David Sarid

D538G Mutation in Estrogen Receptor-α: A Novel Mechanism for Acquired Endocrine Resistance in Breast Cancer

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.

Cutaneous and subcutaneous metastases of rectal cancer

The occurrence of cutaneous metastatic disease from colorectal cancer is uncommon and typically signifies widespread disease with poor prognosis. Colorectal metastases usually occur within the first 3 years of follow up, and the median survival of patients after the appearance of cutaneous metastatic lesions is 18 to 20 months. We describe an unusual case of a 60-year-old woman with a metachronous skin lesion as the sole site of metastatic disease, and a relatively long interval between the appearance of skin metastases and death. The woman was found to have an adenocarcinoma of the rectum, a Dukes’ C lesion, extending over the entire rectal wall into the perirectal fat; five of eight regional lymph nodes showed metastases. Adjuvant radiotherapy followed by chemotherapy was administered for about 1 year. A subcutaneous lump on the left abdominal wall found 16 months postoperatively was metastatic of rectal origin. A metastatic adenocarcinoma of rectal origin was found in a single left lower axillary node 26 months later. Despite metastatic work-up for the next 2 years, an enlarged and palpated metastatic left inguinal lymph node appeared and was subjected to radiation. Computerized tomography (CT) examination 5 years after the first presentation of the rectal tumor and almost 4 years after the diagnosis of abdominal skin metastases disclosed recurrent pelvic disease with severe left hydronephrosis. Treatment by systemic chemotherapy was partially successful, but she died 8 months after this chemotherapy was initiated.

The protective effect of zoledronic acid on bone loss in postmenopausal women with early breast cancer treated with sequential tamoxifen and letrozole: a prospective, randomized, phase II trial.

Objective: This study reports the efficacy and safety of zoledronic acid (ZOL) in preventing bone loss in postmenopausal patients receiving an aromatase inhibitor (AI) following tamoxifen. Methods: Postmenopausal patients with stage I–III hormone receptor-positive breast cancer who received tamoxifen for 2.5–3 years were randomized to receive letrozole (2.5 mg/day) with (n = 47) or without (n = 43) ZOL (4 mg i.v. every 6 months) for 2 years. The primary endpoint was percent change from baseline in lumbar spine (LS) bone mineral density (BMD) up to 60 months. Results: Ninety patients (86 evaluable) with a median age of 59 years (42.9–83.6), 50/86 of whom had previously been treated with chemotherapy, were followed for a median time of 41.4 months. While the control group showed a significant decrease in LS T-score (p = 0.0005), the ZOL group presented an increase over time (p = 0.0143). Change over time in LS T-score was significantly different between groups, favoring ZOL (p < 0.0001 at 24 and 48 months). No fractures, renal dysfunction or osteonecrosis of the jaw were reported. The toxicity profile was similar to those previously reported for each drug. Conclusion: The addition of ZOL to letrozole was safe and efficacious in maintaining LS BMD in postmenopausal patients with hormone receptor-positive breast cancer and who were receiving letrozole following 2.5–3 years of tamoxifen.

ErbB1–ErbB4 nuclear and cytoplasmic overexpression, ethnicity and predicted outcome in prostate cancer

Few inconclusive studies are reported on ErbB1–ErbB4 overexpression in prostate cancer. The goal of this study is to evaluate ErbB1–ErbB4 nuclear and cytoplasmic expression in prostate cancer patients and to correlate it to the patients’ ethnicity and outcome. T-stage, Gleason score, pre-treatment prostate-specific antigen (PSA) levels and ethnicity were recorded in 50 patients. Ethnicity was defined as either Ashkenazic (immigrated from Europe or North America) or Sephardic origin (Middle East and North Africa). Kattan nomogram was used to predict 5-year progression-free probability (PFP). ErbB1–ErbB4 nuclear and cytoplasmic expression were evaluated by immuno-histochemistry staining. The Ashkenazic (n = 27) and Sephardic (n = 23) patients were comparable in age, T stage, PSA level and Gleason score. ErbB1 cytoplasmic overexpression was found in 66% and none had nuclear overexpression. ErbB2 overexpression was not found in all patients. ErbB3 overexpression was seen in 5%. ErbB4 cytoplasmic and nuclear overexpression was seen in 28% and in 30% to a total of 38%. The ErbB1 and ErbB4 in the Ashkenazic and Sephardic patients were 65, 67, 34 and 44% respectively. PFP of >80%, 60–80% and <60% were seen in 55, 34, and 11% respectively. Ethnicity and overexpression did not significantly contributed to the PFP. In conclusion, ErbB1 and ErbB4 overexpression was seen in 66% and in 38% of prostate cancer patients, while ErbB2 and ErbB3 were almost not overexpressed in prostate cancer patients. Neither overexpression nor ethnicity significantly contributed to the predicted outcome. Further studies on ErbB expression, ethnicity and outcome in prostate cancer patients are warranted.

Potential impact of prior high-dose IL-2 on the outcomes of sunitinib (Su) treatment (tx) in patients (pts) with metastatic renal cell carcinoma (mRCC).

494 Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhauser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib. Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naive pts (n=27). Progression free survival and overall survival were determined by Cox regression. Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gend...