Citations

Abstract Background: The Preoperative Endocrine Prognostic Index (PEPI) scores the independent prognostic effects of tumor pathologic staging and expression levels of ER and the “proliferation” marker Ki67 in the surgical sample to predict long term outcomes after completion of neoadjuvant endocrine treatment (Ellis et al JNCI 100:1380, 2008). A limitation of the PEPI is that the prognostic information becomes available only after 4 months of treatment. We therefore evaluated the value of an early assessment of the Ki67 level in a tumor biopsy sample taken two to four weeks after initiating treatment in two neoadjuvant endocrine therapy trials for the purposes of the early identification of non- respondersMethods: A Ki67 cut point of greater than 10% for poor outcome in ER+ breast cancer was derived by comparing the PAM50 intrinsic subtype profile using a qRT-PCR assay with Ki67 data in a 700+ sample data set. A baseline level of 10% or less correlated most closely with a PAM50-based definition of LumA breast cancer and above 10% LumB breast cancer. We subsequently applied the 10% cut point to the baseline and early on-treatment Ki67 data in two trials, POL (Olson et al JACS 208:906, 2009) and IMPACT (Smith et al JCO: 23, 5108, 2005).Results: At baseline the dichotomized Ki67 definition was not significantly predictive for surgical Ki67 level, PEPI score or RFS in this modest size sample set. In contrast, in a result that emphasizes the enhaced prognostic properties of the on-treatment Ki67 approach, the one month POL sample Ki67 values (62 patients) predicted a higher level of Ki67 in the surgical samples at four months after treatment initiation (P=.01), a poorer PEPI score (P=0.01), a smaller number of patients in the PEPI risk point zero group (P=0.08) and worse relapse free survival (P=0.003). The IMPACT data (153 patients) confirmed that a two week Ki67 >10% predicted higher Ki67 in the surgical specimen (P=0.001), a poorer PEPI score (P=0.001), smaller numbers of patients in the PEPI 0 risk point group (P= 0.004) and worse relapse free survival (P=0.008).Ki67 and OutcomePOL 4W Ki67% PEPI 0RFS (events)10%>1/19 (5%)5/21 (23%)10%≤10/36 (28%)1/41 (2.4%)P ValueP=0.08 (Fisher)P=0.003 (log rank)IMPACT 2W Ki67% PEPI 0RFS (events)10%>0/32 (0%)9/35 (26%)10%≤21/101 (21%)13/118 (11%)P ValueP=0.004 (Fisher)P=0.008 (log rank) Conclusions: A tumor Ki67 assessment taken a short time (2 to 4 week window) after the initiation of neoadjuvant AI identifies patients with poor outcome ER+ disease. Amendment 6 of the neoadjuvant endocrine therapy protocol ACOSOG Z1031 will triage patients with an “on treatment” Ki67 value above 10% to chemotherapy in order to assess the pathological response rate to cytotoxic therapy in this important tumor subset.Supported by R01 CA095614, Avon PFP award 3P50 CA68438-07S2, U01 CA114722, ACOSOG U10 CA 76001, Breakthrough Cancer UK and AstraZenica (IMPACT trial). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 78.

Abstract Abstract #3103 Introduction: Lymphedema is well-known in the arm but can also occur in the breast. Diagnosis is currently non-standardized and based on clinical impression. We sought to determine if skin thickness could serve as a useful measure in the diagnosis of breast lymphedema (BLE).
 Methods: Patients undergoing unilateral non-mastectomy procedures were enrolled on this prospective clinical study preoperatively and evaluated for signs and symptoms of lymphedema in the operated breast in the postoperative period. Patients with established BLE were also studied. BLE diagnosis was independent of ultrasound findings and was based on a graded physical exam targeting clinical signs of edema and erythema. Skin thickness was measured with ultrasound at the 6 o'clock position of both breasts. Differences in skin thickness were assessed by the ratio of skin thickness in the operated and contralateral breasts, with comparison of means by two-sample t-test. Receiver operating characteristic curves were constructed to estimate the area under the curve (AUC) and to determine optimal cutpoints.
 Results: Ninety-seven women were studied; 85 were enrolled preoperatively and 12 postoperatively after a diagnosis of BLE. Median length of follow-up overall was 8 months. Of the 97 women, 46 had BLE at one or more follow-up visit with median time to first diagnosis of 3 months. Mean measured skin thickness was 2.3 ± 0.5mm in unaffected breasts and 3.2 ± 1.0 mm in operated breasts. Women with BLE had significantly greater skin thickness in the operated breast compared to the contralateral breast, with a mean skin thickness ratio of 1.83 ± 0.57 in patients with BLE compared to 1.18 ± 0.40 among those without BLE (p<0.0001). Skin thickness ratio provided excellent discrimination for BLE, with an area under the curve (AUC) of 0.86. At a ratio of 1.32 or greater (32% greater skin thickness in operated versus contralateral breast), sensitivity and specificity for diagnosing BLE were 81% and 82% respectively. A single measure of skin thickness in the operated breast also correlated well with diagnosis of BLE, with skin thickness of 3.2 mm or greater demonstrating sensitivity of 78% and specificity of 82%, AUC 0.82.
 Conclusions: Breast lymphedema results in skin edema and increased skin thickness that can be quantified with ultrasound. Measuring breast skin thickness- either as a single reading or as a ratio to the unaffected breast- may be useful in the diagnosis of breast lymphedema. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3103.

Abstract Abstract #2131 Introduction: TAS-108 is an oral steroidal anti-estrogen agent that selectively inhibits ERα and is mainly metabolized by CYP3A4. The purpose of this study is to investigate the efficacy and safety of TAS-108 administrated orally in three dose levels in patients with locally advanced, locally recurrent inoperable or metastatic breast carcinoma (BC) in four countries (USA, Russia, Mexico and Chile).
 Methods: Postmenopausal women with confirmed ER and/or PgR positive BC who had previously responded to one or two standard endocrine therapies, with or without one prior chemotherapy were randomly assigned to three doses of TAS-108, 40 mg, 80 and 120 mg daily. Using a modified Panageas' optimal two-stage trinomial design, the enrollment of 60 evaluable patients (first-stage: 19) was required to each individual dose group. Tumor response was assessed every 8 weeks according to RECIST criteria. Adverse events (AEs) were graded by CTC-AE v3.0.
 Results: A total of 146 patients with mean age of 63 years old were enrolled with 61 patients in the 40 mg group and 66 in the 80 mg group. The 120 mg group was terminated at the end of stage 1 with 19 patients enrolled due to lack of efficacy. The mean duration of study treatment was 172 days for the 40 mg group and 160 days for the 80 mg group. Partial response (PR) was documented in 6 (10%) patients in the 40 mg group and 4 (6.7%) patients in the 80 mg group. The rate of disease stabilization (CR+PR+SD) reported by the investigators was 43% (95%CI, 31%,56%) in the 40 mg group and 45% (95%CI, 32%,58%) in the 80 mg group. Adjudicated clinical benefit (CR+PR+SD more than 24 wks) was observed in 22% of patients in the 40 mg group and 20% of patients in the 80 mg group. Clinical benefit was achieved in 25% of patients with 1 prior hormonal therapy and 15% of patients with more than one line of prior hormonal therapy. Median time to progression (TTP): 15 weeks for the 40 mg group and 15.9 weeks for the 80 mg group. Median duration of clinical benefit was 32 weeks in the 40 mg group and 64 weeks in the 80 mg group. In the 40/80/120 mg groups, the commonly reported treatment-related AEs included nausea (15%/11%/16%), fatigue (10%/11%/16%), headache (10%/6%/16%), hot flushes (10%/5%/32%), diarrhea (2%/6%/5%), constipation (3%/3%/5%), and arthralgia (2%/5%/11%). No endometrial cancer and treatment-related deaths occurred during the study.
 Conclusions: TAS-108 has demonstrated anti-tumor activity in this population and was generally well tolerated. The 40 mg dose was chosen as the recommended dose for future clinical evaluation in patients with advanced breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2131.

Background: Historical outcomes in anaplastic thyroid carcinoma (ATC) are poor, with a median survival of only 5 months and <20% of patients surviving 1 year from diagnosis. We hypothesized that survival in newly diagnosed patients with stages IVA and IVB locoregionally confined ATC might be improved by utilizing an aggressive therapeutic approach, prioritizing both the eradication of disease in the neck and preemptive treatment of occult metastatic disease. Methods: Between January 1, 2003, and December 31, 2007, 25 new ATC patients were evaluated at our institution. Of these 25 patients, 10 (40%) had metastatic disease at diagnosis and therefore underwent palliative treatment, whereas 5 (20%) had regionally confined disease and desired treatment at their local medical facilities. The remaining 10 consecutive patients (40%) had regionally confined ATC and elected aggressive therapy combining individualized surgery (where feasible), intensity-modulated radiation therapy (IMRT), and radiosensitizing + adjuvant chemotherapy intending four cycles of docetaxel + doxorubicin. Outcomes were assessed on an intention to treat basis. Results: There were no deaths from therapy, but hospitalization was required in two patients (20%) because of treatment-related adverse events. Five patients (50%) are alive and cancer-free, all having been followed >32 months (range: 32–89 months; median: 44 months) with a median overall Kaplan–Meier survival of 60 months. Overall survival at 1 and 2 years was 70% and 60%, respectively, compared to <20% historical survival at 1 year in analogous patients previously treated with surgery and conventional postoperative radiation at our and other institutions. Conclusions: Although based upon a small series of consecutively treated patients, an aggressive approach combining IMRT and radiosensitizing plus adjuvant chemotherapy appears to improve outcomes, including survival in stages IVA and IVB regionally confined ATC, but remains of uncertain benefit in patients with stage IVC (metastatic) disease. Also uncertain is the optimal chemotherapy regimen to use in conjunction with IMRT. Further multicenter randomized trials are required to define optimal therapy in this rare but deadly cancer.

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m2) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.