Chemotherapy For Metastatic Breast Cancer Research Articles

Durable disease control in patients with metastatic breast cancer treated with single agent capecitabine.

e12522Background: Capecitabine is effective chemotherapy in metastatic breast cancer (MBC) and is usually given as a third line chemotherapy. Since there is no cumulative dose, if tolerability is good treatment can be given for long time until disease progression. However there are limited data of treatment duration in patients with MBC treated with single agent capecitabine. Methods: At the Institute for Oncology and Radiology of Serbia, a cohort of 24 MBC patients treated with single agent capecitabine and durable disease control have been analyzed. Durable disease control is defined as absence of disease progression during at least 24 months of continuous capecitabine treatment. All patients had progression during or after antracycline and taxane based chemotherapy +/-hormonal therapy +/-trastuzumab therapy. Lapatinib was not available at the time of treatment initiation in 3 patients with HER2 3+ MBC Dose of capecitabine ranged from 1500-2000 mg/m2 bd, days 1-14, q3w; tolerability and clinical evaluat...

Biomarker analysis of S-1 in SELECT-BC: A randomized phase III study of taxane versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT-BC EURECA).

e23274Background: S-1 is oral fluoropyrimidine which is a biochemically modulated drug to increase 5-FU concentration and to avoid gastrointestinal toxicities. SELECT-BC, a randomized phase III tri...

How Long to Continue Capecitabine Chemotherapy for Metastatic Breast Cancer?

How Long to Continue Capecitabine Chemotherapy for Metastatic Breast Cancer?

Indication of metronomic chemotherapy for metastatic breast cancer: Clinical outcomes and responsive subtypes.

The survival of patients with metastatic breast cancer (MBC) has not improved, despite recent advances in therapeutic strategies. This is mainly due to the fact that cytotoxic agents cannot be administered over a long period, even if they exhibit favorable activity, due to treatment-related side effects or acquisition of tumor resistance to the administered agents. Thus, the development of therapeutic strategies that may be used over a long time period is required to improve survival. We assessed the availability and clinical outcomes of metronomic chemotherapy, which is defined as continuous or frequent treatment with low doses of cytotoxic drugs. A total of 80 patients with MBC received chemotherapy in the metastatic setting, and the clinicopathological factors and clinical outcomes were retrospectively compared between 52 patients who received metronomic regimens and 28 patients who received other cytotoxic regimens. As regards clinical outcomes, the median time-to-treatment failure (TTF) and overall survival (OS) were significantly longer in the metronomic group compared with those in the non-metronomic group (TTF, 15 vs. 4 months, P=0.0001; and OS, 53 vs. 28 months P=0.0012, respectively). In the metronomic group, none of the 18 patients who responded to the regimen had triple-negative (TN) cancer (17 had luminal-type tumors and 1 had a human epidermal factor receptor 2-type tumor). Furthermore, TTF and OS were significantly longer in patients with non-TN cancer compared with those in patients with TN cancer in the metronomic group (TTF, 16 vs. 7 months, P=0.0014; and OS, 108 vs. 20 months, P=0.000007, respectively). The proportion of patients who experienced treatment-related adverse events was significantly lower in the metronomic group compared with that in the non-metronomic group (36.5 vs. 61.5%, respectively; P=0.038). In conclusion, metronomic chemotherapy is a viable option for luminal-type MBC in terms of effectiveness and minimal toxicity, regardless of metastatic sites or prior treatment. However, an alternative treatment is required for TN cancer.

Abstract P2-11-09: A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data

Abstract Background: Indoleamine 2,3 dioxygenase (IDO) is a tryptophan-catabolizing enzyme that plays a key role in the normal regulation of peripheral immune tolerance. Tumors also employ this mechanism to induce a state of immunosuppression, evading immune mediated destruction. Indoximod (D-1-methyltryptophan) is a broad IDO pathway inhibitor as it has been shown to potentially interfere with multiple targets within the IDO pathway. Preclinical studies in MMTV-neu mouse models have demonstrated that combining indoximod with cytotoxic chemotherapy had a greater in-vivo anti-tumor effect than either agent alone. A phase 1 trial combining docetaxel and indoximod demonstrated safety and responses in metastatic breast cancer (mBC) patients. Based on these data a phase 2 trial evaluating indoximod in combination with taxane chemotherapy as first line therapy in patients with metastatic breast cancer was initiated. Methods: The study is a 1:1 randomized, placebo controlled, four arm phase 2 trial. The study treatment is docetaxel 75mg/m2 IV D8 plus indoximod 1200mg PO BID D1-14 every 21 days or matching placebo in study arms 1A and 2A or paclitaxel 80 mg/m2 IV weekly 3 out of 4 weeks with indoximod or matching placebo given BID Days 1-14 in arms 1B and 2B. The primary endpoint is progression free survival. Secondary endpoints include overall survival, response rate, safety, and immune response correlative assays. Patients with measurable, histologically confirmed mBC, no prior chemotherapies (hormonal therapies allowed) in the metastatic setting, ER+ or ER –, HER2 -, ECOG PS 0-1, no active CNS disease, no active autoimmune disease are eligible. Target enrollment is 154 patients. Results: At submission, 65 patients have evaluable safety data on trial. The pooled, blinded data was evaluated for any safety signals. Patient demographics include median age 58 years, 95% female, 17% African American, 25% triple-negative disease, and 82% with multiple sites of metastatic disease. 28% of patients had at least one Grade 3 or 4 adverse event. Those occurring in multiple patients include dyspnea 5%, pleural effusion 3%, non-cardiac chest pain 3%, and febrile neutropenia 3%. Most patients had at least one adverse event (86%). The most common were anemia 14%, tearing 11%, constipation 19%, diarrhea34%, nausea 44%, vomiting 22%, fatigue 48%, peripheral edema 17%, increased liver function tests 10%, lymphopenia 17%, hyperglycemia 15%, myalgia 14%, dizziness 14%, dysguesia 16%, headache 20%, peripheral neuropathy 12%, dyspnea 19%, alopecia 34%, and rash 14%, all compatible with the side effect profile of single agent taxanes. No immune specific serious advents were reported. No treatment related deaths have been reported. Conclusion: The aggregate safety data for these 65 patient are similar to what is typically observed with docetaxel and paclitaxel. No unexpected serious immune linked adverse events were reported. The trial is currently open at multiple clinical sites in the US and Europe and actively enrolling patients. Updated data will be presented. NCT01191216. Citation Format: Tang S-C, Montero A, Munn D, Link C, Vahanian N, Kennedy E, Soliman H. A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-09.

Abstract P1-13-07: Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT)

Abstract Background The partial chemo-sensitivity of MBC, together with pre-clinical models, provided a rationale for studies of extreme dose-escalation with autologous haematopoietic progenitor support (ASCT). Early studies of HDC as salvage following failure of CDC produced high rates of temporary response. Subsequent single arm studies in pts who were preselected for responsiveness to CDC yielded 10-20% durable remissions suggesting that HDC might cure some MBC pts. The likelihood of selection bias mandated randomised trials of this CDC induction-HDC consolidation approach. We hypothesised that an alternative strategy-accelerated multi-cycle HDC- might provide an optimal HDC strategy (Crown J, Norton L, Ann Oncol 1996). Methods In IBDIS, pts received a brief phase of CDC induction (doxorubicin/docetaxel-"AT"), followed by tandem cycles of HDC, or, further CDC (AT followed by CMF), as initial CRx for MBC. Hormone receptor-positive patients received endocrine therapy post-chemotherapy, and pts with localized metastases received consolidative radiotherapy. Results: Accrual failed in the aftermath of the disclosure of research fraud involving a South African HDC study, and the reporting of negative PRCTs at ASCO 1999. Only 110 of a planned 264 patients were enrolled, but it was decided to maintain follow-up, which is now 15 years. HDC and CDC groups were well-balanced for prior adjuvant (25 v 25), prior anthracycline (8 v 10), positive receptor status (32 v 31). There were 8 treatment-related deaths (6-HDC, 2 CDC). Complete and overall response rates (CR/OR) were significantly superior for HDC v CDC (CR-29% v 6%, OR-71% v 44%). Event-free-survival at median 5 yrs were HDC 6 (11%) versus CDC 0 (p=.027). At fifteen years three HDC pts remain alive and free from relapse. All CDC are deceased. The hazard ratio for PFS is currently 0.59 (0.39-0.88) favouring HDC p=.009. The HR for overall survival is 0.72 (0.48-1.08)p=.11 Discussion: Despite accrual failure, IBDIS was and remains a positive study for its primary endpoint of PFS. The 100% relapse and death rate for CDC on our study is typical of the published literature. Data from IBDIS are included in the Cochrane meta-analysis of HDC which showed an advantage for PFS. The contention that HDC produced superior activity to CDC appears to have been correct, however the magnitude of the benefit is smaller than was hoped by investigators in the field. While our data support the hypothesis that there is a dose response relationship in the chemotherapy of MBC, the small benefit and high toxicity of HDC, preclude it being recommended as a standard treatment for any pts with MBC. Citation Format: Crown J. Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-07.

Abstract OT1-03-12: MANTA: A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer

Abstract Background: Resistance to endocrine therapy remains a major clinical challenge in ER+ breast cancer. Aberrant PI3K/AKT/mTOR pathway activation frequently occurs in ER+ breast cancer and is associated with resistance to endocrine therapy. Randomised clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine treatment. However, there is increasing evidence that inhibition of only mTORC1 with rapalogues such as everolimus sets off a negative feedback mechanism that leads to increased AKT signalling and is linked with treatment resistance. AZD2014 is a dual inhibitor of both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive); compared to rapalogues, AZD2014 has a broader range of growth inhibitory activity in preclinical models based on a more profound mTORC1 inhibition and the additional inhibition of mTORC2. AZD2014 is especially effective in ER+ breast cancer models, showing superior activity to everolimus both in hormone-sensitive and resistant models. Trial objectives: The main aims of this trial are (i) to determine whether dual inhibition of mTORC1 and mTORC2 with AZD2014 will increase the activity of endocrine therapy with fulvestrant in ER+ breast cancer, (ii) whether inhibition of mTORC1 and mTORC2 using AZD2014 will have superior anti-tumour activity compared to inhibition of mTORC1 alone with everolimus, and (iii) to compare the safety and efficacy of two schedules of AZD2014. Methods: MANTA is an international investigator led, sponsored, open-label, randomised phase II trial. Patients are randomised in a 2:3:3:2 ratio to receive either fulvestrant (500mg) alone, fulvestrant and AZD2014 at a continuous daily schedule (50mg BD), fulvestrant and AZD2014 at an intermittent schedule (2 days on, 5 days off; 125mg BD) or fulvestrant and everolimus (10mg OD). Patients are stratified by disease measurability and response to prior endocrine therapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Eligibility criteria: This study enrols post-menopausal women with ER+, HER2-negative, advanced or metastatic, hormone refractory breast cancer. Patients must have at least one measurable lesion and no life-threatening visceral disease. Patients with significant pulmonary dysfunction, cardiovascular disease or uncontrolled diabetes are excluded. Patients must not have had previous treatment with fulvestrant, PI3K/Akt or mTOR inhibitors or no more than one line of chemotherapy for metastatic breast cancer. Endpoints: The primary endpoint is progression-free survival . Secondary endpoints include objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, patient reported outcomes and pharmacokinetic parameters of AZD2014 and fulvestrant. Archival tumour tissue must be available to evaluate biomarkers associated with therapeutic response and resistance. Target accrual: Approximately 316 patients will be enrolled at ∼90 sites in the UK, Germany, Spain, Portugal, France, Hungary, Romania, Georgia, and South Korea. Recruitment opened in 2014 and 121 patients have been recruited to date. NCT02216786. Citation Format: Schmid P, Ferreira M, Dubey S, Zaiss M, Harper-Wynne C, Makris A, Brown V, Kristeleit H, Patel G, Perelló A, Jones A, Mithal N, Ruiz I, Kümmel S, Brunt AM, Guerra JA, Gonzalez Cao M, Saura C, Mousa K, Sarker S-J, Coetzee C, Swann R, Cortes J. MANTA: A randomized phase II study of fulvestrant in combination with the dual mTOR inhibitor AZD2014 or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-12.

Abstract P5-11-01: Preferences for chemotherapy side effect profiles in breast cancer- The view of oncologists

Abstract Background The best sequencing of chemotherapy in metastatic breast cancer is unclear and the choice of chemotherapy agent is often influenced by side effect profile. A number of studies have examined patient preferences for chemotherapy toxicities but none have looked specifically at the preferences of prescribing oncologists. There is clear potential for the preferences of individual oncologists to bias discussions about chemotherapy and it is important to take into account any differences in the relative weighting of potential toxicities to help inform a more reasoned discussion with patients. The aim of this study was to survey the opinions of a group of consultant breast cancer oncologists asking what they deemed to be the most and least severe chemotherapy side effects, and to compare with similar patient opinion studies. Methods Consultant breast cancer oncologists at the UK Breast Cancer Meeting (UKBCM) 2014 were asked to vote using an electronic keypad voting system. A slide listed nine chemotherapy side effects: nausea/vomiting, hand-foot syndrome, sensory neuropathy, motor neuropathy, myalgia, mucositis, diarrhoea, fatigue and alopecia. Delegates were asked to vote on which was the worst side effect, assuming grade 3/4 toxicity. The vote was then repeated asking the question which was the most acceptable side effect. Results 106 electronic keypad voting responses were received to both questions. Sensory neuropathy (21.7%), nausea/vomiting (19.8%), motor neuropathy (17.9%) and fatigue (17.9%) were voted the most troublesome side effects. When asked about the most acceptable side effects, alopecia was the most popular response (40.6%) followed by fatigue (22.6%). Sensory (<1%) or motor (0%) neuropathies were not felt to be acceptable. A previous study in breast cancer patients found that diarrhoea (34%), nausea/vomiting (15%) and hand-foot syndrome (13%) were considered the worst side effects. In contrast only 4.7% of oncologists ranked diarrhoea as the worst symptom. Both the patient and oncologist studies ranked alopecia as the most acceptable side effect (34% and 40.6% respectively). Conclusions The effect of fatigue in cancer treatment is often underestimated. Only 9% of patients recognised fatigue as the worst side effect compared with 17.9% of oncologists, although a similar proportion of oncologists (22.6%) felt it to be most acceptable - even professionals have a varying understanding of severe fatigue. Oncologists might underestimate the impact of diarrhoea caused by drugs such as capecitabine on quality of life, but tend to rank longer term toxicities such as neuropathy higher than patients. This is the first study to assess the concerns of oncologists with regard to chemotherapy side effects and as such gives some insight into how certain regimes might be chosen or presented to patients. Citation Format: Beresford MJ, Makris A. Preferences for chemotherapy side effect profiles in breast cancer- The view of oncologists. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-11-01.

Abstract P2-02-15: Discovery of putative circulating tumor cells through somatic mutation profile of epithelial cell adhesion molecule positive single cells from blood of metastatic breast cancer patients

Abstract Background: Circulating tumor cell (CTC) enumeration provides prognostic information for chemotherapy in metastatic breast cancer. However, due to its rarity and heterogeneity, it is difficult to distinguish true CTCs from normal blood cells and perform genomic analysis on them for use in therapeutic strategies. The main application of most currently available CTC detection systems consists of an enumeration of putative CTCs without further analysis. The aim of this study was to evaluate the feasibility of single cell picking and target sequencing of epithelial cell adhesion molecule (EpCAM)-positive cells for detecting CTCs. Methods: Whole blood sampled from metastatic breast cancer patients who were newly diagnosed with metastasis or who had disease progression during palliative treatment were used for this study. After applying IsoFlux Circulating Tumor Cell Enrichment Kit (Fluxion, South San Francisco, CA, USA), single CTC candidates were picked from a pool of EpCAM-positive cells. Genomic DNA from the picked cells was whole genome amplified and target sequencing was performed using Ion AmpliSeq™ Cancer Hotspot Panel (Life Technologies, Carlsbad, CA, USA). Target sequencing reads were mapped to human genome reference (hg19) using BWA-MEM (0.7.10). Single nucleotide variants (SNVs) were annotated using dbSNP, Variome Data 0.2, and COSMIC databases. Results: A total of 172 EpCAM-positive cells were selected according to size and EpCAM status from whole blood of 11 patients. The remaining cells were grouped into a pooled sample for each patient. The mean read depth of the target genes was 13455×. A mean 7.82 mutations as determined by SNVs listed in the COSMIC database but not in dbSNP and Variome Data 0.2 were detected in each patient. Cells with multiple mutated genes, or those with a mutated gene repeatedly observed in another cell from the same patient were judged to be putative CTCs. At least 2 putative CTCs were detected in 7 patients while no CTCs were detected in 2 patients. Mutated genes observed in the putative CTCs were ABL1, AKT1, APC, CDH1, CDKN2A, ERBB2, FGFR3, HRAS, IDH1, JAK2, KDR, NPM1, RB1, RET, SMARCB1, STK11, and TP53. Conclusions: Potential CTCs were successfully identified by single cell picking and target sequencing of EpCAM-positive cells from whole blood of metastatic breast cancer patients. Unique mutations not detected in other single cells and pooled samples can be used to distinguish putative CTCs from normal cells. Genomic profiling of corresponding primary tumor and metastatic site biopsy is warranted to verify the CTCs and investigate their role in disease progression. Citation Format: Lee H-B, Jeon S, Kim BC, Jho S, Kim J, Kang YJ, Yoo T-K, Han JH, Kim Y, Im S-A, Moon H-G, Noh D-Y, Han W. Discovery of putative circulating tumor cells through somatic mutation profile of epithelial cell adhesion molecule positive single cells from blood of metastatic breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-02-15.

Abstract P3-07-42: Predicting outcome and benefit to first-line bevacizumab in advanced/metastatic hormone receptor (HR)+/HER2-negative breast cancer (BC) treated with endocrine therapy: A correlative science study from the LEA phase III clinical trial (GEICAM/2006-11_GBG 051)

Abstract Introduction: The role of bevacizumab in combination with chemotherapy in metastatic BC is controversial, and no biomarker exists as of today that predicts benefit to this agent. In the LEA clinical trial, a numerical, statistically non-significant benefit from the addition of bevacizumab to endocrine therapy (ET) was observed in the first-line metastatic setting (18.4 vs. 13.8 months of Progression-Free Survival (PFS), p=0.14). Here, we explored various gene expression-based predictors of outcome and benefit to bevacizumab. Methods and materials: LEA trial randomized 380 patients with HR+/HER2- advanced disease to bevacizumab in combination with ET (ET+B) vs. ET alone. Primary endpoint was PFS. Expression of BC selected genes was evaluated in formalin-fixed paraffin-embedded (FFPE) primary tumors using the nCounter platform from patients randomized in Spain that consent for biomarker analyses. The following variables were evaluated: 1) research-based PAM50 intrinsic subtypes (categorical variable; Luminal A, Luminal B, HER2-enriched, Basal-like and Normal-like); 2) research-based PAM50 signatures (continuous variable; scores showing the distant of the gene expression values of an individual sample compared to the centroid gene values for each PAM50 intrinsic subtype); 3) risk of recurrence (ROR) groups (low, medium and high); 4) the 13-gene hypoxia/VEGF signature (continuous); and 5) Ki67 by immunohistochemistry (continuous). Uni- and multivariable Cox models for PFS were used to test the prognostic significance of each variable. To determine whether each variable is predictive of bevacizumab benefit, we tested the interaction term of each variable by treatment arm in a Cox model. Results: Tumor samples from 103 patients were analyzed: 55 (53%) in ET+B arm and 49 (47%) in ET arm. Subtype distribution was as follows: 57 (55.3%) Luminal A, 32 (31.1%) Luminal B, 5 (4.9%) HER2-enriched, 1 (1.0%) Basal-like, and 8 (7.8%) normal-like. In a univariate analysis, Luminal B tumors had a poorer outcome using Luminal A as reference (13.8 vs. 21.3 months, respectively; (hazard ratio, HR=1.80, 95% CI 1.10-2.95, p=0.019). Concordant with this finding, Luminal A signature was associated with a better outcome. Similarly, ROR-P high group showed a poorer outcome than ROR-P low group (8.5 vs. 19.4 months; HR=2.88, 95% CI 1.30-6.35, p=0.009). Neither VEGF-13 signature nor Ki67 were found to be associated with PFS. Similar findings were obtained after adjustment for treatment, age, previous ET, ECOG, visceral disease and number of metastatic sites. In terms of treatment benefit, the HER2-enriched signature was the only variable found predictive of bevacizumab PFS benefit in univariate (p=0.010) and multivariate (p=0.015) analyses. Conclusions: In advanced HR+/HER2- disease, intrinsic subtype (i.e. Luminal A vs. B) independently predicts PFS following first-line ET. In addition, HR+/HER2-negative tumors with high expression of the HER2-enriched signature, a biomarker of estrogen-independence, benefit the most from bevacizumab. Further validation of these prognostic and predictive biomarkers is warranted. Citation Format: Prat A, de la Haba-Rodriguez J, Guerrero Á, García-Sáenz JA, Morales S, Antón A, Muñoz M, Ramos M, Martínez-Jáñez N, Margelí M, Servitja S, Rojo F, Galván P, González S, Cruz J, Sánchez-Rovira P, Perelló A, Rodríguez-Martin C, Casas M, Carrasco E, Caballero R, Martín M. Predicting outcome and benefit to first-line bevacizumab in advanced/metastatic hormone receptor (HR)+/HER2-negative breast cancer (BC) treated with endocrine therapy: A correlative science study from the LEA phase III clinical trial (GEICAM/2006-11_GBG 051). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-42.

Abstract OT1-01-07: nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC)

Abstract Background: Nivo is an inhibitory antibody against programmed death receptor-1 (PD-1), a regulator of antitumor immunity. Nivo is approved for treatment of unresectable or metastatic melanoma and disease progression (PD) following ipilimumab or, in BRAF V600 mutation–positive melanoma, following a BRAF inhibitor, and for metastatic squamous non-small cell lung cancer (NSCLC) following PD during or after platinum-based chemotherapy. Nivo and other immune checkpoint inhibitors are also being investigated in other tumor-types. nab-P is a novel taxane formulation and does not require prophylaxis with immunosuppressive steroids. It has demonstrated superior efficacy over control regimens in phase III studies of MBC, pancreatic cancer, and NSCLC. This open-label, 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P in 3 cancer types (2 arms/disease): MBC, advanced NSCLC (+ carboplatin), and advanced pancreatic cancer (± gemcitabine). The study design for the MBC portion is described below. Methods: Eligibility criteria include histologically/cytologically confirmed HER2-negative MBC; 1 prior chemotherapy for MBC, including an anthracycline unless clinically contraindicated; no relapse < 12 months after taxane adjuvant therapy; measurable disease by RECIST v1.1; ECOG performance status 0-1; adequate organ function; and preexisting peripheral neuropathy grade < 2. Patients (pts) with MBC will be treated in 2 arms: nab-P 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus Nivo 3 mg/kg on days 1 and 15 starting at cycle 3 or nab-P 260 mg/m2 on day 1 of each 21-day cycle plus Nivo 5 mg/kg on day 15 starting at cycle 3. Pts will be treated until PD or allowed to continue treatment beyond RECIST v1.1–defined PD if they continue to meet study eligibility; do not have rapid PD or clinical deterioration or unacceptable toxicities; and can benefit from continuation of study treatment in the treating physician's opinion and will not delay an imminent intervention to prevent serious complications of PD. The primary endpoints of the study are the number of pts with dose-limiting toxicities (DLTs) in each treatment arm (part 1) and the percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to a TEAE (parts 1 and 2). Part 1 of the study will assess whether the starting dose of Nivo is deemed safe (≤ 1 DLT in 6 pts); otherwise, the Nivo dose will be de-escalated and assessed in a new cohort at the next lower dose level. The Nivo dose in combination with nab-P deemed safe in a treatment arm may be further assessed in part 2 of the study, with enrollment expanded to an additional ∼ 14 pts/arm (total of 20 Nivo-treated pts/arm). Secondary study endpoints include TEAEs leading to dose reduction, delay, interruption, or treatment discontinuation; progression-free survival; overall survival; disease control rate; overall response rate; and duration of response (per RECIST v1.1). Exploratory endpoints include tumor-associated PD-L1 expression, modulation of immune activation in the tumor and peripheral blood in response to Nivo treatment, Nivo serum levels, and development of anti-globulin antibodies. ClinicalTrials.gov identifier NCT02309177. Citation Format: Waterhouse D, Gutierrez M, Bekaii-Saab T, DeRosa W, Wainberg Z, George B, Duval Fraser C, Ko A, Pierce DW, Stergiopoulos S, Soliman H. nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-07.

Abstract OT1-03-19: Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Eribulin mesylate, a microtubule inhibitor, is indicated for treatment of patients (pts) with metastatic breast cancer (MBC) with ≥2 prior chemotherapies for metastatic disease, including an anthracycline or taxane. Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for treatment of pts with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600-mutation positive, a BRAF inhibitor. Pembrolizumab is also being evaluated for treatment of metastatic triple-negative breast cancer (mTNBC) and multiple tumor types. We report the design of an open-label, single-arm, multicenter, phase 1b/2 study to evaluate safety and efficacy of the eribulin and pembrolizumab combination in pts with mTNBC previously treated with 0 to 2 lines of therapy in the metastatic setting. From August 2015 to February 2017, approximately 95 pts (aged ≥18 yrs) will be enrolled (n=12 phase 1b; n=83 phase 2) to reach 80 evaluable pts. Accrual has not yet commenced. Pts with measurable disease of ≥1 lesion >10 mm in long-axis diameter (nonlymph nodes) or >15 mm in short-axis diameter (lymph nodes) and an ECOG status of 0 or 1 will be included. Exclusion criteria include pts who received adjuvant chemotherapy within the past 6 months, chemotherapy/biological therapy within the past 3 wks, or radiation or small molecule targeted therapy within the past 2 wks. Pts will also be excluded if they have an autoimmune disease requiring immunosuppression or were previously treated with eribulin or any anti-PD-1, PD-ligand (L) 1, or PD-L2 agent. Phase 1b includes a safety run-in cohort in which ≥6 pts will receive intravenous (IV) eribulin 1.4 mg/m2 (equivalent to 1.23 mg/m2 eribulin [expressed as free base]) on day (d) 1 and d8 and IV pembrolizumab 200 mg on d1 of a 21d cycle. Dose-limiting toxicity (DLT) will be assessed in the first cycle. This dose will be selected as the recommended phase 2 dose (RP2D) if ≤1 pt has a DLT or, if necessary, alternative doses may be explored. Pts will be stratified by prior chemotherapy for MBC (0, ∼70%; 1–2, ∼30%) and will receive RP2D combination treatment. Pts can remain on 1 or both study drugs with clinical benefit until intercurrent illness, unacceptable toxicity, or disease progression. Bayesian predictive probability of response rate, based on the goal of claiming combination superiority at study end, will be used to monitor response rate after postbaseline tumor assessments for ≥38 pts. The study can be stopped early for efficacy or futility. Primary objectives include determination of safety and tolerability (phase 1b) and evaluation of objective response rate of the drug combination; secondary endpoints include evaluation of progression-free survival (PFS), overall survival (OS), and duration of response (DOR). PFS, OS, and DOR will be analyzed using Kaplan–Meier product-limit estimates. Median PFS, OS, and cumulative probability of PFS, OS, and DOR at 6 and 12 months will be presented with 2-sided 95% confidence intervals. Relationship between PD-L1 tumor status and efficacy endpoints will also be evaluated. For further information please contact Erhan Berrak (erhan_berrak@eisai.com). Citation Format: Berrak E, Atkan G, Song J, Almonte A, Karantza V, Yuan R. Design of a phase 1b/2 study to evaluate the efficacy and safety of eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-19.

Low-Dose Metronomic Chemotherapy in Metastatic Breast Cancer: A Retrospective Analysis of 40 Patients

Purpose: Low-dose metronomic chemotherapy is an emergent treatment schedule in which low doses of cytotoxic agents are given orally continuously, with no or short drug-free intervals. In general, it provides better tolerance, especially in patients who have been previously exposed to other oncologic treatments, with a favorable cost-effectiveness profile. It is well known that all these low-dose schedules have a favorable safety profile and may provide an adequate tumor control in patients with metastatic breast cancer. However, there are no data in literature reporting the patient’s tolerance and response to subsequent lines of chemotherapy after receiving metronomic regimens. Methods: We retrospectively analyzed 40 patients with metastatic breast cancer treated with low doses of Cyclophosphamide and/or Methotrexate and/or Capecitabine in a single center from June 2009 to April 2014. The following data were collected: age, hormone and epidermal growth factor receptor 2 (HER-2) status, number of lines of chemotherapy prior to and after low-dose metronomic treatment, duration of metronomic treatment, toxicity reason for treatment discontinuation. Duration of low-dose metronomic chemotherapy was also correlated with the variables analyzed and treatment outcomes. Results: The median time on metronomic chemotherapy was 5.4 months. The most frequent drugs administered were cyclophosphamide, methotrexate and capecitabine alone. Asthenia, myelotoxicity, gastrintestinal symptoms and handfoot syndrome were the most commonly recorded treatment related toxicity. Twenty six (65%) patients had the opportunity to receive a classic chemotherapy regimen following metronomic regimen interruption. Although patients who developed toxicity to low-dose metronomic chemotherapy remained less time (s that the use of prolonged metronomic treatment does not affect a patient’s ability to tolerate subsequent therapy.

107P Metronomic oral chemotherapy in metastatic breast cancer

107P Metronomic oral chemotherapy in metastatic breast cancer

Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial

Oral fluoropyrimidines are used for the first-line treatment of metastatic breast cancer to avoid severe adverse effects, although firm supporting evidence is lacking. We aimed to establish whether S-1 is non-inferior to taxanes in this setting. We did an open-label, non-inferiority, phase 3 trial at 154 hospitals in Japan. We enrolled individuals who had HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease, and who were resistant to endocrine treatment. Patients were randomly assigned (1:1) either to taxane (docetaxel 60-75 mg/m(2) at intervals of 3-4 weeks; paclitaxel 80-100 mg/m(2) weekly for 3 of 4 weeks; or paclitaxel 175 mg/m(2) at intervals of 3-4 weeks) or to S-1 (40-60 mg twice daily for 28 consecutive days, followed by a 14-day break). Randomisation was done centrally with the minimisation method, with stratification by institution, liver metastasis, oestrogen and progesterone receptor status, previous treatment with taxanes or oral fluorouracil, and time from surgery to recurrence. The primary endpoint was overall survival, with a prespecified non-inferiority margin of 1·333 for the hazard ratio (HR). The primary efficacy analysis was done in the full analysis set, which consisted of all patients who took at least one study treatment and who had all data after randomisation. This trial is registered with the University Hospital Medical Information Network, Japan (protocol ID C000000416). Between Oct 27, 2006, and July 30, 2010, we enrolled 618 patients (309 assigned to taxane; 309 assigned to S-1). The full analysis set consisted of 286 patients in the taxane group and 306 in the S-1 group. Median follow-up was 34·6 months (IQR 17·9-44·4). Median overall survival was 35·0 months (95% CI 31·1-39·0) in the S-1 group and 37·2 months (33·0-40·1) in the taxane group (HR 1·05 [95% CI 0·86-1·27]; pnon-inferiority=0·015). The most common grade 3 or worse adverse events were neutropenia (20 [7%] of 307 patients in the S-1 group vs nine [3%] of 290 patients in the taxane group), fatigue (ten [3%] vs 12 [4%]), and oedema (one [<1%] vs 12 [4%]). Treatment-related deaths were reported in two patients in the taxane group. S-1 is non-inferior to taxane with respect to overall survival as a first-line treatment for metastatic breast cancer. S-1 should be considered a new option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. Comprehensive Support Project for Oncology Research of the Public Health Research Foundation, Japan; Taiho.

What is the benefit of treatment with multiple lines of chemotherapy for patients with metastatic breast cancer? A retrospective cohort study

BackgroundDespite the extensive clinical experience, it is still under debate to what extent patients with metastatic breast cancer (MBC) benefit from multiple lines of chemotherapy beyond standard first or second line treatment. Selection of patients with MBC who will benefit from treatment is crucial to improve outcome and reduce unnecessary toxicity. In this retrospective study, systemic treatment outcome for patients with metastatic MBC is being evaluated. We evaluated to what extent the clinical benefit of prior chemotherapy can predict the success of a subsequent treatment line. MethodsNinety-one patients treated with chemotherapy for MBC between January 2005 and January 2009 were included in this study. Clinical characteristics of patients, choices of chemotherapy and response at first evaluation of every treatment line was evaluated based on radiologic and clinical data. ResultsPatients received multiple systemic cytotoxic and biological (combination) therapies. 30% of these patients received more than five consecutive systemic (combination) treatments. First line chemotherapy was mostly anthracycline-based, followed by taxanes, capecitabine and vinorelbine. The response rate (RR, complete response plus partial response according to RECIST 1.1) decreased from 20% (95% CI 11–28%) upon first line of treatment to 0% upon the fourth line. The clinical benefit rate (combining RR and stable disease) decreased from 85% (95% CI 78–93%) in the first to 54% (95% CI 26–67) upon the fourth line. 24% of the patients with clinical benefit at first evaluation did not receive a subsequent line of treatment when progressive disease occurred, while sixty-one percent of the patients with progressive disease at first evaluation of a treatment did not receive a subsequent line of chemotherapy. When applied, the efficacy of a subsequent line of treatment was similar for patients independent of previous treatment benefit. ConclusionThe clinical benefit at first evaluation from systemic treatment in MBC does not predict for subsequent treatment benefit in this retrospective analysis. The fact that 61% of patients did not receive subsequent treatment after previous treatment failure suggests that either clinical judgement is of critical value in selection of patients to prevent them from unnecessary toxicity or, alternatively indicates that based on the assumption that prior treatment failure predicts for lack of benefit undertreatment of patients occurs. Therefore, a more adequate clinical judgement tool or predictive biomarkers for response are urgently needed to improve treatment outcome.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Systemic chemotherapy for metastatic breast cancer

Abstract Breast cancer is the leading cause of cancer among women worldwide and the most common cancer in China. Many factors influence the treatment strategy for metastatic breast cancer (MBC). Chemotherapy should be administered to patients with hormone receptor-negative tumors, symptomatic visceral metastasis, and a short disease-free interval. Sequential single-agent chemotherapy has similar efficacy as combination agents in terms of overall survival and quality of life. Anthracyclines are the cornerstone of first-line treatment for MBC, and taxanes represent the second treatment option after resistance. When progression or intolerable toxicity occurs after optimal treatment, the alternative treatments include capecitabine, vinorelbine, and gemcitabine. Ixabepilone and eribulin are relatively new effective single agents. A combination of cytotoxic agents for patients with rapid clinical progression can further improve the overall response rate and time to progression compared to single-agent treatment. For patients with MBC who were pretreated with anthracyclines in the neoadjuvant/adjuvant setting, a taxane-containing regimen such as docetaxel plus capecitabine or gemcitabine plus paclitaxel should be administered. Platinum-based therapies such as cisplatin or carboplatin have a role in the treatment of triple-negative breast cancer. Meanwhile, the efficacy of the addition of targeted drugs such as iniparib, bevacizumab, and cetuximab to chemotherapy remains unproven. Maintenance chemotherapy is routinely recommended in clinical practice at present. Patients who were previously treated with paclitaxel and gemcitabine have better progression-free and overall survival with maintenance chemotherapy according to a Korean phase III clinical trial. Sequential maintenance treatment with capecitabine monotherapy after capecitabine-based combination chemotherapy (X-based X) appears favorable based on a series of domestic studies.

Impact of prior anthracycline or taxane use on eribulin effectiveness as first-line treatment for metastatic breast cancer: results from two phase 2, multicenter, single-arm studies.

Eribulin mesylate has efficacy in patients who have received ≥2 prior chemotherapies for metastatic breast cancer (MBC) including an anthracycline and taxane. Phase 2 trials showed clinical activity and acceptable tolerability of first-line eribulin (HER2− MBC; Study 206) and eribulin plus trastuzumab (HER2+ MBC; Study 208). Prespecified analyses evaluated efficacy by prior anthracycline and/or taxane use. Patients received eribulin mesylate (1.4 mg/m2 IV; Days 1 and 8) and, in Study 208, trastuzumab (8 mg/kg IV/Cycle 1, then 6 mg/kg; Day 1) in 21-day cycles. Endpoints included objective response rate (ORR), progression-free survival (PFS), and tolerability. In Study 206 (N = 56), 48 % of patients had received prior anthracycline, 46 % prior taxane, 36 % prior anthracycline and taxane, and 41 % were chemotherapy-naïve. In Study 208 (N = 52), these percentages were 21, 44, 17, and 52 %, respectively. In Study 206, ORR and median PFS were similar for anthracycline-pretreated (25.9 %, 5.8 months), taxane-pretreated (26.9 %, 5.8 months), anthracycline- and taxane-pretreated (25.0 %, 6.7 months), and anthracycline/taxane-naïve patients (30.4 %, 7.6 months). In Study 208, ORR/median PFS were 63.6 %/6.7 months among anthracycline-pretreated patients, 56.5 %/6.8 months among taxane-pretreated patients, 55.6 %/5.9 months among anthracycline- and taxane-pretreated patients, and 81.5 %/13.1 months among anthracycline/taxane-naïve patients. Tolerability was generally similar among subgroups. In these studies, first-line eribulin in HER2− MBC and eribulin/trastuzumab in HER2+ MBC was effective with acceptable tolerability, regardless of prior anthracycline/taxane treatment. Prior chemotherapy was associated with lower ORR and shorter PFS with eribulin/trastuzumab in HER2+ MBC but not with eribulin in HER2− MBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-1322-y) contains supplementary material, which is available to authorized users.

1881 Does agents sequencing matter across multiple line of chemotherapy in metastatic breast cancer? A mono-institutional retrospective analysis on 550 women

1881 Does agents sequencing matter across multiple line of chemotherapy in metastatic breast cancer? A mono-institutional retrospective analysis on 550 women