Negative Metastatic Breast Cancer Patients Research Articles

Trends in the choice of first line treatment for hormone - responsive (HR+), human epidermal growth factor receptor - 2 negative (HER2-) metastatic breast cancer (MBC) patients (pts): Results of a multicentric Italian observational study.

e13053Background: Most of HR+ MBC pts receive both hormonal therapy (HT) and chemotherapy (CT) during the course of their disease. According to international guidelines, HT should be preferred over CT in the first-line setting, restricting CT only to pts not responsive to HT or at risk of visceral crisis. Observational studies indicate that nearly 50% of this pts receive CT as first - line treatment. We aimed to evaluate if this behaviour does change in recent years. Methods: All consecutive MBC pts receiving a first-line treatment at 13 centers of GIM group (Gruppo Italiano Mammella) from 2000 to 2017 were registered. For the purpose of this analysis, we selected only HR+ MBC. The choice between first - line HT or CT was performed by the treating physician on the basis of pts and disease characteristics. The type of first line treatment (HT or CT) was analyzed according to four different cohorts: 2000 - 2005; 2006 - 2010; 2011 - 2013; 2014 - 2017. Results: 1709 pts with MBC were included in the GIM regis...

Olaparib for the treatment of breast cancer

ABSTRACTIntroduction: Mutations in BRCA1 and BRCA2 genes account for around 2–3% of breast cancer events and more than 10% of triple negative breast cancers. Olaparib (Lynparza®), an orally administered PARP inhibitor, demonstrated clinical benefit in a phase III trial for mutated BRCA-positive HER2 negative metastatic breast cancer.Areas covered: This review gives an overview of available preclinical and clinical data regarding olaparib, including its chemistry, mechanism of action, pharmacokinetics and pharmacodynamics, and evidence supporting antitumor efficacy and safety profile in breast cancer patients.Expert commentary: Olaparib improves progression-free survival in germline BRCA mutated HER2 negative metastatic breast cancer patients as compared to standard chemotherapy, with a manageable toxicity profile. Efficacy is of clinical relevance especially in the context of triple negative breast cancer. However, several aspects, such as sequencing or combination of these agents with other anticancer agents and identification of appropriate biomarkers, still need to be clearly defined.

Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy.

The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1/PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients.

Abstract P2-01-02: Heterogeneity and variability of human epidermal growth factor receptor 2 (HER2) expression on circulating tumor cells (CTC) in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab in a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study

Abstract Background: It has been reported in women with advanced estrogen-receptor (ER)-positive/(HER2)-negative breast cancer the acquisition of a HER2-positive CTC subpopulation during therapy (Jordan NV Nature 2016). The clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. We report here the analysis of HER2 status of CTC before and after one cycle of treatment in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab. Patients & methods:The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome. We confirmed previously the outcome of patients with high CTC count at base line and after one cycle of treatment (Bidard et al, Lancet Oncol 2014). We present here the analysis on 203 pts evaluated for the expression of HER2 on CTC using the FDA cleared CellSearch method. The HER2 expression of CTCs (CB11 clone) was categorized (class 0–3) as described by Riethdorf et al.CCR2010. Results: At base line, 144 out of 203 pts had at least one detectable CTC (71%), (median 4, and range 1- 30,000). Among them, 104 (72%) had one or more HER2 positive CTC (1-21,484). In 25 patients with HER2 2+ primary tumor with FISH or CISH non amplified, the incidence of CTC HER2+ cases (13/25, 52%) was similar than in pts with HER2 0 or HER2 1+ (51%) primary tumor. In each case, 3 to 100% of detectable CTC could be HER2+ stained (median 50% of CTC). Only 12 cases (8% of all CTC cases) had 2+ HER2 staining score on CTC and none 3+. After one cycle of treatment, the number of pts with detectable CTC dropped to 64, including 42 with HER2+ CTC (65%). Out of these cases, 14 were 3+ or 2+ HER2 score (22% of CTC+ cases). This was a significant increase compared to baseline (8%) (p<0.001), including 6 cases with 100% of HER2+ CTC. To note, 7 patients without HER2+ CTC at baseline, had detectable HER2+ CTC after one cycle of treatment. With a median follow-up of 2 years, correlation of CTC variations with pts outcome is planned. Conclusion: HER2 staining on CTC was heterogeneous with HER2 positive and negative subpopulations in the same patient with primary HER2 negative breast cancer. We observe a variability of HER2 CTC status with an increased intensity or appearance of immunostaining in few cases during treatment. We hypothesize that these phenotypes changes within patient-derived circulating tumor cells could contribute to progression of breast cancer and acquisition of drug resistance. Citation Format: Pierga J-Y, Proudon C, Tredan O, Decraene C, Dubot C, Lorgis V, Jacot W, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Lemonnier J, Berger F, Bidard F-C. Heterogeneity and variability of human epidermal growth factor receptor 2 (HER2) expression on circulating tumor cells (CTC) in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab in a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-02.

Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors – Data from the German PRAEGNANT breast cancer registry

PurposeThis study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). MethodsThe PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed. ResultsThis analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern. ConclusionsThis analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities.

Safety and efficacy of non-pegylated liposomal doxorubicin (NPLD) in HER2 negative metastatic breast cancer (mBC) patients (PTS) as second-line (2L) and beyond: a restrospective single institution analysis

Safety and efficacy of non-pegylated liposomal doxorubicin (NPLD) in HER2 negative metastatic breast cancer (mBC) patients (PTS) as second-line (2L) and beyond: a restrospective single institution analysis

Trends in the choice of first line treatment for hormone - responsive (HR+), human epidermal growth factor receptor - 2 negative (HER2-) metastatic breast cancer (MBC) patients (pts): results of a multicentric Italian observational study

Trends in the choice of first line treatment for hormone - responsive (HR+), human epidermal growth factor receptor - 2 negative (HER2-) metastatic breast cancer (MBC) patients (pts): results of a multicentric Italian observational study

280P - FICHE-YOUNG: FIrst-line treatment CHoicE in hormone receptor positive (HR+)/HER2- negative metastatic breast cancer patients (MBC) ≤45 years old. A large observational multicenter cohort survival analysis

280P - FICHE-YOUNG: FIrst-line treatment CHoicE in hormone receptor positive (HR+)/HER2- negative metastatic breast cancer patients (MBC) ≤45 years old. A large observational multicenter cohort survival analysis

Capecitabine and cisplatin (XP) combination systemic chemotherapy in heavily pre-treated HER2 negative metastatic breast cancer.

Purpose/Objective(s)After taxane and anthracycline failure, no standard chemotherapy regimen is established in metastatic breast cancer (MBC). Capecitabine and cisplatin (XP) combination shows promising results in gastrointestinal cancer, but there are relatively scarce data in MBC. We reviewed the clinical outcome of XP regimen in anthracycline and taxane resistant, heavily pretreated MBC patients.Materials/MethodsBetween Jan. 2010 to Feb. 2016, 48 HER2 negative MBC patients who failed anthracycline and taxane based chemotherapy were enrolled. In 43.8% of patients, more than 4 regimens were administrated before XP. Thirty-four patients (70.8%) were hormone receptor (HR) positive MBC. Patients were treated with XP (capecitabine [2000mg/m2 per oral; day 1–14] plus cisplatin [60mg/m2 IV; day 1], every 3 weeks) regimen.ResultsMedian progression-free survival (PFS) in total population was 4.33 months (range 1.1~33.57 months). HR positive patients showed trends for superior PFS compared to triple negative breast cancer (TNBC), without statistical significance (6.53 vs. 3.83 months, P = 0.168). In HR positive group, patients receiving 3 or less lines of chemotherapy showed superior PFS compared to others (10.1 vs. 3.0 months, P = 0.039). In multivariate analysis, HR positive patients receiving 3 or less lines of regimens still showed superior PFS (HR = 2.624, 95% CI; 1.071~6.43, P = 0.032). Most common toxicity was grade 3–4 neutropenia, without treatment-related deaths.ConclusionsXP combination regimen showed clinical benefit with tolerable toxicity in heavily pretreated patients, including HR positive patients. After anthracycline and taxane failure, early administration of XP regimen in selected patients may have improve clinical outcome in breast cancer.

Abstract P1-01-02: Circulating tumor cells (CTC) and endothelial cells (CEC) prognostic value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: First results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study

Abstract Background: increased levels of circulating tumor cells (CTC) are associated with worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC). It has been hypothesized that bevacizumab could modify CTC prognostic value. CEC variations to predict benefit of anti-angiogenic treatment is still controversial. Predictive markers for response to bevacizumab combined to chemotherapy in MBC remains a clinical unmet need. Patients & methods: The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, CEC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat assessed by initial CTscan, serum estradiol level, and quality of life). We present here the first planned analysis on 203 pts evaluated for CTC and CEC using the FDA cleared CellSearch method. Results: For CTC substudy, 211 patients were included from 09/2012 to 5/2014. Median follow-up is 24 months. Median PFS was 10 months (CI95 9-12) and response rate was 57%. Median OS was not reached. 203 patients were evaluable for both CTC and CEC at baseline and first day of second cycle of CT (D1C2). At baseline, 97/203 (48%) pts had ≥ 5 CTC (median 4 (range 0-30,000). Median number CEC was 21 (0-2231) at baseline and 22 (1-881) at D1C2. LDH, CEA, CA15.3 and CYFRA 21 were above normal at baseline in 44%, 46%, 73% and 71% of the cases respectively. CTC level was not correlated with any patients' characteristics except a number of metastatic site >3. After one cycle of chemotherapy (D1C2) 37 pts (22%) had still ≥ 5 CTC: 36 pts with initial high level and only one patient with low CTC at baseline had increased CTC above 5. Prognostic factors for PFS at univariate analysis were visceral disease, number of metastatic sites (> 3), triple negative status, LDH, CTC level at baseline and CTC level after one cycle of chemotherapy (D1C2). None of serum marker nor CEC level at baseline or any variations had prognostic value. In multivariate analysis for PFS, CTC level after one cyle of chemotherapy predicts poor outcome Table 1 Multivariate analysis for PFSPts' characteristicsnRRCI 95%p-valueNumber of metastatic sites <3 sites971 >=3 sites1001.65[1.13 ; 2.41]0.010CTC D1C2 < 51321 >= 5372.17[1.43 ; 3.29]<0.001Hormonal status Luminal (HR+)1531 Triple negative372.86[1.85 ; 4.54]<0.001 Conclusion: We confirm in a large prospective series the lack of clinical validity of CEC to predict response to an antiangiogenic based treatment in MBC. A persistent elevated level of CTC after just one cycle of chemotherapy is a very strong and independent marker of poor outcome in a homogeneously bevacizumab-treated cohort of MBC patients. This marker could be used to stopped earlier an inefficient and costly treatment. Citation Format: Pierga J-Y, Tredant O, Chevrier M, Dubot C, Lorgis V, Romieu G, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Berger F, Lemonnier J, Proudhon C, Bidard F-C. Circulating tumor cells (CTC) and endothelial cells (CEC) prognostic value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: First results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-02.

Abstract OT2-01-06: Phase III study of palbociclib (PD-0332991) in combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to aromatase inhibitors. “The PEARL study” (GEICAM/2013-02)

Abstract Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer patients. However, endocrine resistance is a major clinical challenge.Treatment options at recurrence/progression to AIs include sequential endocrine-based therapiesin monotherapy or in combination with a targeted agent or chemotherapy. Preclinical data suggest that ER+/HER2- BC is dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in overcome endocrine resistance. Palbociclib (P) is an oral novel CDK4/6 inhibitor that is synergistic with ET in preclinical and clinical studies. Initially this study was designed to demonstrate the clinical benefit of P plus exemestane (E) vs capecitabine (C) (cohort1). Recent studies revealed that the acquisition of ESR1 mutations is a major mechanism of resistance to the treatment of AIs in the metastatic setting. Retrospective analyses show that patients with ESR1 mutation derived no benefit from sequential AI monotherapy. In contrast, preclinical and clinical data indicated that SERD, fulvestrant (F), is active in ESR1 mutant tumors. Hence the choice of endocrine partner with P is particularly important to create optimal synergy in endocrine resistance setting. The current design added cohort 2 of P plus F vs C. The overall study goal is to prospectively answer the question of optimal endocrine partner with P and its efficacy/safety over chemotherapy in endocrine resistant setting. Trial Design:This is an international (5 countries) randomized phase III study with 2 cohorts, patients will be randomized 1:1 to ET (cohort 1: E 25 mg daily, cohort 2: F 500mg days 1 and 15 cycle 1 and then day 1 every 4 weeks) plus P (125 mg daily x3 weeks every 4 weeks) vs. C (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2- MBC are eligible if resistant to previous AI (letrozole or anastrozole in cohort 1 or any AI in cohort 2) defined as:recurrence while on or within 12 months after the end of adjuvant treatment orprogression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or bone lesions, lytic or mixed, in the absence of measurable disease. The primary objectives are to demonstrate that P plus F is superior to C and that P plus ET is superior to C inwomen whose tumor had estrogen receptor ESR1 wild type in terms of Progression-Free Survival (PFS); secondary objectives are PFS regardless the ESR1 mutational status, overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarkers. The study will recruit approximately 302 patients in cohort 1 and 300 patients in cohort 2. The study started recruitment in March 2014; 290 patients have been included so far (289 cohort1 + 1 cohort 2). Analysis of primary endpoint is planned in Sep2019 (ClinTrials.gov reference NCT02028507. Citation Format: Martín M, Kahan Z, Carrasco E, Bartlett CH, Casas M, Gil-Gil M, Muñoz M, Ciruelos EM, Ruiz-Borrego M, Margelí M, Antón A, Bermejo B, Morales S, Gal-Yam E, Koehler M, García-Sáenz JA, de la Haba J, Chacón I, Zielinski C. Phase III study of palbociclib (PD-0332991) in combination with endocrine therapy (exemestane or fulvestrant) versus chemotherapy (capecitabine) in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to aromatase inhibitors. “The PEARL study” (GEICAM/2013-02) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-06.

Hormonal therapy followed by chemotherapy or the reverse sequence as first-line treatment of hormone-responsive, human epidermal growth factor receptor-2 negative metastatic breast cancer patients: results of an observational study.

Introduction Although hormonal-therapy is the preferred first-line treatment for hormone-responsive, HER2 negative metastatic breast cancer, no data from clinical trials support the choice between hormonal-therapy and chemotherapy.Methods Patients were divided into two groups according to the treatment: chemotherapy or hormonal-therapy. Outcomes in terms of clinical benefit and median overall survival (OS) were retrospectively evaluated in the two groups. To calculate the time spent in chemotherapy with respect to OS in the two groups, the proportion of patients in chemotherapy relative to those present in either group was computed at every day from the start of therapy.Results From 1999 to 2013, 119 patients received first-line hormonal-therapy (HT-first group) and 100 first-line chemotherapy (CT-first group). Patients in the CT-first group were younger and with poorer prognostic factors as compared to those in HT-first group. Clinical benefit (77 vs 81%) and median OS (50.7 vs 51.1 months) were similar in the two groups. Time spent in chemotherapy was significantly longer during the first 3 years in CT-first group (54-34%) as compared to the HT-first group (11-18%). This difference decreased after the third year and overall was 28% in the CT-first group and 18% in the HT-first group.Conclusions The sequence first-line chemotherapy followed by hormonal-therapy, as compared with the opposite sequence, is associated with a longer time of OS spent in chemotherapy. However, despite the poorer prognostic factors, patients in the CT-first group had a superimposable OS than those in the HT-first group.

Eribulin improved overall survival in patients with HER-2 negative metastatic breast cancer: Comparison to bevacizumab plus paclitaxel.

e12035Background: Eribulin mesylate demonstrated to significant improvement in overall survival (OS) in patients with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician’s choice. On the other hand, Bevacizumab improved progression fee survival (PHS), but did not do OS. Thus, OS does not necessarily accord with PHS, and there was few clinical study that assess OS as primary endpoint. Methods: HER-2 negative metastatic breast cancer (MBC) patients who underwent chemotherapy of eribulin monotherapy or bevacizumab plus paclitaxel for first to fourth line chemotherapy in our department from November 1, 2011 to September 30, 2015 were reviewed. Kaplan-Meier method was utilized to estimate median OS and log-rank test was used to compare OS. The primary efficacy measure assessed OS, which was calculated as the time from the diagnosis of MBC until death from any case. Results: A total of 56 patients with MBC were assessed in this study (eribulin (E):29cases, b...

The efficacy and safety of endostar combined with taxane-based regimens for HER-2-negative metastatic breast cancer patients.

The purpose of the present study was to prospectively evaluate the efficacy and safety of endostar, a recombinant product of endostatin, combined with taxane-based regimens for HER-2 negative metastatic breast cancer (MBC) patients. Women with ages between 18–70 years with histologically confirmed MBC documented as HER-2-negative were included. Endostar was administered at 7.5 mg/m2, d1–14, q21d and was continued until progressive disease, unacceptable toxicity, consent withdrawal, or completion of 24 months of endostar, whichever came first. Taxane-based chemotherapy was continued until progressive disease, unacceptable toxicity, consent withdrawal, or up to 8 cycles. The primary endpoint was overall response rate (ORR). Fifty-seven patients were recruited. The ORRs for the whole population, first-, second-, and third-line therapy or beyond were 68.4%, 79.3%, 54.5%, and 16.7%, respectively. The median PFS was 10.8 (8.0–12.1) months, yet the median OS was still not attained. For the patients receiving first-, second-, and third-line therapy or beyond, median PFS was 11.9, 7.5, and 7.4 months, respectively (P=0.048). No significant difference in median PFS between hormonal receptor-positive and -negative patients was observed. The most common drug-related grade 3–4 hematologic toxicities were neutropenia (80.7%) and leukopenia (77.2%). Six (10.5%) patients experienced febrile neutropenia. The most frequent drug-related grade 3–4 non-hematologic toxicities were liver dysfunction (10.5%) and peripheral neurotoxicity (8.8%). No treatment-related deaths were reported. We conclude that Endostar combined with taxane-based regimens may be effective and safe for the treatment of HER-2-negative MBC. However, further investigations on its long-term efficacy and toxicity are warranted.

A49 - Phase I of weekly nab-paclitaxel in combination with weekly liposomal encapsulated doxorubicin as first-line treatment for HER2 negative metastatic breast cancer patients: preliminary results

A49 - Phase I of weekly nab-paclitaxel in combination with weekly liposomal encapsulated doxorubicin as first-line treatment for HER2 negative metastatic breast cancer patients: preliminary results

A26 - Outcomes of hormone-responsive (HR+) HER2 negative (HER2-) metastatic breast cancer (MBC) patients (P) according to their starting first-line (1st) treatment (T): chemotherapy (CT) or hormonal therapy (HT)

A26 - Outcomes of hormone-responsive (HR+) HER2 negative (HER2-) metastatic breast cancer (MBC) patients (P) according to their starting first-line (1st) treatment (T): chemotherapy (CT) or hormonal therapy (HT)

Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer.

The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0-11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8-30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1-28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting.

Abstract P6-08-09: Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients

Abstract Background Newly identified SNPs in genes encoding metabolizing enzymes (CYP2C8, CYP3A4) and drug target (TUBB2A) of paclitaxel have been associated with PNP1-3. A recent GWAS has found novel SNPs in EPHA5 and FGD4 possibly predictive for PNP4. Likewise, SNPs in genes (CDA, CES2) involved in capecitabine activation may play a role in HFS5. Here, we attempted to confirm these SNPs as predictive markers for PNP and HFS in patients (pts) receiving first-line paclitaxel (T) and bevacizumab (A) without or with capecitabine (X). Patients and methods In the phase II ATX trial (NTR1348;BOOG2006-06), 312 pts were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 & A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 & X 825 mg/m2 bid d1–14 q3w x 8 cycles → the same dose of A & X q3w for next cycles). Toxicity was graded by using NCI CTCAE v3 at each cycle. Germline DNA was isolated for genotyping CYP2C8*3 (1196A>G & 416G>A), CYP3A4*22 (522-191C>T), EPHA5 2895G>A, FGD4 2044-236G>A, CES2 823C>G, TUBB2A 101C>T, TUBB2A 112G>A, CDA 943insC and CDA 451C>T. Results of TUBB2A and CDA SNPs will be presented at the meeting. The association between SNPs and toxicity was analyzed for 1) maximum grade of treatment-related toxicity per patient by Pearson’s X2 or Fisher's exact test; 2) cumulative dose level of drugs until first grade ≥1 toxicity or first dose reduction by Kaplan-Meier curve and Gehan-Breslow test. Results 188 pts had SNPs genotyped; characteristics reflected the trial cohort. Table 1 shows the maximum grade of PNP. When grouped into grades 0–1 and 2–3, no differences in rates of PNP were noted among SNPs. Median cumulative dose of T until grade ≥1 PNP was 1,800 mg/m2 (95% CI 1,534–2,065). Carriers of the CYP2C8 416 A-allele had a significantly lower cumulative dose of T until grade ≥1 PNP compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.011). Carriers of the FGD4 2044-236 A-allele had a significantly higher cumulative dose until first dose reduction of T compared to those with a homozygous G/G genotype (Gehan-Breslow p=0.037). Table 1. toxicity by maximum grade per patient Grade 0123Paclitaxel-treated patients (N=188)PNP, No. (%)62 (33)33 (36)41 (22)17 (9)Capecitabine-treated patients (N=93)HFS, No. (%)17 (18)21 (23)25 (27)30 (32) For ATX-treated pts, rates of HFS are shown in Table 1. With regard to maximum grade of HFS, there was a trend of a lower rate of grade 2–3 HFS for CES 823C/G compared to C/C genotype (33% vs 64%, Fisher’s exact p=0.059). The median cumulative dose of X until grade ≥1 HFS was 98.7 g/m2 (95%CI 82.1–115). CES 823C>G was not associated with the cumulative dose of X until grade ≥1 HFS or dose reduction. Conclusions Our results indicate that CYP2C8 416G>A and FGD4 2044-236G>A might be predictive markers for paclitaxel-induced neurotoxicity, whereas reported associations of other SNPs with toxicity could not be confirmed. 1Hertz et al. Ann Oncol 2013, 2De Graan et al. Clin Cancer Res 2013, 3Leandro-Garcia et al. Clin Cancer Res 2012, 4Baldwin et al. Clin Cancer Res 2012, 5Caronia et al. Clin Cancer Res 2011 Financial support from Roche Netherlands. Citation Format: Siu W Lam, Charlotte N Frederiks, Tahar van der Straaten, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Jojanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Henk-Jan Guchelaar, Epie Boven. Genetic polymorphisms (SNPs) as predictive markers for paclitaxel-induced peripheral neuropathy (PNP) and capecitabine-induced hand-foot syndrome (HFS) in HER-2 negative metastatic breast cancer patients [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 P6-08-09.

Abstract P4-01-12: Circulating tumor cells (CTC) and endothelial cells (CEC) changes in HER2 negative metastatic breast cancer (MBC) patients treated with first line weekly paclitaxel and bevacizumab: Preliminary results of a prospective cohort from the French Breast Cancer

Abstract Background: increased levels of circulating tumor cells (CTC) are associated with worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with MBC (Bidard FC et al, Lancet Oncol 2014). The failure of chemotherapy to reduce CTCs to levels below five CTCs per 7.5 mL whole blood at first follow-up after initiating a new systemic therapy for MBC predicts shorter time to progression and OS. It has been hypothesized that bevacizumab could modify CTC prognostic value due to extravasation or epithelio-mesenchymal transition induction. CEC variations to predict benefit of anti-angiogenic treatment is still controversial. Patients & methods: the French cohort COMET is a prospective study including first line HER2 negative pts receiving weekly paclitaxel and bevacizumab according to EMEA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, CEC, VEGFA levels, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat assessed by initial CTscan, serum estradiol level, and quality of life). We present here the first planned analysis on 206 patients evaluated for CTC and CEC using the FDA cleared CellSearch method. Results: inclusions started in 09/2012. At time of analysis, 219 patients were included, 211 were evaluable for CTC at baseline (failure rate 4%) and 207 for CEC at baseline (failure rate 5%). Due to short follow-up, 173 pts and 166 pts were evaluable for both CTC and CEC at baseline and first day of second cycle of CT (D1C2) respectively. At baseline, 100/211 (47%) pts had ≥ 5 CTC (median 4 (range 0-30,000) and 30% had no detectable CTC (0 CTC). After one cycle of chemotherapy (D28) 38 pts (22%) had still ≥ 5 CTC: 37 pts with initial high level and only one patient with low CTC at baseline had increased CTC above 5. Median number CEC was 21 (0)-2231) at baseline and 22 (1-881) at D1C2. CEC increased in 16% and decreased in 15% of the cases. CTC & CEC changes after one cycleCTC BaselineCTC at D1C2CEC BaselineCEC at D1C2≥ 5≥ 537 (21%)>20>2065 (39%)≥ 5<545 (26%)>20≤ 2025 (15%)<5≥ 51 (<1%)≤ 20>2027 (16%)<5<590 (52%)≤ 20≤ 2049 (30%)Total173166 CTC number at baseline line and CTC D1C2 were correlated (p<0.01) (Spearman test). There was no correlation between CEC at baseline or at D1C2 with CTC or CTC changes. Final analysis will be completed when 206 couples for both CTC and CEC at baseline and D1C2 will be available. Accrual is still ongoing. Conclusion: this 22% rate of failure to reduce CTC < 5 after one cycle of first line CT in a homogeneously bevacizumab-treated cohort of MBC patients did not differ from previous series. As second lines of chemotherapy do not improve the poor prognosis of this group of patients according to the SWOG 500 study results (Smerage et al, JCO 2014), trials of novel therapeutic agents should be considered at the time of progression. Citation Format: Jean-Yves Pierga, Isabelle Vaucher, Maya Gutierrez, Olivier Tredan, Séverine Guiu, Gilles Romieu, Anthony Goncalves, Marc Debled, Christelle Levy, Jean-Marc Ferrero, Christelle Jouannaud, Elisabeth Luporsi, Marie-Ange Mouret-Reynier, Florence Dalenc, Bernard Asselain, Jerome Lemonnier, Francois-Clement Bidard. Circulating tumor cells (CTC) and endothelial cells (CEC) changes in HER2 negative metastatic breast cancer (MBC) patients treated with first line weekly paclitaxel and bevacizumab: Preliminary results of a prospective cohort from the French Breast Cancer [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 P4-01-12.

Abstract OT1-1-05: Phase III study of palbociclib in combination with exemestane vs. capecitabine, in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to non-steroidal aromatase inhibitors (NSAI): PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006)

Abstract Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer (BC) patients. AIs have become the treatment of choice in postmenopausal patients. The high response rates with ET in these patients are partially undermined by the resistance developed by most of them over time. On early disease recurrence/progression to AIs, the treatment options include other AI, estrogen-receptor antagonists or chemotherapy (being capecitabine one of the best options). Preclinical data suggest that ER+/HER2- BC are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; the inhibition of this target may be effective in delaying/reverting endocrine resistance. Palbociclib is an oral novel CDK4/6 inhibitor that seems to be synergistic with ET in preclinical and clinical studies. Trial Design: This is an international (6 countries) randomized phase III study. Patients are randomized 1:1 to exemestane (25 mg daily) plus palbociclib (125 mg daily x3 weeks every 4 weeks) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks every 3 weeks). Postmenopausal patients with HR+/HER2- MBC are eligible if resistant to previous NSAI (letrozole or anastrozole) defined as: recurrence while on or within 12 months after the end of adjuvant treatment or progression while on or within 1 month after the end of treatment for MBC. Previous chemotherapy is permitted either in the (neo)adjuvant setting and/or as first line for MBC. Patients must have measurable disease according to RECIST 1.1 or lytic bone lesions in the absence of measurable disease. The primary objective is Progression-Free Survival (PFS); secondary objectives are overall survival, response rate, clinical benefit rate, response duration, safety, quality of life and biomarker’s defined changes. The study will recruit 348 patients to detect a difference of 2.75 months in the median PFS (from 6 to 8.75 months; hazard ratio= 0.686), with a power of 80% and a 5% two sided significance level. The study started recruitment in March 2014 and 14 patients have been included so far (ClinTrials.gov reference NCT02028507). Citation Format: Miguel Martín, Semir Beslija, Eva Carrasco, Zsuzanna Kahan, Ma José Escudero, Istvan Lang, Begoña Bermejo, Moshe Inbar, José Ignacio Chacón, Dan Jinga, José Ángel García-Saenz, Juan de la Haba, Serafín Morales, Miguel Gil, Laura Murillo, Antonio Antón, Manuel Ruiz-Borrego, Christoph Zielinski, Günther Steger, Bella Nisenbaum. Phase III study of palbociclib in combination with exemestane vs. capecitabine, in hormonal receptor (HR) positive/HER2 negative metastatic breast cancer (MBC) patients with resistance to non-steroidal aromatase inhibitors (NSAI): PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006) [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 OT1-1-05.