Real-world analysis of clinical and economic impact of 21-gene recurrence score (RS) testing in early-stage breast cancer (ESBC) in Ireland.

PURPOSE: Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. METHODS: From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. RESULTS: 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0-15, 63 (24.5%) 16-20, 39 (15.3%) 21-25 and 40 (15.2%) RS 26-100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16-20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of €4 million in treatment costs. Deducting assay costs, savings of €1.9 million were achieved. CONCLUSION: Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over €1,900,000.

Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial.

Background: CD73 is an ecto-enzyme that promotes tumor immune escape through the production of immunosuppressive extracellular adenosine in the tumor microenvironment. Several CD73 inhibitors and adenosine receptor antagonists are being evaluated in phase I clinical trials. Patients and methods: Full-face sections from formalin-fixed paraffin-embedded primary breast tumors from 122 samples of triple-negative breast cancer (TNBC) from the BIG 02-98 adjuvant phase III clinical trial were included in our analysis. Using multiplex immunofluorescence and image analysis, we assessed CD73 protein expression on tumor cells, tumor-infiltrating leukocytes and stromal cells. We investigated the associations between CD73 protein expression with disease-free survival (DFS), overall survival (OS) and the extent of tumor immune infiltration. Results: Our results demonstrated that high levels of CD73 expression on epithelial tumor cells were significantly associated with reduced DFS, OS and negatively correlated with tumor immune infiltration (Spearman's R= -0.50, P < 0.0001). Patients with high levels of CD73 and low levels of tumor-infiltrating leukocytes had the worse clinical outcome. Conclusions: Taken together, our study provides further support that CD73 expression is associated with a poor prognosis and reduced anti-tumor immunity in human TNBC and that targeting CD73 could be a promising strategy to reprogram the tumor microenvironment in this BC subtype.

Impact of palbociclib plus letrozole on pain severity and pain interference with daily activities in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer as first-line treatment.

Background Palbociclib is a recently approved drug for use in combination with letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with advanced estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer. This report assesses the impact of palbociclib in combination with letrozole versus letrozole alone on patient-reported outcomes of pain. Methods Palbociclib was evaluated in an open-label, randomized, phase II study (PALOMA-1/TRIO-18) among postmenopausal women with advanced ER+/HER2- breast cancer who had not received prior systemic treatment for their advanced disease. Patients received continuous oral letrozole 2.5 mg daily alone or the same letrozole dose and schedule plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over repeated 28-day cycles. The primary study endpoint was investigator-assessed progression-free survival in the intent-to-treat population, and these results have recently been published (Finn et al., Lancet Oncol 2015;16:25-35). One of the key secondary endpoints was the evaluation of pain, as measured using the Brief Pain Inventory (BPI) patient-reported outcome tool. The BPI was administered at baseline and on day 1 of every cycle thereafter until disease progression and/or treatment discontinuation. Clinical trial registration This study is registered with ClinicalTrials.gov (NCT00721409). Results There were no statistically significant differences in Pain Severity or Pain Interference scores of the BPI between the two treatment groups for the overall population or among those with any bone disease at baseline. A limitation of the study is that results were not adjusted for the concomitant use of opioids or other medications used to control pain. Conclusions The addition of palbociclib to letrozole was associated with increased efficacy without negatively impacting pain severity or pain interference with daily activities.

The cocaine- and amphetamine-regulated transcript mediates ligand-independent activation of ERα, and is an independent prognostic factor in node-negative breast cancer.

Personalized medicine requires the identification of unambiguous prognostic and predictive biomarkers to inform therapeutic decisions. Within this context, the management of lymph node-negative breast cancer is the subject of much debate with particular emphasis on the requirement for adjuvant chemotherapy. The identification of prognostic and predictive biomarkers in this group of patients is crucial. Here, we demonstrate by tissue microarray and automated image analysis that the cocaine- and amphetamine-regulated transcript (CART) is expressed in primary and metastatic breast cancer and is an independent poor prognostic factor in estrogen receptor (ER)-positive, lymph node-negative tumors in two separate breast cancer cohorts (n=690; P=0.002, 0.013). We also show that CART increases the transcriptional activity of ERα in a ligand-independent manner via the mitogen-activated protein kinase pathway and that CART stimulates an autocrine/paracrine loop within tumor cells to amplify the CART signal. Additionally, we demonstrate that CART expression in ER-positive breast cancer cell lines protects against tamoxifen-mediated cell death and that high CART expression predicts disease outcome in tamoxifen-treated patients in vivo in three independent breast cancer cohorts. We believe that CART profiling will help facilitate stratification of lymph node-negative breast cancer patients into high- and low-risk categories and allow for the personalization of therapy.

Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup Phase III BIG 02-98 Trial.

BACKGROUND: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. PATIENTS AND METHODS: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. RESULTS: CNS relapse occurred in 4.0% of control patients and 3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. CONCLUSION: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse.

Odynorgasmia.

Painful ejaculation ("odynorgasmia") is not well recognized. When it occurs it may indicate the precise site of pathology.

The platinum agents: a role in breast cancer treatment?

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Most chemotherapy groups have activity in this disease, and the most active single drugs are the taxanes, especially docetaxel (Taxotere; Aventis Pharmaceuticals, Inc, Parsippany, NJ), and the anthracyclines. The alkylating agents, antimetabolites, and vinca alkaloids are also widely used. The platinum coordination complexes, which are widely used in oncology, are also active in metastatic breast cancer, but the availability of other drugs that are less toxic and easier to administer has resulted in their having a strictly limited use in this setting. Cisplatin appears to be somewhat more active than carboplatin, but direct comparative studies are lacking. The identification of the prominent activity of the taxanes has led to the investigation of wholly novel non-anthracycline-containing combination regimens, and platinum/taxane doublets appear to be particularly active. More recently, reports that trastuzumab (Herceptin, Genentech, South San Francisco, CA), a novel monoclonal antibody directed against the protein product of the HER2/(neu) oncogene, has a powerful synergistic interaction with docetaxel and with platinum agents have prompted evaluation of the triplet docetaxel/platinum/trastuzumab in the therapy of metastatic breast cancer.

Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: feasibility and efficacy.

PURPOSE: Dose-dense chemotherapy is predicted to be a superior treatment plan. Therefore, we studied dose-dense doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) as adjuvant therapy. METHODS: Patients with resected breast cancer involving four or more ipsilateral axillary lymph nodes were treated with nine cycles of chemotherapy, using 14-day intertreatment intervals. Doses were as follows: doxorubicin 90 mg/m2 x 3, then paclitaxel 250 mg/m2/24 hours x 3, and then cyclophosphamide 3.0 g/m2 x 3; all doses were given with subcutaneous injections of 5 microg/kg granulocyte colony-stimulating factor on days 3 through 10. Amenorrheic patients with hormone receptor-positive tumors received tamoxifen 20 mg/day for 5 years. Patients treated with breast conservation, those with 10 or more positive nodes, and those with tumors larger than 5 cm received radiotherapy. RESULTS: Between March 1993 and June 1994, we enrolled 42 patients. The median age was 46 years (range, 29 to 63 years), the median number of positive lymph nodes was eight (range, four to 25), and the median tumor size was 3.0 cm (range, 0 to 11.0 cm). The median intertreatment interval was 14 days (range, 13 to 36 days), and the median delivered dose-intensity exceeded 92% of the planned dose-intensity for all three drugs. Hospital admission was required for 29 patients (69%), and 28 patients (67%) required blood product transfusion. No treatment-related deaths or cardiac toxicities occurred. Doxorubicin was dose-reduced in four patients (10%) and paclitaxel was reduced in eight (20%). At a median follow-up from surgery of 48 months (range, 3 to 57 months), nine patients (19%) had relapsed, the actuarial disease-free survival rate was 78% (95% confidence interval, 66% to 92%), and four patients (10%) had died of metastatic disease. CONCLUSION: Dose-dense sequential adjuvant chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide (A-->T-->C) is feasible and promising. Several ongoing phase III trials are evaluating this approach.

Expanding options in breast cancer.

In metastatic breast cancer, docetaxel is the only drug to have shown superior activity to doxorubicin [objective response rates (ORRs) 48 versus 33%] by direct comparison in a randomized trial. Importantly, this greater activity was accompanied by a lower risk of cardiotoxicity. Docetaxel has also proved superior to various combination regimens in patients who had previously failed anthracyclines. In the comparison versus mitomycin C plus vinblastine, survival was significantly prolonged in the docetaxel arm. The combination of paclitaxel with doxorubicin has achieved remarkably high rates of response. However, the combination is cardiotoxic (with the highest response rates reporting an incidence of clinical congestive heart failure in the region of 18%). In comparison, the combination of docetaxel with doxorubicin, while also highly active (ORR > 70%), is relatively non-cardiotoxic (with only one case of clinical congestive heart failure in 96 patients treated). Given that docetaxel appears to be the most active single agent in metastatic breast cancer, there is a compelling case for the drug to be evaluated in the adjuvant setting and such studies are ongoing.

The development of docetaxel (Taxotere) in non-small cell lung cancer--docetaxel in new combinations and new schedules: an overview of ongoing and future developments.

Non-small cell lung cancer is the most common cause of cancer death in the western world. Non-small cell lung cancer is modestly sensitive to chemotherapy with a small survival benefit in locally advanced and metastatic disease. Newer agents such as docetaxel are yielding encouraging response rates both as single agents and in combination. A phase I/II study is in progress in our institution to determine the maximum tolerated dose and noncomparative efficacy of the combination of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France), ifosfamide, and cisplatin, with mesna and lenograstim support, in the treatment of patients with advanced non-small cell lung cancer. To date, nine patients have received 37 cycles of treatment at increasing dose levels (no intrapatient dose escalation). Treatment was administered to patients on an inpatient basis every 3 weeks, with lenograstim on days 3 to 10. Dose-limiting toxicity has not occurred at levels I to III (dose level III: docetaxel 75 mg/m2, cisplatin 75 mg/m2, and ifosfamide 3 g/m2). These preliminary results suggest that the combination of docetaxel, ifosfamide, and cisplatin, with lenograstim support, is well tolerated in the doses evaluated. Preliminary efficacy results show a response rate of 67% (six of nine patients). The study continues to determine the maximum tolerated dose of this regimen in preparation for a phase II evaluation.

Resolution of paraneoplastic bile duct paucity following successful treatment of Hodgkin's disease.

We report the case of a 21-year-old woman who developed severe adult onset ductopenia in association with Hodgkin's lymphoma. Chemotherapy resulted in a remission of her Hodgkin's disease (HD) and significant improvement in liver function with resolution of the hepatic and biliary duct histological abnormalities, a therapeutic success not previously described in the literature.

Dose escalation of paclitaxel with high-dose carboplatin using peripheral blood progenitor cell support in patients with advanced ovarian cancer.

A phase I study of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given in combination with high-dose carboplatin was conducted to identify the antitumor efficacy and maximum tolerated dose of paclitaxel in patients who had received sequential cycles of paclitaxel/cyclophosphamide as prior treatment for ovarian carcinoma. Eighteen patients with advanced ovarian cancer were treated in this study. Induction therapy consisted of two cycles of cyclophosphamide 3.0 g/m2 plus high-dose paclitaxel 300 mg/m2 plus filgrastim and leukapheresis to harvest peripheral blood progenitor cells, followed by four courses of rapidly cycled high-dose carboplatin with planned dose escalation of paclitaxel (150, 200, 250, and 300 mg/m2) rescued with peripheral blood progenitor cells. The study was amended after accrual of 11 patients, and the remaining seven patients received a single cycle of induction therapy with paclitaxel/cyclophosphamide, followed by four courses of rapidly cycled high-dose carboplatin with planned dose escalation of paclitaxel through levels 200 and 250 mg/m2. All 18 patients have completed therapy. Of the 15 who are evaluable for response, the pathologic complete response was 33% (five of 15 patients). The administration of escalating doses of paclitaxel in combination with high-dose carboplatin following sequential cycles of paclitaxel/cyclophosphamide induction resulted in significant nonhematopoietic toxicity. Induction with a single cycle of paclitaxel/cyclophosphamide resulted in excellent progenitor cell mobilization, and significantly ameliorated the toxicity of this approach. The response rates thus far obtained are promising and warrant further evaluation.

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

PURPOSE: Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS: Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS: Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION: Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

PURPOSE: Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS: Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION: Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

High-dose chemotherapy with peripheral blood progenitor autografting.

Mobilized PBPs are an acceptable alternative to ABMT for hematopoietic rescue following high-dose therapy (table 10-3). Platelet recovery appears to be faster following PBPs than ABMT. In most series, leukocyte recovery is also accelerated, but this may be particularly due to the use of colony-stimulating factor. Morbidity and mortality also appear to be reduced. The optimal mobilization methodology is not defined, but larger numbers of PBPs are mobilized by chemotherapy plus colony-stimulating factors compared to CSFs alone, at the cost of enhanced toxicity. The use of PBPs has also facilitated the study of very-high-intensity regimens in which multiple courses of high-dose chemotherapy are given at very short intervals. Following completion of feasibility studies, prospective random assignment trials will be necessary to determine the benefit, if any, of this approach.

Factors affecting the mobilization of primitive and committed hematopoietic progenitors into the peripheral blood of cancer patients.

Rapid hematopoietic reconstitution following peripheral blood progenitor cell (PBPC) autotransplantation is thought to result from reinfusion of committed progenitor cells. This has raised concern that PBPC autografts might be rich in committed hematopoietic progentors responsible for early engraftment, but deficient in more primitive progenitors required for long-term hematopoietic reconstitution. The granulomonocytic colony-forming unit (CFU-GM) assay measures committed progenitors responsive to a single species of colony-stimulating activity such as granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas the pre-CFU assay identifies more primitive progenitors by measuring interleukin-3 (IL-3) and kit ligand (KL) induced generation of secondary CFU-GM from CD34+, 4-hydroperoxycyclophosphamide resistant progenitors that require multiple cytokine stimuli. Paired bone marrow (BM) and PBPC samples from 17 breast and ovarian cancer patients participating in four separate clinical trials were compared in these assay systems. In seven of nine patients, PBPC autografts mobilized with cyclophosphamide rebound and G-CSF compared favorably with paired BM autografts in both committed and primitive progenitor capacity. Failure to mobilize substantial primitive progenitor cell numbers occurred in two of nine patients undergoing this mobilization regimen and could not have been predicted by either circulating CFU-GM or CD34+ cell number. Prior myelosuppressive treatment experiences reduced peripheral progenitor yields somewhat, but still allowed for the collection of PBPC autografts which compared favorably with BM autografts in total CFU-GM and Pre-CFU. Mobilization of PBPC with G-CSF or GM-CSF alone in patients who had received prior myelosuppressive therapies produced autografts which were relatively deficient in committed progenitors, but absolutely deficient in primitive progenitors. We conclude that optimization of patient characteristics and mobilization parameters can achieve PBPC autografts rich in both the primitive and committed hematopoietic progenitor cells.

Taxol (paclitaxel) plus recombinant human granulocyte colony-stimulating factor in the treatment of metastatic breast cancer.

We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol (paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.

Excretion of Ascaris lumbricoides during total body irradiation.

We describe the excretion of Ascaris lumbicoides, an intestinal roundworm, in the emesis of an asymptomatic patient undergoing total body irradiation. This suggests that Ascaris is sensitive to irradiation.