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Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or > 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p < 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to >48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Background: Brain metastasis (BM) is a major clinical problem in metastatic breast cancer (MBC), occurring in 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Historically omitted from clinical trials, recent studies of novel HER2-targeted agents have focused on HER2+ BM patients, addressing stable but also progressing BM and leptomeningeal carcinomatosis (LMC). Summary: This review aimed to summarize the most relevant data on treating patients with HER2+ BM and LMC. Key Messages: The treatment paradigm for patients with HER2+ MBC has changed. Local therapies play an important role, but accumulating evidence on the intracranial activity and clinical benefit of anti-HER2 targeting therapies might lead to a shift in the paradigm on treating BM in the next few years towards more widespread use of systemic therapy.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The Suppression of Ovarian Function Trial (SOFT; ClinicalTrials.gov identifier: NCT00066690 ) randomly assigned premenopausal women with hormone receptor–positive breast cancer to 5 years of adjuvant tamoxifen, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. The primary analysis compared disease-free survival (DFS) between tamoxifen plus OFS versus tamoxifen alone; exemestane plus OFS versus tamoxifen was a secondary objective. After 8 years, SOFT reported a significant reduction in recurrence and improved overall survival (OS) with adjuvant tamoxifen plus OFS versus tamoxifen alone. Here, we report outcomes after median follow-up of 12 years. DFS remained significantly improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.82; 95% CI, 0.69 to 0.98) with a 12-year DFS of 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. OS was improved with tamoxifen plus OFS versus tamoxifen (hazard ratio, 0.78; 95% CI, 0.60 to 1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS at 12 years. Among those who received prior chemotherapy for human epidermal growth factor receptor-2–negative tumors, OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. In conclusion, after 12 years, there remains a benefit from including OFS in adjuvant endocrine therapy, with an absolute improvement in OS more apparent with higher baseline risk of recurrence. [Media: see text]

Background Selective internal radiation therapy (SIRT) is applied to hepatocellular carcinoma (HCC), a disease with increased incidence in the elderly. However, SIRT has rarely been specifically studied in elderly population. The aim of this study was to investigate efficacy and safety of SIRT in elderly HCC patients. Methods We studied retrospectively data from patients treated with SIRT for HCC. Clinical and laboratory data were retrieved. We used 70-years old as threshold between younger and elderly populations, to compare outcomes. Results A total of 222 patients treated with SIRT for HCC were studied, of which 134 patients were younger and 88 older. Median overall survival (OS) was not significantly different between younger and elderly group: 15.6 months (95% CI, 11.7-19.5) and 14.8 months (95% CI, 9.4-20.3) (P = 0.86). Age was not associated with OS in multivariable analysis, with a Hazard ratio of 1.09 (95% CI, 0.82-1.45, P = 0.55). Results of progression-free survival and responses were also similar in both groups. Toxicities were similar between the two groups, including the occurrence of radioembolization-induced liver disease (11.5 vs. 11.4%, P = 0.97). Conclusion SIRT appears to be a well-tolerated treatment with the same efficacy in elderly compared to younger patients in HCC. Our study is the first to study its impact with glass microspheres. This warrants confirmation in large prospective studies.

International audience; Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived.Methods: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%).Results: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction).Conclusion: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC.

Detection of BRCA germline mutations (gBRCAm) impacts breast cancer medical treatment—according to differential sensitivity to cytotoxic chemotherapy and the activity of PARP inhibitors—and not only familial prevention. Guidelines for genetic testing—initially mainly based on familial history, age, and triple negative breast cancer (TNBC) subtype—currently are expanding in order to offer new therapeutic options. In the early setting, gBRCAm patients present a similar outcome as the non-carrier population with standard neoadjuvant chemotherapy, and the role of platinum chemotherapy is still a matter of debate. In metastatic setting, international guidelines recommend the use of platinum-based chemotherapy in gBRCAm patients and more broadly in TNBC patients. Olaparib and talazoparib monotherapy are approved in metastatic gBRCAm breast cancer. To date, it remains unclear how the combination of platinum-based regimen and PARP inhibitors should be sequenced.

International audience; BACKGROUND: Early detection of ESR1 mutations is a key element for better personalization of the management of patients with HR+/HER2- Metastatic Breast Cancer (MBC). Analysis of circulating tumor DNA from liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of such patients. MATERIALS AND METHODS: Using the naica® three-color digital PCR platform, we developed a screening assay allowing the detection of 11 ESR1 mutations and designed a sequential strategy for precise mutation identification. We then applied this strategy in the analysis of plasma circulating cell-free DNA from 109 HR+/HER2- MBC patients and performed a double-blind comparison study on a subset of patients with the multiplex assay used at the Institut Curie (IC) for the PADA-1 study. RESULTS: Thirty-one patients (28.4%) harboured at least one ESR1 mutation, with the following frequencies: D538G (41.03%), Y537S (25.64%), E380Q (10.26%), Y537N (10.26%), "(536-540)" (7.69%), Y537C (2.56%), and L536R (2.56%). The presence of ESR1 mutation(s) was significantly associated with liver metastases (p = 0.0091). A very good agreement (91%) was observed with the IC assay. CONCLUSION: Our assays have proven to be robust and highly sensitive and are very well-suited for monitoring ESR1 mutations in the plasma of MBC patients.

Blood-based liquid biopsies have become a real asset for patient treatment management in the field of precision oncology over the past few years, as they allow quick and easy access to tumor genetic alterations of interest. The analysis of circulating tumor DNA (ctDNA) from these liquid biopsies is a particularly well-suited strategy for longitudinal monitoring of patients. In patients with HR+/HER2- metastatic breast cancer (MBC), early detection of ESR1 and PIK3CA mutations is a key element to better personalize disease management. Among the technologies currently used for liquid biopsies, digital PCR (dPCR) has the advantage of being among the fastest and least expensive, providing robust results along with unmatched sensitivity as compared to other methods. Until recently, however, dPCR has been previously limited by multiplex capability. The recent availability of the 6-color version of the naica® platform (Stilla Technologies) has allowed us to develop a single-well multiplexed assay that combines an 11 pathogenic mutation ESR1 assay with a 21 mutation PIK3CA assay, for a combined total of 32 ESR1 and PIK3CA mutations. Here we present data on this new high-plex dPCR panel. As ESR1 and PIK3CA analyses are often requested together, this new screening assay represents a significant saving of time and resources for the analysis of our MBC patients with a relative ease of implementation and analysis. Citation Format: Veronique Quillien, Julien Corne, Thibault De la Motte Rouge, Fanny Le Du, Florence Godey. Development of a 6-color multiplex Crystal Digital PCR assay for the detection of ESR1 and PIK3CA mutations in the plasma of metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2314.

PURPOSE: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. METHODS: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. RESULTS: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). CONCLUSIONS: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

Purpose: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. Methods: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT’s tool scores. Results: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians’ decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). Conclusion: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

The introduction of trastuzumab and other subsequent human epidermal growth factor receptor 2 (HER2)-targeted therapies dramatically shifted the treatment landscape of HER2+ breast cancer, changing the natural history of the disease. There is no standard-of-care for patients with HER2+ metastatic breast cancer (MBC) in third and later lines of treatment; however, continued use of anti-HER2 therapies is recommended. Small-molecule tyrosine kinase inhibitors (TKIs) that target HER2 and other HER family receptors play a central role in this setting. TKIs have demonstrated various degrees of efficacy against central nervous system (CNS) metastases, which are a major clinical challenge for patients with HER2+ MBC. The TKIs lapatinib, neratinib, and tucatinib have received regulatory approval for the treatment of HER2+ MBC, while pyrotinib and afatinib have been evaluated in this setting. These TKIs vary by molecular weight, HER protein specificity and reversibility of binding and in turn have unique safety profiles. Toxicities reported in clinical trials of TKIs in HER2+ MBC that may require specific management strategies include diarrhoea, palmar-plantar erythrodysesthesia syndrome and rash. Here, we review the efficacy data, including CNS activity, and the safety profiles of the TKIs, and we provide guidance on adverse event management. Finally, we discuss how to incorporate the TKIs into the HER2+ MBC treatment algorithm.

Background Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo. Methods We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated. Results Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on–7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement. Conclusions Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway. Trial registration ClinicalTrials.gov NCT01835223, registered on 15 April 2013.

Background: The open-label, randomised Phase 2 AVATAXHER study (NCT01142778) demonstrated that early PET assessment identified HER2-positive breast cancer patients who responded poorly to neoadjuvant docetaxel plus trastuzumab. Adding neoadjuvant bevacizumab for PET-predicted poor-responders improved pathological complete response (pCR) rates (43.8% vs 24.0%). We investigated long-term study outcomes. Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with ≥70% change in the maximum standardised uptake value (∆SUVmax) received four further cycles of standard neoadjuvant therapy (PET responders). PET-predicted poor-responders (∆SUVmax

International audience; Purpose - Radioembolization (RE) is a promising treatment option for biliary tract cancers (BTC). We report here the largest series to date using this treatment modality. Methods - We retrospectively studied data from 64 patients treated outside prospective clinical trial at our institution. We studied baseline characteristics as potential prognostic factors. We studied dose delivered to the tumor as predictive factors of outcomes in patients not receiving concomitant chemotherapy. Results - The Progression-Free Survival and Overall Survival (OS) were 7.6 months [95% Confidence Interval (CI): 4.6-10.6] and 16.4 months [95% CI: 7.8-25.0] in the whole cohort. The factors independently associated with OS in multivariable analysis were the primary localization of ICC (HR = 0.27, 95% CI: 0.11-0.68, p = 0.005) and a PS > 0 (HR = 2.21, 95% CI: 1.11-4.38, p = 0.024). During follow-up, 12 patients (19%) underwent surgery following downstaging, with a median OS of 51.9 months. In patients not treated with concomitant chemotherapy (n = 31), OS was significantly higher in patients with a dose delivered to the tumor 260Gy or higher than in patients with a dose delivered to the tumor lower than 260Gy (median 28.2 vs 11.4 months, log-rank p = 0.019). Conclusion - Our results confirm that RE is a promising treatment modality in BTC. A high proportion of patients could be downstaged to surgery, with promising long-term survival. Dose delivered to the tumor correlated with clinical outcomes when chemotherapy was not used concomitantly.

Background: The HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) demonstrated efficacy in heavily pretreated HER2-over- and HER2-low expressing ABC (1, 2). We aimed to assess the activity of T-DXd in HER2-over-, HER2-low and HER2-nul expressing ABC, to describe the drug mechanisms of action in the 3 cohorts and to identify biomarkers associated to drug response or resistance. Study Description: DAISY is a multicenter, open-label phase II trial designed to assess the efficacy of single agent T-DXd at 5.4 mg/kg dose in ABC with extensive biomarkers analysis. Three cohorts of patients were included: Cohort 1 (HER2 over-expressing: HER2 3+ on immunohistochemistry (IHC) or HER2 IHC2+/in situ hybridization [ISH]+), Cohort 2 (HER2 low-expressing: IHC1+ or IHC2+/ISH-) and cohort 3 (HER2-nul: IHC0+). Biopsy of metastatic sites was performed: at baseline, on treatment (mandatory for cohort 1, optional for cohort 2/3) and at tumor progression; blood samples for ctDNA were collected at baseline. The primary endpoint was the Best Overall Response (BOR) in each cohort, according to the investigator assessment. Secondary endpoints were BOR by central assessment, clinical benefit rate, duration of response (DOR), progression-free (PFS), overall survival (OS) and safety. Results:185 women and 1 man were enrolled between November 2019 and March 2021. Among the patients enrolled in the safety population (see Table 1), median (range) age was 55 (24-82) years, all received at least one prior line of therapy and 12 patients were TN. Table 2 shows investigator-reported T-Dxd activity in the 3 cohorts at a median follow-up of 10.1 months [95%CI: 9.2-11.1]. A total of 170 patients (95%) had at least one treatment-related toxicity. Key grade ≥3 treatment-related toxicities included neutropenia (10.6% of patients), fatigue (5.6%), leucopenia (4.5%), vomiting (4.5%) and anemia (3.4%). A total of 4 patients had drug-related interstitial lung disease or pneumonitis (grade 1 in 3 patients and grade 2 in 1 patient), 11 patients discontinued treatment due to treatment-related adverse events. No drug-related deaths occurred. Conclusions: T-DXd showed clinically meaningful activity in patients with HER2-overexpressing ABC and interestingly also in those with HER2low and HER2-nul ABC. Safety profile was consistent with previous reports. 1.Modi S et al N Engl J Med 2020 2.Mosi S et al J Clin Oncol 2020 Table 1.Analysis populationsTotalCohort 1 (HER2 over-expressing)Cohort 2 (HER2 low-expressing)Cohort 3 (HER2 non-detected)Enrolled population186727440Safety population*179687338 (including 12 TN)Full analysis Set**176687236TN: Triple Negative. *: safety population = enrolled population except 7 patients who did not receive at least one dose of study drug. **: Full Analysis Set = safety population except 3 patients (2 who did not have a valid first post-baseline assessment of disease status or who did not have progressive disease and 1 who did not have at least one radiologically measurable lesion according to RECIST v1.1) Table 2.T-DXd activity in the three cohorts according to investigator assessmentTotalCohort 1Cohort 2Cohort 3BOR confirmedn/N82/176 (46.6%)47/68 (69.1%)24/72 (33.3%)11/36 (30.6%)[95%CI][39.1; 54.2][56.7; 79.8][22.7; 45.4]16.3; 48.1]Median DORmonths7.69.97.66.8[95%CI][6.2; 9.7][5.4; NR][4.4; 8.7][2.8; 8.3]Median PFSmonths6.911.16.74.2[95%CI][6.7; 8.7][8.4; NR][4.6; 8.5][2.1; 6.9]NR: Not Reached Citation Format: Véronique Diéras, Elise Deluche, Amélie Lusque, Barbara Pistilli, Thomas Bachelot, Jean-Yves Pierga, Frédéric Viret, Christelle Levy, Laura Salabert, Fanny Le Du, Florence Dalenc, Christelle Jouannaud, Laurence Venat-Bouvet, Jean-Philippe Jacquin, Xavier Durando, Thierry Petit, Céline Mahier - Aït Oukhatar, Thomas Filleron, Maria Fernanda Mosele, Magali Lacroix-Triki, Agnès Ducoulombier, Fabrice André. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: A phase II study with biomarkers analysis (DAISY) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-02.

BackgroundTumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR).MethodsBlood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (β-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low).ResultsWe enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated.ConclusionsApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted.

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.

Purpose We conducted a double-randomised phase III trial to evaluate a concomitant taxane-anthracycline regimen in node-positive breast cancer and the efficacy of trastuzumab in the human epidermal growth factor receptor 2 (HER2)–positive subpopulation. Methods A total of 3010 patients with node-positive breast cancer were randomly assigned to receive 6 cycles of 500 mg/m2 of fluorouracil, 100 mg/m2 of epirubicin and 500 mg/m2 of cyclophosphamide (FEC) or 75 mg/m2 of epirubicin and 75 mg/m2 of docetaxel (ED). Patients with HER2-positive tumours were secondary randomly assigned to either trastuzumab or observation. The primary end-point was disease-free survival (DFS) in the two chemotherapy arms. Results After a 115-month median follow-up, DFS was not significantly better in the ED arm (DFS: 70%, 95% confidence interval [CI]: 67–72) than in the FEC arm (DFS: 68%, 95% CI: 65–70; hazard ratio [HR] = 0.88, 95% CI: 0.77–1.01; p = 0.064). The OS was not different between FEC (OS: 80%, 95% CI: 78–83) and ED (OS: 81%, 95% CI: 79–83); HR = 0.97, 95% CI: 0.81–1.16; p = 0.729). ED appeared more toxic. In the 528 HER2-positive subset, there was trend for a higher DFS, in the intention-to-treat population, in the trastuzumab arm (DFS: 68%, 95% CI: 61–74) than in the observation arm (DFS: 60%, 95% CI: 54–66; HR = 0.77, 95% CI: 0.57–1.03; p = 0.079). In the per-protocol population, DFS was significantly higher in the trastuzumab arm (DFS: 70%, 95% CI: 63–76) than in the observation arm (DFS: 59%, 95% CI: 53–65; HR = 0.69, 95% CI: 0.51–0.94; p = 0.0156). The OS was not different between these 2 arms. Conclusion This study did not show superiority of the concomitant anthracycline-taxane arm which was more toxic in high-risk node-positive breast cancer patients. Long-term results of the HER2-positive subpopulation are in line with those of the other adjuvant trastuzumab trials but quantitatively less pronounced mostly because of lack of power.

Background: The open-label, randomised Phase 2 AVATAXHER study demonstrated that early PET assessment identified patients with HER-2 positive breast cancer who responded poorly to standard neoadjuvant therapy (docetaxel plus trastuzumab). Adding bevacizumab to neoadjuvant therapy in PET-predicted poor-responders improved pathological complete response (pCR) rates (from 24·0% to 43·8%). We investigated whether the improved pCR rate translated into improved long-term outcomes. Methods: Patients were treated in three groups. All patients initially received two cycles of standard neoadjuvant therapy with [¹⁸F]-FDG PET conducted before each cycle. Those with a change in the maximum standardised uptake value (∆SUVmax) ≥70% received four further cycles of standard neoadjuvant therapy (PET responder group). PET-predicted poor-responders (∆SUVmax

Background: The National Comprehensive Cancer Network (NCCN) guidelines for treatment of breast cancer recommend several adjuvant chemotherapy regimens, including sequential or concurrent anthracycline-cyclophosphamide and taxane-based regimens (sequential AC-T or concurrent ACT, respectively); anthracycline alone; cyclophosphamide, methotrexate, and 5-fluorouracil (CMF); and docetaxel and cyclophosphamide (TC). Sequential AC-T is the most commonly prescribed standard regimen. Two types of regimens without anthracycline, TC and platinum-containing regimens, have been speculated to have similar efficacy to that of ACT-based regimens. Platinum-containing regimens have also demonstrated high efficacy in breast cancer with tolerable adverse effects in several previous studies. However, because of the limitations of conventional meta-analysis, we do not know how these regimens compare with one another in terms of survival or adverse events. Thus, the best adjuvant chemotherapy regimen for breast cancer is not known. Bayesian network meta-analysis allows comparison of treatments for which there has been no head-to-head comparison by using indirect comparisons. Methods: We searched the MEDLINE, EMBASE, and Cochrane Library databases for articles published before January 2014; the American Society of Clinical Oncology annual meeting abstracts for 1983-2013; and the American Association for Cancer Research annual meeting abstracts for 1916-2013. We included only randomized controlled trials of adjuvant treatments for breast cancer that compared 2 or more of the following: observation alone; sequential AC-T; concurrent ACT; anthracycline alone; CMF; TC; and platinum-containing regimens. We compared regimens by using a network meta-analysis approach and random-effects models. Network meta-analysis allows derivation of hazard ratios (HRs) for death for each regimen and comparison of these HRs with each other even when there are no direct comparisons between 2 regimens. Results: We identified 24 trials with a total of 28,853 patients. Network meta-analysis showed that OS with TC and platinum-containing regimens were similar to OS with sequential AC-T (TC: HR=0.94; 95% CI, 0.58-1.52; platinum: HR=0.90; 95% CI, 0.69-1.19). Patients receiving CMF or anthracycline alone had significantly worse OS than those with sequential AC-T (CMF: hazard ratio [HR]=1.62; 95% CI, 1.31-2.01; anthracycline: HR=1.23; 95% CI, 1.07-1.43). For overall adverse events, the mean number of adverse events per patient was higher for platinum-containing regimens (2.1) and concurrent ACT (1.22) than for sequential AC-T (1.17). The mean number of hematological adverse events was higher for concurrent ACT (0.67) and TC (0.63), than for sequential AC-T (0.48). The mean number of nonhematological adverse events was higher for platinum-containing regimens (1.76) than for sequential AT (0.7). Conclusion: Our findings suggest that sequential AC-T should continue to be considered the optimal treatment for early-stage breast cancer because of the equivalent survival benefit of concurrent ACT, TC and platinum-containing regiments but superior adverse-event outcomes. Citation Format: Takeo Fujii, Fanny Le Du, Lianchun Xiao, Takahiro Kogawa, Vicente Valero, Yu Shen, Naoto T Ueno. Identification of optimal adjuvant chemotherapy regimen for early-stage breast cancer: A systematic review and bayesian network meta-analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-05.

Background Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. Methods and Findings Whole-exome sequencing was performed on 216 tumor–blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9–155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2−) mBCs (19%). HR+/HER2− mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2− eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2− metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival. Conclusions This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations., Fabrice Andre and colleagues describe the mutations occurring in a large group of patients with metastatic breast cancer., Author Summary Why Was This Study Done? Breast cancer often results in poor outcomes after it has metastasized to distant organs, but, while primary breast tumors have been extensively characterized at the molecular level, metastatic lesions are poorly understood. This study aims to characterize the mutational landscape of metastatic breast cancer by performing and analyzing whole-exome sequencing of a large collection of metastatic breast tumors and corresponding blood samples. Understanding of the mutational landscape of metastatic tumors should open new avenues for assessing resistance to therapy and developing better treatments. What Did the Researchers Do and Find? The authors generated a large collection of whole-exome sequencing data from the DNA of breast cancer metastases and from each patient’s corresponding unmutated DNA in order to identify mutations and gene copy number alterations specific to the tumors. The bioinformatics analyses identified recurrently mutated genes in metastatic tumors and revealed the genes specifically involved in metastatic disease by comparing their mutational frequency to those of primary breast tumors. The study allowed identification of the affected genes and of mutational signatures that were more prevalent in metastatic as compared with primary tumors and that may be involved in the resistance to therapies. What Do These Findings Mean? The identification of mutational and copy number alterations specifically involved in breast cancer metastasis demonstrated that tumors evolve under the pressure of therapy. Characterization of mutations and copy number alterations in metastatic lesions in addition to primary tumors should help to tailor treatment for patients, with the potential for improved clinical outcomes.

The number of patients with breast cancer who participate in therapeutic clinical trials remains low. One reason is a lack of opportunity; another is health care providers who do not recommend trials because they fear poorer outcome from the use of new drugs. Thus, we compared survival outcome in patients with metastatic breast cancer (MBC) who participated in first-line therapeutic clinical trials with outcome in patients who had never enrolled in a clinical trial and received only standard care. We hypothesized that first-line therapeutic clinical trials does not have a negative survival outcome. We reviewed the records of patients with MBC who were treated at MD Anderson Cancer Center between January 2000, and December 2010. The medical records of 5501 patients with MBC were screened, and 652 patients—285 in the trial arm and 367 in the control arm—met our specific eligible criteria. The median follow-up of our cohort was 7.16 years (95 % confidence interval [CI] 6.53–7.64 years). Among the global population, no significant differences in progression-free survival (PFS) or overall survival (OS) were observed between the treatment arms: for the clinical trial cohort, median PFS was 7 months (95 % CI 5.72–8.71 months), and median OS was 28.48 months (95 % CI 22.70–34.60 months). For the control cohort, median PFS was 10.02 months (95 % CI 7.13–11.99 months), and median OS was 28.71 months (95 % CI 24.41–31.31 months) (P = .089 and .335, respectively). Enrollment in first-line MBC therapeutic clinical trials does not result in less favorable survival outcome than that in MBC patients who never enrolled in a clinical trial.

Background Recurrence score (RS) derived from a 21-gene reverse transcriptase-polymerase chain reaction assay is used to stratify patients with early-stage estrogen receptor-positive, HER2-normal breast cancer into 3 groups on the basis of 10-year distant metastasis risk: low, intermediate, and high. Published data are limited regarding the effect of RS on choice of adjuvant therapy for T1 breast cancer. We investigated the relationship between RS and choice of adjuvant therapy, prognosis, and benefit of chemotherapy (CT) in stage I breast cancer. Materials and Methods We reviewed the records of 1030 patients with estrogen receptor-positive, HER2-normal stage I breast cancer and RS available. RSs were correlated with clinicopathologic characteristics, treatment, and outcome. Results Patients with pathologic (p)T1a, pT1b, and pT1c disease did not differ in distribution of low, intermediate, and high RS ( P = .673). Overall, fewer than 10% of patients had a high RS. Histologic grade 1, nuclear grade 1, and low Ki-67 expression had only 1%, 0%, and 6% of high RSs, respectively. Among patients with intermediate RSs, 41% with pT1b and 46% with pT1c disease received CT. Among patients with intermediate RSs, for pT1b disease, distant disease-free survival (DDFS) did not differ between hormonal therapy (HT) alone and CT with HT ( P = .752); for pT1c, DDFS was superior for CT with HT ( P = .020). Histologic grade was the only independent prognostic factor of DDFS ( P = .0007, 1 vs. 3; P = .035, 2 vs. 3); RS did not predict DDFS ( P = .083, high vs. low; P = .066, intermediate vs. low). Conclusion The added value of RS to known prognostic factors appears limited to patients with pT1b breast cancer. However, this study lacked long-term follow-up.

Triple-negative breast cancer (TNBC) is defined by lack of estrogen receptor (ER) and progesterone receptor (PR) expression and by normal levels of HER2. TNBC represents 15–20% of all breast cancers and is associated with poor patient outcomes [1]. While patients with HER2-positive disease can benefit from trastuzumab and patients with ER-positive disease can benefit from endocrine therapy, the only recommended treatment for TNBC is standard chemotherapy; there is no targeted therapy specifically recommended for patients with TNBC. Although efforts so far to identify targeted therapy for TNBC have not been successful, we are hopeful that new approaches will lead to identification of targeted therapies for TNBC in the future.

International audience; PURPOSE OF THE REPORT: Intrahepatic cholangiocarcinoma's incidence is increasing. We studied the efficacy of Y selective internal radiation therapy (SIRT) as first-line treatment, with chemotherapy, and compared with the results of chemotherapy alone. PATIENTS AND METHODS: We retrospectively studied data from patients treated at our institution with glass microspheres SIRT for intrahepatic cholangiocarcinoma as part of first-line treatment in combination with chemotherapy. We compared results with those of similar patients treated in the ABC-02 study (a study in advanced biliary tract cancer that defined the current standard chemotherapy), assessed as not progressing after the first evaluation. We assessed progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-four patients were treated with SIRT. Chemotherapy was given concomitantly in 10 (42%), as induction before SIRT in 13 (54%) or after SIRT in 1 (4%). Grade 3 adverse events were reported in 1 (4%). Median PFS after SIRT was 10.3 months. Longer PFS was observed when chemotherapy was given concomitantly than when chemotherapy was given before SIRT, with respective median of 20.0 versus 8.8 months (P = 0.001). Median OS after SIRT was not reached. Eleven patients went to surgery (46%). Thirty-three patients in ABC-02 had locally advanced nonextrahepatic cholangiocarcinoma, not progressing after first evaluation. From the start of any treatment, the median PFS was 16.0 months in our cohort versus 11.3 months in ABC-02 (P = 0.25), whereas the median OS was significantly higher in our cohort, not reached versus 17.9 months, respectively (P = 0.026). CONCLUSIONS: Selective internal radiation therapy combined with concomitant chemotherapy seems a promising strategy as first-line treatment for unresectable intrahepatic cholangiocarcinoma

Breast cancer is a heterogeneous disease. For the past decades, new technical tools have been developed for biomarkers at the DNA, RNA, and protein levels to better understand the biology of breast cancer. This progress is essential to classify the disease into clinically relevant subtypes, which may lead to new therapeutic opportunities. Novel biomarker development is paramount to deliver personalized cancer therapies. Further, tumor evolution, being natural or under treatment pressure, should be monitored and “liquid biopsies” by detecting circulating tumor cells or circulating free tumor DNA in blood samples will become an important option. This article reviews the new generation of biomarkers and the current evidence to demonstrate their analytical validity, clinical validity and clinical utility.

Contralateral hypertrophy after 90Y radioembolization has been described in case reports, but the incidence and quantitative extent of liver volume modifications after this therapy are unknown. This retrospective study examined patients with hepatocellular carcinoma and underlying cirrhosis treated by 90Y radioembolization. The main inclusion criteria were unilateral treatment, no prior liver surgery, and computed tomographic scans allowing for volumetric assessments. Treated, tumor, and contralateral liver volumes were measured. Whole liver volume and the ratio of contralateral to total functional liver volume after a virtual hepatectomy were calculated. Data of 34 patients were analyzed. Response rates were 26 % according to Response Evaluation Criteria in Solid Tumors (RECIST) and 63 % according to modified RECIST. Median overall survival was 13.5 months. Median treated volume decreased from 938 mL (interquartile range [IQR] = 719) to 702 mL (IQR = 656) (p

11034 Background: Tumor cells with amesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis. Circulating tumor cells (CTCs) undergoing epithelial-mesenchyma...

Background: Tumor cells with a mesenchymal phenotype include cancer stem-like cells (CSCs), which are known to contribute to metastasis. Circulating tumor cells (CTCs) are epithelial cells in peripheral blood that are detected using an anti-EpCAM antibody; however, CTCs undergoing epithelial-mesenchymal transition (EMT) may not be detected using this method. We have developed an antibody-independent CTC enrichment platform, Apostream®, which does not rely on EpCAM-based capture. We used this instrument to determine the clinical relevancy and feasibility of measuring EMT-CTCs in breast cancer patients. Methods: Blood samples from newly diagnosed breast cancer patients were prospectively collected at baseline (T0), after primary systemic therapy (T1), and after definitive surgery (T2) and processed using the Apostream® system. Isolated cells were stained with antibodies to cytokeratin (anti-CK), leukocytes (anti-CD45), and the nuclear stain, 4,6-diamidino-2-phenylindole (DAPI), to identify CTCs. These CTCs were also stained with additional markers and examined on a laser scanning cytometer to measure protein expression levels of epithelial (EpCAM, E-cadherin), mesenchymal (β-catenin, vimentin) and CSC-markers (CD44, CD24). Pathological complete response (pCR) and residual cancer burden (RCB) statuses after preoperative treatment were obtained to correlate baseline CTCs and marker expression with treatment response. Results: The study enrolled 33 patients (10 with early-stage, 19 with locally advanced, and 4 with metastatic breast cancer); 32, 12, and 10 patients provided samples at T0, T1, and T2, respectively. Of the 20 patients who underwent surgery, 6 patients achieved pCR. CTCs were detected (≥ 1 cell in at least one of the three samples) in 47%, 75%, and 80% of the T0, T1, and T2 samples, respectively. EMT markers (either vimentin or β-catenin) were detected in 67%, 11%, and 38% of these CTCs, respectively. The mean number of CTCs per mL detected at T0 was 0.43 (range, 0-3.7). CTC detection was correlated with a high histological Nottingham index (P=0.039). Conversely, vimentin-positive CTC detection was inversely correlated with clinical stage at T0 (P=0.034). No significant correlation was observed between CTCs detected at baseline and breast cancer subtypes. However, there was a trend for CTCs detected at T0 to be predictive of chemotherapy response, as 62% of patients with CTCs at T0 achieved a pCR, whereas only 11% of patients without CTCs at T0 had a pCR (P=0.057). The other EMT and CSC markers we tested did not predict response. Conclusions: Apostream® was successful in detecting EMT-CTCs in this prospective study. There was a trend for the presence of CTCs at baseline to predict pCR. We will present our final data analysis of 50 patients. pCR (n=6)†RCB-I (n=2)RCB-II (n=5)RCB-III (n=4)P-valueCK+CD45- CTCsNegative (n=9)1(11)2(22)3(33)3(33)0.146 0.057*Positive (n=8)5(62)0(0)2(25)1(13)† All data are no. of patients (%) Two did not have an RCB status available, and 1 did not have a T0 sample. * Comparing pCR status (pCR vs no-pCR) between CTCs negative and positive. Citation Format: Fanny Le Du, Dzifa Y Duose, Elisha J Dettman, Jackson A Summer, Mariana Chavez-MacGregor, Carlos H Barcenas, Abenaa M Brewster, Alvarez H Ricardo, Vincente Valero, Ana M Gonzalez-Angulo, James M Reuben, Naoto T Ueno. Predictive impact of circulating tumor cells with an epithelial-to-mesenchymal transition phenotype in patients with primary breast cancer treated with primary systemic therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-10.

586 Background: A recurrence score (RS) derived from a 21-gene RT-PCR assay (Oncotype DX) stratifies patients (pts) with early estrogen receptor (ER)-positive, HER2-normal breast cancer (BC) into 3...

// Fanny Le Du 1, 2 , Bedrich L. Eckhardt 1 , Bora Lim 1, 6 , Jennifer K. Litton 1, 3, 6 , Stacy Moulder 1, 6 , Funda Meric-Bernstam 4, 6 , Ana M. Gonzalez-Angulo 1, 5, 6 , Naoto T. Ueno 1, 6 1 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Medical Oncology, Eugene Marquis Cancer Center, Rennes, France 3 Clinical Cancer Genetics Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA 4 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 The University of Texas MD Anderson Women’s Cancer Moons Shot Program, Houston, TX, USA Correspondence to: Naoto T. Ueno, e-mail: nueno@mdanderson.org Keywords: triple-negative breast cancer, gene expression profiling, epithelial-mesenchymal transition, immunotherapy, targeted therapy Received: February 17, 2015 Accepted: April 24, 2015 Published: May 07, 2015 ABSTRACT Significant research has been conducted to better understand the extensive, heterogeneous molecular features of triple-negative breast cancer (TNBC). We reviewed published TNBC molecular classifications to identify major groupings that have potential for clinical trial development. With the ultimate aim to streamline translational medicine, we linked these categories of TNBC according to their gene-expression signatures, biological function, and clinical outcome. To this end, we define five potential clinically actionable groupings of TNBC: 1) basal-like TNBC with DNA-repair deficiency or growth factor pathways; 2) mesenchymal-like TNBC with epithelial-to-mesenchymal transition and cancer stem cell features; 3) immune-associated TNBC; 4) luminal/apocrine TNBC with androgen-receptor overexpression; and 5) HER2-enriched TNBC. For each defined subtype, we highlight the major biological pathways and discuss potential targeted therapies in TNBC that might abrogate disease progression. However, many of these potential targets need clinical validation by clinical trials. We have yet to know how we can enrich the targets by molecular classifications.

550 Background: Overtreatment is a daily concern in the adjuvant setting for breast carcinoma. Most of Hormone Responsive (HR+) pT1a,bN0 breast cancers have an excellent prognosis. The aim of this ...