Line Therapy For Metastatic Breast Cancer Research Articles

Abstract PD6-07: Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill

Abstract Background: An increasing number of molecularly-targeted therapies for metastatic breast cancer (MBC) are clinically-available (approved and investigational). These anti-cancer agents target specific molecular abnormalities such as mutated, amplified, deleted, or rearranged genes. Reporting of unique tumor genetic alterations is not included in routine clinical/diagnostic panels. In MBC, knowledge of mutational status may foster efficient transitions in clinical care and trial enrollment at disease progression. We describe the development and implementation of a clinically-integrated genomic sequencing program and report how information regarding targetable genomic aberrations in MBC patients (pts) is used to improve clinical practice in an academic setting. Methods: Genomic sequencing of investigative biomarkers was prospectively offered to pts with MBC. DNA libraries were prepared separately from a retrieved archival FFPE tumor sample and a matched normal sample from each pt. Relevant targets were enriched by custom Agilent SureSelect hybrid capture baits using standard protocols. Samples were sequenced on Illumina HiSeq 2000/2500 platforms. Mutational findings were reviewed by a molecular tumor board (MTB); variants identified to be potentially actionable underwent confirmatory testing in a CLIA-approved laboratory. Confirmed findings were inserted into the pt's EMR accessible by both the pt and the treating oncologist. Results: Of the 725 MBC pts seen at UNC since 1/1/2012, 194 (27%) contributed samples for genomic sequencing. Of those whose tumors were sequenced, average age at MBC diagnosis was 54 (25 - 91); 73% were Caucasian, 16% African American. De novo MBC accounted for 39 (20%) sequenced pts. Of sequenced patients, sites of metastatic disease included bone only (7%), visceral only (46%), and both bone and visceral (47%). Approximately 1/3 of pts were consented for sequencing at time of initial MBC diagnosis, 1/4 after 1st line therapy for MBC, and the remaining at or beyond their 2nd line. In total, 131 (68%) pts have sequencing results available of which 43% of pts had reportable mutations deemed actionable by the MTB. Specific mutations and observed frequency by subtype are shown below. Pts (19%) whose tumors were sequenced were more commonly enrolled in a therapeutic clinical trial for MBC, a higher rate than seen in the non-sequenced group (7%) (p<0.001). To date, 27% of pts' tumors harbored an alteration that is an eligibility requirement for a molecularly-targeted therapeutic trial accruing pts at UNC. Observed Mutation by Clinical Subype Genes Total # (56 pts)HR+/HER2- (25 pts)HER2+ (13 pts)TNBC (18pts)PIK3CA15933TP5315456CCND19531NF-14103FGFR13300PTEN3012KRAS2011MDM22110PIK3R12002ROS12011TSC12011Other*14518TOTAL73281728*Mutations observed only once Conclusion: Preemptive genomic sequencing can be integrated into the clinical and operational practice of a comprehensive cancer center. Currently this research tool and program provides valuable information that has the potential to foster both clinical trial eligibility and/or enrollment. With longer follow-up, we hope such an approach ultimately will improve patient outcomes. Citation Format: Grilley-Olsen J, Keith KC, Hayward M, Dees EC, Deal A, Ivanova A, Benbow JM, Parker J, Patel NM, Eberhard D, Mieczkowski P, Weck KE, Hayes DN, Muss H, Jolly T, Reeder-Hayes K, Earp HS, Sharpless N, Carey L, Anders CK. Genomic sequencing in metastatic breast cancer patients to inform clinical practice at the University of North Carolina at Chapel Hill. [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 PD6-07.

Real-world symptom burden and early treatment discontinuation in first-line metastatic breast cancer (MBC).

9619 Background: Treatment options in 1st line metastatic breast cancer (MBC) vary and may include chemotherapy, targeted, and hormone therapy. Some patients (pts) do not complete therapy as planned, perhaps due to treatment related toxicities. The current study examined the association of symptom burden with early treatment discontinuation (ETD) of 1st line therapy of MBC in real-world settings. Methods: Data were abstracted from medical records of pts at 9 community oncology practices. Eligible pts had stage IV breast cancer with start of 1st line therapy on 1/2004 to 6/2012, were ≥ 18 years, and had ≥ 1 Patient Care Monitor (PCM) survey during 1st line. The PCM is an 86-item survey of cancer-related symptoms collected as part of routine clinical care. Age, race, HER2 status, hormone status, oral and infused agents, dates of diagnosis, treatment, progression, and death were recorded. ETD was defined by direct indication of early stopping in the medical record, or by treatment duration ≤ 6 weeks without evidence of disease progression. Cox regression of ETD with time varying covariates was used to examine the impact of 23 separate symptoms as well as an overall composite symptom burden score based on pt responses on each symptom. Results: 797 pts were included, with mean age of 58.4 years, 62.1% White; with 340 on Chemotherapy (CT), 349 on CT + Targeted therapy (T) and 108 on Hormone therapy only (H). Overall, ETD occurred in 95 (11.9%) pts, with rates highest among CT (15.3%), followed by T (10.0%) and H (7.4%). Cox regression showed that 21 of 23 symptoms each increased the risk of ETD. In the composite symptom burden score (median 7.1; range 0 - 21) analysis, overall symptom burden was found to be significant (HR = 1.124, p < 0.0001), indicating a 12.4% increased risk of ETD with each additional symptom. Pts with 10+ symptom score had a significantly increased risk of ETD (HR = 3.09, p < 0.0001) compared to pts with < 5 symptom score. Pts with 15+ symptom score had the highest risk of ETD (HR = 5.75, p < 0.0001). Conclusions: Pts treated with CT for 1st line MBC had the highest rate of ETD. The likelihood of ETD increased as the number of symptoms increased. Future research is needed to evaluate ETD on pt outcomes, including overall survival.

Interim safety results of eribulin (E) combined with ramucirumab (RAM) in patients (pts) with advanced metastatic breast cancer (MBC).

110 Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. Methods: Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. Results: Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. Conclusions: Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text]

P3-16-05: A Phase II Trial Expansion Cohort of the PARP Inhibitor Veliparib (ABT888) and Temozolomide in BRCA1/2 Associated Metastatic Breast Cancer.

Abstract Background: Veliparib (ABT-888) is a novel oral inhibitor of Poly (ADP-Ribose) Polymerase (PARP) 1 and 2. Veliparib and temozolomide (TMZ) are synergistic in breast cancer xenograft models. We recently conducted a phase II study of TMZ and veliparib in 41 patients (pts) with metastatic breast cancer (MBC). Activity was observed only in pts with known BRCA1 or BRCA2 deleterious mutations, with a response rate (RR) of 50% (4/8) and clinical benefit rate (CBR) of 62.5%. In order to further evaluate the activity and safety of TMZ and veliparib, we enrolled an expansion cohort of 20 additional patients with BRCA1 or 2 mutations. Methods: We previously conducted a single arm phase II trial of veliparib and TMZ in 41 MBC pts. Eligibility included measurable disease, ≥1 prior MBC therapy and PS ≤ 2. Available archived tumor samples were collected. In this expansion cohort, first line therapy for MBC and prior PARP inihibitor therapy were allowed, and eligible patients were required to have a known deleterious BRCA1 or BRCA2 mutation identified from prior clinical testing. The dose of veliparib in the original cohort was reduced from 40 mg PO BID to 30 mg PO BID. In the expansion cohort all patients received veliparib (30 mg PO BID days 1–7) and TMZ (150mg/m2 PO QD days 1–5) on a 28 day cycle. RECIST response was evaluated every 2 cycles. The primary endpoint was overall response rate. Secondary endpoints included PFS, OS, safety and toxicity. Results: Between June 24, 2010 and Sept 29, 2010, 20 eligible pts (median age 42) were enrolled. Baseline characteristics included: median PS=0 (range 0–2); 9 BRCA1 carriers, 9 BRCA2 carriers, and 2 unknown. 17 pts (85%) received prior adjuvant chemotherapy. 9 patients received a prior platinum chemotherapy. The most common grade 3/4 toxicities included thrombocytopenia and neutropenia. Best response for the 20 patients evaluable at the time of abstract submission includes 3 PR (15%), 6 SD (30%), 11 PD, and a clinical benefit rate of 45%. Combined with the initial cohort of 8 known carriers from the original 41 patients, the total RR is 25% (7/28) and clinical benefit rate of 50% (7 PR, 7 SD). The RR was 40% (6/15) in pts without prior platinum treatment, and 9% (1/11) in pts with prior platinum treatment. The median PFS for the 20 BRCA carriers was 85 days, and among patients with prior platinum treatment compared to no prior platinum, the median PFS was 70 and 179 days, respectively. Three pts remain on study, 1 with a CR for >20 mo. Discussion: We previously demonstrated that veliparib and TMZ is an active combination in BRCA1/2 associated MBC. In this larger expansion cohort of 20 additional patients, the combination continued to show activity, although the response rate was not as robust as previously observed. Differences between the original cohort and the expansion cohort may account for some variation in response, such as prior platinum or PARP inhibitors therapy, number of lines of prior therapy, and the dose of veliparib used (40mg vs 30 mg). These results support further evaluation of this regimen in the BRCA1/2 carrier population, and provide the opportunity to evaluate potential factors that may predict response or resistance to this regimen. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-05.

P1-14-01: Randomized Phase II Trial of Weekly vs. q 2-Weekly vs. q 3-Weekly Nanoparticle Albumin-Bound Paclitaxel with Bevacizumab as First-Line Therapy for Metastatic Breast Cancer.

Abstract Background: Nanoparticle albumin-bound paclitaxel (nab-P) 260 mg/m2 is superior to paclitaxel 175 mg/m2 (P) every 3 weeks (Gradishar et al. JCO 2005) in metastatic breast cancer (MBC), and weekly uninterrupted P is more effective than q3wk P in MBC (Seidman et al. JCO 2008). Bevacizumab (bev) nearly doubles response rate and time to progression (TTP) when added to P as 1st line therapy for MBC (Miller et al. NEJM 2007). Methods: This open-label, phase II study randomized patients (pts) to nab-P at 260 mg/m2 q3wk (arm A) vs. 260 mg/m2 q 2wk with filgrastim (arm B) vs. 130 mg/m2 weekly uninterrupted (arm C), all with bev (15 mg/kg q 3 weeks arm A, 10 mg/kg q 2 weeks arms B and C). Patients were required to have measurable, HER2 negative MBC and no prior chemotherapy for MBC. The primary endpoints were response rate and toxicity. Results: Of 212 pts randomized, 208 (75 arm A, 54 arm B, 79 arm C) were treated, with balanced demographics and baseline characteristics. The median age was 57 (range 29–85), 82% were postmenopausal and 89% had visceral disease (64% lung, 50% liver). ECOG PS 0:60%, 1:35%, 2:5%. 62% had prior neo-adjuvant or adjuvant chemotherapy for early stage disease: anthracycline: 54%, taxane: 38%. No significant differences in confirmed complete and partial response rates were noted (A: 40%, B: 44%, C: 46%). Median TTP was longer in Arm C (9.0 months) versus both arms B (6.3 months) and A (8.0 months), overall p=0.065. There were no differences in overall survival (Arm A: 21.3 months, Arm B: 19 months, Arm C: 25.3 months). As per protocol-specified stopping rule, arm B was closed early due to an unacceptable safety profile with significantly more grade ≥ 2 fatigue (B:57%, A: 39%, C:39%, p=0.048) and bone pain (B:19%, A:10%, C:4%, p=0.024). Sensory neuropathy was common; grades 2/3/4: Arm A: 29%/32%/1%, Arm B: 15%/50%/2%, Arm C: 27%/43%/1%). Sensory neuropathy was commonly readily reversible with dose delay and reduction. Febrile neutropenia occurred in <2% of pts in all arms. Arm C patients experienced significantly less arthralgia compared with arms A and B, but dose delays were frequent (86% of pts) on this planned uninterrupted weekly schedule. Bevacizumab-related events were consistent with prior phase III trials of taxane/bev; there were no new safety signals. Conclusions: Significant and similar antitumor activity was observed in all arms. Weekly nab-P with bev (arm C) resulted in longer TTP. Weekly nab-P with bev (arm C) appears to have the highest therapeutic index, however sensory neuropathy is limiting, suggesting that a 3 week on/1 week off schedule could be preferable and should be studied comparatively. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-01.

Phase I trial of vinorelbine and sorafenib in metastatic breast cancer (MBC).

e13576 Background: Vinorelbine, a semisynthetic vinca alkaloid, at 20–25 mg/m2 has a response rate of 15–30% for second line therapy of MBC. Sorafenib is an oral multi-kinase inhibitor against the tyrosine kinases for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), Flt-3 and c-Kit receptors. In preclinical studies, sorafenib demonstrated antitumor activity by inducing complete tumor stasis in a variety of tumor types through the Raf/MEK/ERK pathway. In the NCI H460 cell line for NSCLC tumor xenograft, synergy between vinorelbine and sorafenib were observed. Methods: Eligibility include: MBC with adequate end-organ function and performance status (<2) with up to two lines of prior chemotherapy regimens. Intravenous vinorelbine on days 1, 8, 15 and oral sorafenib twice daily each 28-day cycle were given. Dose escalation using 3+3 design was determined based on course 1 toxicities. Vinorelbine was started at 20 mg/m2 and sorafenib at 200 mg. Tumor response was evaluated every two cycles by RECIST. Results: 11 patients were enrolled from 1/09 to 6/09 with a median age of 59 years (range 39–70). Prior chemotherapy regimens were 1/6/4 patients with 0/1/2 prior regimens. Dose limiting toxicities (DLT) on the second dose level, vinorelbine 25 mg/m2 and sorafenib 200 mg twice daily, were grade 3 hand-foot skin reactions in 1 and grade 3 febrile neutropenia in 2 out of 5 patients, establishing the maximum tolerated dose (MTD) as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. At the MTD, 6 patients were treated with 1 patient having grade 3 treatment-related toxicities (low sodium, neutropenia) during course 1. Additional grade 3 or 4 toxicities noted (in subsequent cycles) at the MTD include hypertension (2), neutropenia (1), and fatigue (1). The median number of cycles delivered at the MTD was 7 (range 2- 12+). We observed 1 partial response (PR) and 3 stable diseases (>4 months) at the MTD, with 1 additional stable disease at the DLT level. Conclusions: We established the phase II MTD as vinorelbine 20 mg/m2 and sorafenib 200 mg twice daily. With acceptable toxicity and encouraging initial response, a phase II trial is now on-going. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx

Identifying Patients at High Risk for Neutropenic Complications During Chemotherapy for Metastatic Breast Cancer With Doxorubicin or Pegylated Liposomal Doxorubicin

To develop a cycle-based risk prediction model for neutropenic complications (NC) during chemotherapy with doxorubicin (DOX) or a pegylated liposomal formulation (PLD) for patients with metastatic breast cancer (MBC). Data analyzed was from a phase III, randomized clinical trial of DOX (60 mg/m(2) every 3 weeks) or PLD (50 mg/m(2) every 4 weeks) for the first line therapy for MBC (n = 509) (O'Brien et al, Ann Oncol. 2004;15:440-449). NC were defined as an absolute neutrophil count < or =1.5 x 10(9) cells/L (ie, > or =grade II) before the next cycle, febrile neutropenia or neutropenia with a documented infection. Patient and hematologic factors potentially associated with NC were evaluated. Factors with a P value of < or =0.25 within a cycle were included in a generalized estimating equations regression model. Using backward elimination, we derived a risk scoring algorithm (range 0-63) from the final reduced model. Risk factors retained in the model included poor performance status, absolute neutrophil count < or =2.0 x 10(9) cells/L in the previous cycle, the first cycle of chemotherapy, DOX versus PLD and advanced age. A precycle risk score from > or =25 to <40 for a given patient was identified as being the optimal threshold for sensitivity (58.0%) and specificity (78.7%). Patients with a score at or beyond this threshold would be considered at high risk for developing NC in later cycles. The use of this model may enhance patient care by targeting preventative therapies (eg, granulocyte colony stimulating factor or PLD) to those MBC patients most likely to experience NC during anthracycline-based chemotherapy.

A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.

TEXAS (Taxotere® EXperience with Anthracyclines Study) trial: mature results of activity/toxicity of docetaxel given with anthracyclines in a community setting, as first line therapy for MBC

The TEXAS (Taxotere EXperience with Anthracyclines Study) study examined docetaxel in combination with an anthracycline, as first line treatment of metastatic breast cancer (MBC), in everyday practice, and compared the findings with a randomised controlled trial. Four hundred and seventy patients were registered on the TEXAS trial. Patients were assigned, according to treating clinician's discretion, to either doxorubicin 50 mg/m2 or epirubicin 75 mg/m2 both given day1 15 min intravenous bolus every 3 weeks, followed by docetaxel 75 mg/m2, day 1, 1 h intravenous infusion every 3 weeks. The overall response rate (ORR) was approximately 61%. The main toxicity reported was neutropenia, with 75 patients (55%) in the AT group and 203 (61%) in the ET arm. Febrile neutropenia or neutropenic sepsis was reported for 32 (24%) of the AT arm and 78 (23%) of the ET arm. This open access study demonstrates that AT or ET are highly active treatments for MBC, with similar response rates to those observed in a phase III clinical trial. This may be important for patients with rapidly progressive visceral disease. Side effects can be managed effectively with growth factors and/or prophylactic antibiotic.

Phase II trial of gemcitabine and carboplatin, plus trastuzumab in HER2+ patients as first line therapy in metastatic breast cancer

10590 Background: Gemcitabine (G) and carboplatin (C) demonstrate significant preclinical synergy together as well as in combination with trastuzumab (H) in metastatic breast cancer (MBC) pts. This multicenter phase II trial evaluates the efficacy and safety of G + C with trastuzumab in HER2 + pts as 1st line therapy in MBC. Methods: Eligibility requirements: females &gt; 18 with no prior regimens for MBC, ECOG 0–2, RECIST bidimensional disease, and adequate organ function. FISH HER2 + pts received H with GC. Treatment: G 1,000 mg/m2 D1&amp; 8 with C AUC 5 D1 in the first 20 pts. Following a toxicity assessment revealing significant myelosuppression, C was administered in subsequent pts at AUC 4. 14 HER2+ pts received H 8 mg/kg loading dose followed by 6 mg/kg q21 days. Pts were evaluated for response after 9 weeks; treatment continued until progression or toxicity except in HER2+ pts who received up to 6 cycles GCH followed by single agent H. Results: Between 11/03 &amp; 11/05, 45 pts have been treated: median age 55 for GC, 65 for GCH, ECOG 0/1 22/23. 19 pts were chemonaive. 26 pts received prior adjuvant chemotherapy: 20 pts adjuvant anthracyclines (A) &amp; taxanes (T), 3 only prior A and 3 prior T. 73% had 2 or more metastatic sites of disease. 31 pts received GC &amp; 14 pts received GCH. 18 of 41 evaluable pts (44%) had objective responses (PR 16, CR 2) with 17 pts (42%) exhibiting SD &amp; 6 pts PD (15%). 91% of AT pretreated pts demonstrated SD or better. 9 remain on study. 6 went off study due to heme related toxicities and 9 due to MD discretion [4 max benefit, 3 XRT]. Median # of cycles was 5. Combined G3/4 hematologic toxicity was notable for 66% neutropenia (only 1 FN), 55% thrombocytopenia, and 32% anemia, predominately occurring at the carboplatin AUC 5 dose level. Transfusions of PRBCs and plts were administered in 14 and 8 pts respectively. Nonhematologic toxicity was minimal and remarkable for G3/4 fatigue in 20%. Conclusions: In FISH HER2+ pts, the addition of trastuzumab to GC yielded a 50% RR, with no evident cardiotoxicity. The combination of gemcitabine with carboplatin AUC 4 is active, albeit with moderate hematologic toxicity, warranting further exploration of alternate GC ± H schedules in breast cancer. [Table: see text]

Experience of weekly paclitaxel therapy in patients with metastatic breast cancer at a single cancer institution

855 Background: Paclitaxel is an active agent for the treatment of metastatic breast cancer (MBC) and is commonly administered on a three weekly schedule. However, this regimen is associated with toxicity, in particular, neuropathy and myelotoxicity, which can make it difficult for patients of poorer performance to tolerate. There are emerging data indicating that weekly administration is both better tolerated and may be more efficacious. Methods: We performed a retrospective case note review of all patients with MBC treated weekly paclitaxel (WP) at a single institution, the Christie Hospital, Manchester, from November 2001 to June 2004. Results: 43 patients with MBC received WP; 32 receiving WP alone and 11 patients also received concurrent trastuzumab (WP+T). WP was given as first line therapy for MBC in 58% patients. The median age of the patients receiving WP alone was 59.5yrs; 53% with WHO PS 2–4. Those also receiving WP+T were younger (median age 52yrs) with better PS (18% PS 2–4). Patients on WP alone received a median of 10 weeks treatment; those receiving WP+T received a median of 17 weeks paclitaxel. Only 5 patients (16%) receiving WP alone had grade 3 or 4 neutropenia, and 3 patients (9%) had an episode of febrile neutropenia. In the WP+T patients, there was no grade 3 or 4 neutropenia, however, 27% of patients experienced grade 3 neuropathy. Grade 3 lethargy occurred in 6 patients (14%). Overall, 9 of 43 patients achieved a partial response (PR 21%), 15 had stable disease (SD 35%). 8 of 11 (72%) of the patients receiving WP+T achieved SD or better. The median time to progression was 133 days and 191 days in the WP alone and WP+T groups respectively. The median overall survival is 289 days in the WP alone group, and has not yet been reached in the WP+T group. Survival was not significantly associated with performance status. Conclusions: In keeping with recently published literature, we have found weekly paclitaxel to be an effective and well tolerated regimen for patients with MBC including those with poor performance status. No significant financial relationships to disclose.