Zoneddy Dayao

Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: Results from the American college of surgeons oncology group Z1031 trial (alliance)

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Abstract PD07-01: Z1031B Neoadjuvant Aromatase Inhibitor Trial: A Phase 2 study of Triage to Chemotherapy Based on 2 to 4 week Ki67 level > 10%.

Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was > 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if Results: 51 patients (21%) had 2 to 4 week Ki67>10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 Conclusion. A Ki67 value >10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.

The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer

Breast cancer is the second most common cancer among American women and has a high rate of metastasis to bone. Patients regularly undergo adjuvant therapy (chemotherapy or hormonal therapy) following surgical resection of the tumor. In addition to potential direct effects on bone cells, both chemotherapy and hormonal therapy induce ovarian dysfunction and dramatically decrease estrogen levels in both pre- and postmenopausal women. This leads to decreased bone mineral density and increased fracture risk. Antiresorptive therapies (e.g, zoledronic acid and denosumab) have demonstrated efficacy in preventing cancer therapy-induced bone loss in patients with breast cancer and are approved for the prevention of skeletal-related events in patients with bone metastases from breast cancer. This review will focus on the evolving role of these antiresorptive therapies in the care of women with early or metastatic breast cancer.

The Conundrum of Adjuvant HER2 Treatment Options

Improving outcomes in HER2 over-expressing breast cancer has been an impressive success story over the years. Remarkable clinical benefit and large hazard ratios in earlier metastatic and adjuvant trials rendered hope to more contemporary adjuvant trials of a similar large-scale benefit. Recent FDA approvals of dual HER2-blockade with trastuzumab plus pertuzumab and neratinib based on the APHINITY and ExteNET trials, respectively, were modest and rather underwhelming. Future trials need to focus on identifying robust biomarkers and clinical parameters that can best define the subset of patients where the anticipated toxicities and cost of therapy are justified.

Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature

BackgroundHemophagocytic lymphohistiocytosis is becoming an increasingly recognized disorder in adults. Classical Hodgkin lymphoma is a relatively uncommon etiology of hemophagocytic lymphohistiocytosis and may complicate treatment options. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin are discussed here as a treatment regimen. Case presentationA 66-year-old Hispanic man previously in good health presented with a 1-month history of recurrent fevers, chills, and night sweats and a 3-week history of new onset jaundice. A bone marrow biopsy revealed a normocellular bone marrow with increased histiocytes with areas of hemophagocytic activity. He met five out of eight criteria for hemophagocytic lymphohistiocytosis diagnosis including fevers, pancytopenia, hemophagocytosis, ferritin of 23,292 ng/mL (>500 ng/mL), and soluble-CD25 of 15,330 pg/mL (>1033 pg/mL). A right cervical lymph node biopsy revealed CD15, CD30, MUM-1, and Epstein–Barr virus-encoded small ribonucleic acid-positive cells with morphologic findings of classical Hodgkin lymphoma, lymphocyte-rich subtype. He completed 2 weeks of hemophagocytic lymphohistiocytosis-directed therapy with etoposide and dexamethasone, but then was switched to rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin due to minimal improvement in his pancytopenia and hepatic impairment. He completed one full cycle of rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin with notable improvement in serial hepatic function panels and had an undetectable Epstein–Barr virus viral load. However, he eventually died due to complications of Enterococcus faecalis bacteremia and colonic microperforation in the setting of persistent pancytopenia.ConclusionsThis case discusses the challenges facing treatment of adult malignancy-associated hemophagocytic lymphohistiocytosis. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin may be a viable option for patients with secondary hemophagocytic lymphohistiocytosis and Hodgkin lymphoma who cannot tolerate standard therapies due to hepatic impairment. Targeted therapy and immunotherapy are promising new areas of developing treatments.

Abstract 1710: Quantitative 3D mapping of total choline in human breast cancer using high-speed MR spectroscopic imaging at 3T

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL INTRODUCTION We report initial experience with 3D mapping of tCho to monitor treatment response in patients undergoing neoadjuvant chemotherapy to predict outcome [1]. METHOD Eleven patients aged: 28 - 77 years with biopsy-confirmed, infiltrating ductal carcinoma (IDC) were studied before and during neoadjuvant therapy. Data were collected on a 3T MR scanner equipped with 8- and 16-channel breast array using PRESS volume prelocalized 3D high-speed Proton-Echo-Planar-Spectroscopic-Imaging (PEPSI) [2] with MEGA lipid suppression (TR/TE=2000ms/135ms, matrix size up to 32×16×8, voxel size=1cc, scan time: 10 minutes including a water reference scan). Spectral quantification was performed using LCModel-based spectral fitting in reference to tissue water [3] using a customized basis set with empirically modeled Lorentzian singlet peaks to account for broad and irregular line shapes of residual lipid signals, relaxation correction and automated spectral quality thresholds. RESULTS Strongly elevated tCho with mean concentrations up to 5.1 mmol/kg was measured in 7 patients with single and multi-centric enhancing lesions (Table 1). Decreases in tCho concentration and number of voxels with detectable tCho were measured in 4 patients who underwent neoadjuvant therapy. DISCUSSION AND CONCLUSION This study demonstrates feasibility of quantitative 3D mapping of tCho in invasive breast carcinoma and assessment of regional tCho changes during neoadjuvent therapy. The long-term goal is to utilize 3D high-speed MRSI as an early predictor of treatment failure in women undergoing neoadjuvant therapy. REFERENCES [1] Danishad, A., et al. NMR Biomed. 2010; 23: 233-241. [2] Posse, S., et al., Magn Reson Med, 1997. 37(6): p. 858-65. [3] Provencher et al MRM 1993. GRANT SUPPORT: NIH, DoD, UNM Cancer Center. ![Figure][1] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1710. doi:1538-7445.AM2012-1710 [1]: pending:yes

Prevalence of BRCA1/2 Mutations and Variants in a Southwest Hispanic Population.

Background: There have been a limited number of studies of BRCA mutations in U.S. Hispanics. Of those previously published, two common mutations have been identified, and estimates of their prevalence vary, depending on the population studied. North American Hispanics are a heterogeneous population, consisting of Mexican, Caribbean, Central and South American descent. Furthermore, each of these groups has a significant admixture of other racial and ethnic groups. A limitation of most published studies is that they do not differentiate between these ethnically and genetically diverse Hispanics. In New Mexico, there is a large but relatively homogeneous Hispanic population. Since the University of New Mexico Cancer Center (UNMCC), sees a socially and economically diverse group of patients, the demographics of its Hispanic patients are similar to those of the whole state. Herein, we describe the prevalence of specific mutations and variants in Hispanics from a clinic-based population. Materials and Methods: A chart review of all patients evaluated for hereditary breast cancer risk from 1/1/2005 through 5/30/2009 was conducted. Data collected included patient age, self-reported ethnicity (including, if known, area of ancestral origin), cancer status, family history, BRCA testing status, including method (comprehensive analysis, Ashkenazi panel, single site, and/or comprehensive rearrangement testing), and what, if any, BRCA mutations or variants were found. Results: BRCA testing was performed on 312 patients, 70 of whom identified as NM Hispanic. Another 24 patients were of other Hispanic origins, mainly Mexican. Approximately 30% of those identified as NM Hispanic tested positive for mutations, and most mutations were found in BRCA1. All variants of uncertain significance in this group were found in BRCA2. Approximately 20% of other Hispanics tested positive for mutations, but variants of uncertain significance comprised a higher percentage of the results. In New Mexican Hispanics, 47% tested positive for BRCA1 187delAG, and another 19% tested positive for BRCA1 deletion of exons 9-12, both of which are previously described in the Hispanic populations from southern California and Colorado. Discussion: Although we found a large proportion of previously described mutations in our Hispanic population, 34% had other mutations. In this group, no mutation was seen more than once, indicating the need to offer these patients comprehensive BRCA testing or a combination of founder mutations testing followed by comprehensive sequencing. As most of our patients, even those identified as “Other Hispanic” have Colonial Spanish origins (via Mexico), this data is likely not applicable to Hispanics with other admixtures or historic arrival in the New World, such as Hispanics from the Caribbean. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4077.