrichment analysis was performed using xCell to calculate the percentage of infiltrating immune cells [Aran et al., Genome Biol 2017]. Results: Paired samples were available from 87 (58%) of the 151 treated pts; response results in this subset were representative of the overall population. Calculated infiltrating immune cell scores (xCell) increased from BL to C1D8 in both treatment arms, exemplified by increases in multiple immune cell biomarkers (eg CD8A, GZMA, CXCL9, CD274/PD-L1). In the PBO arm, higher C1D8 immune score showed a significant association with better response (pCR or response by MRI); the association was stronger for C1D8 than for BL or change from BL immune score. However, there was no association between immune score (BL, C1D8, or change from BL) and response in the IPAT arm. At C1D8, IPAT-treated pts with a CR by MRI had lower average immune scores than PBO-treated pts with a CR. Among the 14 IPAT-treated pts who achieved a CR by MRI, all 7 pts with immune scores below the median had PIK3CA/AKT1/PTEN-altered tumors compared with only 3 of 7 pts with immune scores above the median. Conclusions: This exploratory gene expression analysis revealed differential associations of immune infiltration and tumor response depending on treatment. PAC treatment appears to increase immune cell infiltration in the eTNBC setting, and the presence of a T cell-rich environment (at C1D8) is strongly associated with improved outcomes in pts treated with single-agent PAC. However, the addition of AKT inhibition to PAC is especially effective in pts with PIK3CA/AKT1/PTEN-altered tumors, including those with low immune infiltration. Together, the results hint at multiple mechanisms in killing tumor cells when combining IPAT with PAC. Citation Format: Zhen Shi, Steven J. Isakoff, Cristina Saura, Paolo Nuciforo, Isabel Calvo, Jay Andersen, José Luis Passos Coelho, Miguel Gil Gil, Begoña Bermejo, Debra A. Patt, Eva Ciruelos, Matthew J. Wongchenko, Stina M. Singel, Na Xu, Lorena de la Peña, José Baselga, Steven Gendreau, Mafalda Oliveira. Gene expression analysis of paired baseline (BL) and on-treatment tumor samples from FAIRLANE, a double-blind placebo (PBO)-controlled randomized phase II trial of neoadjuvant ipatasertib (IPAT) plus paclitaxel (PAC) in early triple-negative breast cancer (eTNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4891.

Abstract 3547: MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1

Abstract Background and Objectives: Del-1 is linked to the pathogenesis of various cancers including breast cancer; however, the regulation of Del-1 expression remains unclear. The current study investigated how microRNA-496 (miR-496) regulates Del-1 expression in triple negative breast cancer (TNBC). Methods: Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined in MTT, wound healing, and Matrigel Transwell assays, respectively. Results: In MDA-MB-231, miR-496 levels were remarkably low and Del-1 mRNA was higher compared to other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3′-UTR of Del-1 and that Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P &amp;lt; 0.005) and the levels of Del-1 in the plasma was significantly elevated as compared to normal controls (P = 0.0142). TCGA data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. Conclusions: In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and Del-1 might act as modulating factors in TNBC and are new biomarkers for patients with TNBC. Citation Format: Dong Won Baek, Jae-Hwan Jeong, Soo Jung Lee, Jiyeon Lee, Yee Soo Chae, Wan WooK Kim, Jieun Kang, Ho Yong Park, Jin Hyang Jung, Ji Yun Jeong, Ji Young Park, Keon Uk Park. MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3547.

Oncogenic lncRNA downregulates cancer cell antigen presentation and intrinsic tumor suppression.

The mechanisms through which tumor cells genetically lose antigenicity and evade immune checkpoints remain largely elusive. Here, we report that tissue-specific expression of the human long-noncoding RNA LINK-A in mouse mammary glands initiated metastatic mammary gland tumors, which phenotypically resembled human triple-negative breast cancer (TNBC). LINK-A expression facilitated crosstalk between phosphatidylinositol-(3,4,5)-trisphosphate and inhibitory G-protein–coupled receptor (GPCR) pathways, attenuating protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase TRIM71. Consequently, LINK-A expression enhanced K48–polyubiquitination-mediated degradation of the antigen peptide-loading complex (PLC) and intrinsic tumor suppressors Rb and p53. Treatment with LINK-A-locked nucleic acids or GPCR antagonists stabilized the PLC components, Rb, and p53, and sensitized mammary gland tumors to immune checkpoint blockers (ICBs). Importantly, PD-1 blockade-resistant TNBC patients exhibited elevated LINK-A levels and downregulated PLC components. Hence, we demonstrated lncRNA-dependent downregulation of antigenicity and intrinsic tumor suppression, which may provide the basis for developing a therapeutic regimen of combinational immunotherapy and effective early prevention for TNBCs.

Intrinsic Prognostic Impact of Tumor-infiltrating Lymphocytes in Systemically Untreated Patients With Early-stage Triple-negative Breast Cancer

The prognostic value of tumor-infiltrating lymphocytes (TILs) in curatively resected, but systemically untreated early-stage triple-negative breast cancer (TNBC) was investigated. Patients with systemically untreated early TNBC between 1999 and 2012 were retrospectively reviewed. A low TIL level was defined as the presence of ≤10% stromal TILs Relapses were classified into locoregional and distant relapse. The primary endpoint was breast cancer-specific survival (BCSS). In 72 patients, the median TIL value was 10%, and low TIL status was found in 54.2%. Patients with pT1 and nodal-positive disease constituted 75% and 11.1%, respectively. With a median follow-up of 99 months, 26.4% patients experienced relapse; local in 63.2%, distant in 36.8%, and 9.7% died of disease progression. A low TIL level was significantly associated with distant relapse (p=0.013), and inferior 10-year BCSS, which was consistently observed in patients with T1a/b or N0 disease. A low TIL level seems to be an intrinsic prognostic factor in systemically untreated patients with early-stage TNBC, even in the T1a/bN0 subset.

Prognosis value of a genetic score based on germline genetic variants in a prospective cohort of early triple-negative breast cancer patients.

1529 Background: Triple-negative breast cancers (TNBC) are a heterogeneous group of tumors with poor outcome. In this study, the association between germline genetic variants and invasive disease-free survival (iDFS) was analyzed in TNBC patients. Methods: A genome wide-association study (GWAS) aimed to identify variants (single nucleotide polymorphisms – SNPs) associated with prognosis in 1121 patients with TNBC in the SIGNAL prospective cohort. Associations between gene variants and iDFS were assessed in univariate Cox regression models. Variants were combined in a score to identify risk categories. A prognostic model based on breast cancer stage and genetic variants was estimated using a multivariate Cox regression. Interaction between stage and genetic score was tested. Discrimination of the model was assessed by the Harrell’s C statistic and internal validity by bootstrap method. Results: The characteristics of the 1121 patients were representative of a population with early TNBC. Four SNPs on chromosomes 9 and 2 were found significantly associated to iDFS in univariate Cox models. Homozygous status for the most frequent allele was associated with poorer iDFS for two SNPs and this status was present in 50% and 57% of the population. For the two other SNPs, the most frequent allele was associated with more favorable iDFS. Three prognostic categories were derived from the genetic score. The following table presents the results from the multivariate Cox model including genetic score and disease stage. Clinical trial information: RECF1098. Conclusions: In a prospective cohort of 1121 patients with early TNBC, 4 genetic variants (SNPs) were associated with iDFS. A score involving SNPs provided similar prognostic indications as breast cancer stages. A search assessing the function and the role of the involved genes is ongoing.[Table: see text]

A randomized phase III trial comparing dose-dense epirubicin and cyclophosphamide (ECdd) followed by paclitaxel (T) with paclitaxel plus carboplatin (PCdd) as adjuvant chemotherapy for early triple-negative breast cancer patients with high-recurrence risk.

528 Background: There are no well-established adjuvant chemotherapy (AC) regimens for early triple negative breast cancer (TNBC). Our randomized phase III trial was designed to compare dose dense paclitaxel plus carboplatin (PCdd) with commonly used dose dense epirubicin and cyclophosphamide, followed by paclitaxel (ECdd-T) regimen as AC for TNBC with high recurrence risk. Methods: Between May 2011 and November 2015, TNBC patients were randomized in 1:1 ratio to receive PCdd or ECdd-T regimen as AC every two weeks for 8 cycles with administration of granulocyte stimulating factor (G-CSF) support. The primary endpoint was 3-year disease free survival (DFS).The secondary endpoints included overall survival (OS) and safety. Survival analyses were also performed for different subgroups stratified by age status (≤40 years vs &gt;40 years), Ki 67(&lt;50 vs ≥50), tumor size (&lt;2cm vs ≥2cm), nodal status (N- vs N+) and treatment free survival (TFS) (&lt;30 days vs ≥30 days). Results: In total, 132 patients with a median age of 49 years (PCdd 64 patients, ECdd-T 68 patients) were enrolled. After a median follow-up of 57.3 months, 23 events were observed (18 in ECdd-T, 5 in PCdd). Patients in the PCdd arm had significantly higher DFS rate than that in the ECdd-T arm (log-rank p = 0.0046, hazard ratio (HR) 0.305, 95% confidence interval (CI) = 0.134-0.693). The 3-year DFS rate was 93.7% with PCdd versus 77.9% with ECdd-T,respectively. Difference in 3-year OS rate was observed between the two arms (98.4% vs 92.6%), significantly higher in the PCdd arm ( p = 0.0268). Both regimens were well tolerated with manageable adverse events(AEs). Worse neutropenia (Grade 3/4: 48.5% in ECdd-T vs. 21.9% in PCdd, p=0.002) was found in ECdd-T arm. 3-year DFS rate for PCdd was superior in the following subgroups, age&gt;40 years, clinically evaluated lymph nodes, TFS &lt;30 days, with statistical significance ( p &lt;0.05). Conclusions: Our data suggested that PCdd was superior to ECdd-T as AC for early TNBC in terms of improving 3-year DFS and OS. PCdd with lower hematological toxicity might be an appropriate regimen for early TNBC patients with high recurrence risk. Clinical trial information: NCT01378533.

ALEXANDRA/IMpassion030: A phase III study of standard adjuvant chemotherapy with or without atezolizumab in early-stage triple-negative breast cancer.

TPS598 Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer and promising clinical activity has been reported with the anti–PD-L1 antibody, atezolizumab, in Phase 1/1b metastatic TNBC trials. Furthermore, the randomized phase 3 IMpassion130 study demonstrated enhanced anti-tumor activity when atezolizumab was co-administered with chemotherapy in the first line metastatic setting, with benefit mainly observed in PD-L1+ cohort. ALEXANDRA/IMpassion030 will evaluate the efficacy and safety of atezolizumab in combination with standard anthracycline/taxane adjuvant chemotherapy in early TNBC patients. Methods: ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard chemotherapy versus chemotherapy alone in early TNBC. In total, 2300 patients with operable stage II or III TNBC, confirmed by central pathology review, will be randomized. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant treatment will consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary end-point is invasive disease-free survival (iDFS) and secondary end-points include iDFS by PD-L1 and lymph node status, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first patient was enrolled on August 2nd 2018, and approximately 430 sites are expected to be opened globally in 30 countries. Clinical trial information: NCT03498716.