Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

ER-Targeted PET for Initial Staging and Suspected Recurrence in ER-Positive Breast Cancer.

Importance: There are insufficient data comparing 16α-18F-fluoro-17ß-estradiol (FES) positron emission tomography (PET) computed tomography (CT) with standard-of-care imaging (SOC) for staging locally advanced breast cancer (LABC) or evaluating suspected recurrence. Objective: To determine the detection rate of FES PET/CT and SOC for distant metastases in patients with estrogen receptor (ER)-positive LABC and recurrences in patients with ER-positive BC and suspected recurrence. Design, Setting, and Participants: This diagnostic study was conducted as a single-center phase 2 trial, from January 2021 to September 2023. The study design provided 80% power to find a 20% detection rate difference. Participants included patients with ER-positive LABC (cohort 1) or suspected recurrence (cohort 2). Data were analyzed from September 2023 to February 2024. Exposure: Participants underwent both SOC imaging and experimental FES PET/CT. When there were suspicious lesions on imaging, 1 was biopsied for histopathological reference standard to confirm presence (true positive) or absence (false positive) of malignant neoplasm. Main Outcomes and Measures: The outcome of interest was the detection rate of FES PET CT vs SOC for distant metastases and recurrences. Results: A total of 124 patients were accrued, with 62 in cohort 1 (median [IQR] age, 52 [32-84] years) and 62 in cohort 2 (median [IQR] age, 66 [30-93] years). In cohort 1, of 14 true-positive findings, SOC imaging detected 12 and FES detected 11 (P > .99). In cohort 2, of 23 true-positive findings, SOC detected 16 and FES detected 18 (P = .77). In 30 patients with lobular histology, of 11 true-positive findings, SOC detected 5 and FES detected 9 (P = .29). There were 6 false-positive findings on SOC and 1 false-positive finding on FES PET/CT (P = .13). Conclusions and Relevance: In this diagnostic study with pathological findings as the reference standard, no difference was found between FES PET/CT and current SOC imaging for detecting distant metastases in patients with ER-positive LABC or recurrences in patients with ER-positive tumors and suspected recurrence. FES PET/CT could be considered for both clinical indications, which are not part of current Appropriate Use Criteria for FES PET. The findings regarding FES PET/CT in patients with lobular tumors, and for lower false positives than current SOC imaging, warrant further investigation.

A retrospective study of induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiotherapy with cetuximab in locally advanced head and neck cancer.

BACKGROUND: The objective was to study the results of induction chemotherapy followed by external beam radiation therapy with concurrent cetuximab in the treatment of locally advanced head and neck cancer. METHODS: Seventeen patients with stage III or IV squamous cell carcinomas of the head and neck who received docetaxel, cisplatinum, and 5-fluorouracil followed by radiation therapy with concurrent cetuximab were retrospectively analyzed. All radiation was delivered with image-guided intensity-modulated radiation treatments. Primary end points analyzed were local control and overall survival. RESULTS: With a median follow-up of 17 months, the approximate 2-year local control was 85%, with overall survival being 91%. At time of last follow-up, only 1 death was observed, with the cause of death unknown. Two local failures were observed, and the patients were under active management for their recurrences at time of last follow-up. No distant metastatic failures were noted among the patients. CONCLUSIONS: Induction chemotherapy with docetaxel, cisplatinum, and 5-fluorouracil followed by concurrent radiation with cetuximab provides for excellent locoregional control of disease. Future prospective studies can better establish the efficacy of this treatment regimen to current favored protocols.

Does continuous-infusion interleukin-2 increase survival in metastatic melanoma?

Pharmacy logbooks and clinical trial records were used to identify all 60 patients with metastatic melanoma who were treated as inpatients with intermediate-dose, continuous-infusion interleukin-2 (IL-2) in Hoag Hospital during 1987 to 1998. The hospital tumor registry was used to identify contemporary controls who had not received inpatient IL-2, matched for having distant metastatic melanoma, and by year and stage at original diagnosis, gender, and age. The mean time from original diagnosis to the documentation of distant metastatic disease was similar in both groups, 24 to 26 months. From the date of starting IL-2 therapy, patients had a median survival of 8.8 months, 38% 1-year survival, and 20% 5-year survival, with 8 patients alive beyond 5 years. However, there was no difference in survival from the first date of distant metastatic disease (median 25.8 months for IL-2 versus 31.5 months for controls, with survival rates 5 years after metastatic disease of 26% versus 31%). There was also no difference in overall survival from the date of original diagnosis (60.1 months for the IL-2 group versus 86.3 months for controls, with 5-year survival rates of 51% versus 64%, and 10-year survival rates of 29% versus 33%). This single-institution study failed to establish a survival advantage for patients with metastatic melanoma who received intermediate-dose, continuous-infusion IL-2 administered in the inpatient setting, compared to contemporary, matched-control patients who never received inpatient IL-2 therapy. However, the 5-year survival rates after a diagnosis of distant metastatic disease were a surprisingly high 26% to 31% in both groups. In the absence of a control group, the survival impact of IL-2 has probably been overestimated from single-arm phase II and III trials.

Autologous tumor cell line-derived vaccine for patient-specific treatment of advanced renal cell carcinoma.

AIM: We previously reported the laboratory methodology for producing patient-specific irradiated autologous tumor-cell products derived from short-term cultured tumor cells from resected renal cell carcinoma, and described preliminary clinical results. In this study, we report the final clinical results and efforts to define vaccine potency on the basis of clinical outcome for these 25 patients with advanced renal cell carcinoma. MATERIALS AND METHODS: Approximately 10(8) cells from successful short-term cell lines were irradiated, frozen in aliquots of 10(7) cells, then thawed and administered subcutaneously (s.c.) once a week for 3 weeks, then once a month for 5 months. Patients included 19 men and 6 women, who were 43-82 years of age. Six (6) patients had a large primary lesion, 2 patients had regionally advanced disease, 3 patients had been rendered disease-free by surgical resection of distant metastases, and 14 patients had measurable distant metastatic disease. RESULTS: The vaccines were well tolerated, and no delayed autoimmune effects were documented. Delayed-type hypersensitivity (DTH) tests of irradiated tumor cells were positive in only 1 of 25 patients at week 0, but converted to positive in 6 of 18 patients of DTH-negative patients who were retested at week 4. Objective response rate in patients who had measurable metastatic disease was 0 of 14 patients. With a median follow-up of greater than 7 years from the date of the first DTH test, median survival is 33.4 months, 5-year survival is 43%, and 10 patients are alive 3-12 years later. The 7 DTH+ patients survived a median of 2.5 years, and 3 patients are alive after 3, 4, and 7 years. There was no correlation between the number of irradiated cells or viable irradiated cells injected and tumor DTH reactivity or survival. CONCLUSION: This approach is feasible and the therapy is well tolerated, but clinical benefit was not established in this trial. Any further exploration of this product should be limited to the adjuvant setting in a randomized trial.

Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic melanoma?

For more than 20 years interleukin-2 (IL2) was the preferred treatment for medically fit metastatic melanoma patients, but recently two new agents, ipilimumab and vemurafenib, were approved for stage IV disease. Single-institution data were used to determine the long-term survival rate for IL2-treated melanoma patients, and whether use of inpatient IL2 had declined recently. Between May 1987 and April 2010, 150 patients were hospitalized for high-dose, intravenous (i.v.) IL2. The average number of IL2 patients increased from 5.4 per year during 1987-1991 to 5.8 during 1992-1997 after regulatory approval of IL2, to 8.3 during 1998-2006 after a marketing indication in metastatic melanoma was granted, but dropped to 3.0 during 2007-2010. At the time of treatment, median age was 52 years; 27% were 60 years of age or older. At the time of analysis 122 patients were deceased. Median survival from the start date of IL2 treatment was 15.6 months, with a 20% 5-year survival. Among patients enrolled in clinical trials, there were as many nonresponders who survived 5 years as responders, which is consistent with a delayed immunotherapy benefit. In the absence of long-term survival data for these newer agents, IL2 probably should still be the preferred initial treatment for most patients with metastatic melanoma who are medically fit.

Should high-dose interleukin-2 still be the preferred treatment for patients with metastatic renal cell cancer?

Interleukin-2 (IL-2) was the preferred treatment for medically fit patients with advanced kidney cancer, but recently, several targeted therapies have been approved for metastatic renal cell carcinoma. We wished to determine the long-term survival rate for patients with kidney cancer treated with IL-2 and whether the use of intense inpatient IL-2 has declined since the introduction of targeted therapies. Patients who received IL-2 were identified from clinical trial enrollment, pharmacy logs, and financial billing records. Survival was determined from the earliest date of IL-2 therapy. There were 79 patients hospitalized for high-dose infusional IL-2 between March 1989 and March 2009. Median age was 58 years, and 27% were older than 65 years at the time of treatment. At the time of this analysis, 72 patients had deceased. Median survival was 9.9 months, but 5-year survival was 19.4%. The average number of patients with IL-2 increased from 2.2 per year during 1989-1992 to 5.6 during 1993-2001 after FDA approval, but dropped to 2.0 during 2002-2009. High-dose IL-2 is associated with a 5-year survival rate that is higher than objective response rates, suggesting a delayed immunotherapy benefit for some patients. The use of intensive IL-2 has declined dramatically in recent years, but unless a long-term survival benefit can be shown for these new targeted products, we feel that inpatient IL-2 remains the preferred initial treatment.

High-dose chemotherapy and autologous stem cell rescue for metastatic breast cancer: superior survival for tandem compared with single transplants.

During 1990-1999, we treated 60 patients with breast cancer who had distant metastases with high-dose chemotherapy and autologous stem cell rescue (HDC) after they had responded to induction chemotherapy. HDC regimens were MiTepa (60 mg/m2 mitoxantrone by continuous intravenous infusion over 3 days plus 300 mg/m2 thiotepa intravenously over 2 hours daily x 3 days) and ICE (12 g/m2 ifosfamide, 1800 mg/m2 carboplatin, 2 g/m2 etoposide; all 3 by continuous intravenous over 4 days). At a median follow up >8 years, the median failure-free survival (FFS) was 13.9 months, median overall survival (OS) 29.1 months, 5-year FFS 12%s and 5-year OS 25%. Thirty-three patients underwent tandem (T) transplants; 27 underwent a single (S) HDC. Median ages for these 2 groups were 45 and 48 years; bone and liver metastases were more prevalent in the T cohort, whereas lung metastases were more prevalent in the S cohort. At a median follow up of 6.5 years for the S group and >9 years for the T group, there were 52 deaths. FFS was better for T: median 15.7 versus 7.7 months (p2 = 0.010) as was OS: median 32.7 versus 17.7 months, 2-year survival 68% versus 41%, and 5-year survival 32% versus 15% (p2 = 0.010). As a group, patients with distant metastatic breast cancer who underwent tandem transplants had a better posttransplant survival than patients who underwent a single HDC.