Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report.

Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor-positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.

A phase II study of docetaxel and vinorelbine plus filgrastim for HER-2 negative, stage IV breast cancer: SWOG S0102.

Docetaxel and vinorelbine have demonstrated Single-agent activity in breast cancer. Preclinical studies suggest potential synergy between these antitubulin chemotherapy agents. This study evaluates these drugs in combination in metastatic breast cancer. Taxane-naive patients with HER-2 negative, stage IV breast cancer without prior chemotherapy for metastatic disease, were eligible. Docetaxel (60 mg/m(2)) was given intravenously on Day 1, vinorelbine (27.5 mg/m(2)) intravenously on Days 8 and 15, and filgrastim on Days 2-21 of a 21-day cycle. The primary study outcome was one-year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate (RR), and toxicity. Of 95 patients registered, 92 were eligible and received treatment. One-year OS was 74 % (95 % CI 64-82 %) with a median OS of 22.3 months (95 % CI 18.8-31.4 months). One-year PFS was 34 % (95 % CI 24-43 %) with median of 7.2 months (95 % CI 6.4-10.3). OS at 2 and 3 years were 49 % (95 % CI 38-59 %) and 30 % (95 % CI 21-40 %), respectively. OS was poorer for women with estrogen-receptor negative disease (n = 32) compared to estrogen-receptor positive (n = 60) (log-rank p = 0.031), but PFS was not significantly different (p = 0.11). RR was 59 % among the 74 patients with measurable disease. Grade 3 and 4 adverse events were 48 and 16 %, respectively. Grade 4 neutropenia was 12 % and grade 3/4 febrile neutropenia was 3 %. Common grade 3/4 nonhematologic toxicities were fatigue (14 %), pneumonitis (10 %), and dyspnea (9 %). The combination of docetaxel and vinorelbine is an active first-line chemotherapy in HER-2 nonoverexpressing, metastatic breast cancer. This combination is associated with significant hematologic and nonhematologic toxicity. The safety profile and expense of the filgrastim limit recommendations for routine use.

Phase II Feasibility Study of a Weight Loss Intervention in Female Breast and Colorectal Cancer Survivors (SWOG S1008).

OBJECTIVE: This study aimed to test the feasibility of a 12-month weight loss intervention using telephone-based counseling plus community-situated physical activity (PA) in female breast cancer (BC) and colorectal cancer (CRC) survivors. METHODS: This multisite cooperative group study enrolled sedentary, female, postmenopausal BC and CRC survivors with BMI ≥ 25 kg/m2 to receive 12-month fitness center memberships and telephone counseling encouraging 150 min/wk of PA and a 500-kcal/ddecrease in energy intake. Feasibility criteria included accrual, adherence, and retention. Target weight loss was ≥ 5%. RESULTS: Among 25 BC survivors, median baseline BMI was 37.2 (range: 27.7-54.6), accrual occurred in 10 months, 60% and 28% met diet and exercise goals, 80% provided 12-month measures, and average weight loss was 7.6% (95% CI: -3.9%, 19.2%). Among 23 CRC survivors, median BMI was 31.8 (range: 26.4-48.7), accrual occurred in 24 months, 61% and 17% met diet and exercise goals, 87% provided measures, and average weight loss was 2.5% (95% CI: -8.2%, 13.3%). CONCLUSIONS: It is feasible to recruit and retain BC survivors in a cooperative group diet and PA weight loss trial. BC survivors achieved clinically meaningful weight loss but did not meet a priori adherence goals. In CRC survivors, recruitment was more difficult, and the intervention was less effective.

Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines.

PURPOSE: The HER-2/neu protein is a nonmutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. Many tumor antigens, such as MAGE and gp100, are self-proteins; therefore, effective vaccine strategies must circumvent tolerance. We hypothesized that immunizing patients with subdominant peptide epitopes derived from HER-2/neu, using an adjuvant known to recruit professional antigen-presenting cells, granulocyte-macrophage colony-stimulating factor, would result in the generation of T-cell immunity specific for the HER-2/neu protein. PATIENTS AND METHODS: Sixty-four patients with HER-2/neu-overexpressing breast, ovarian, or non-small-cell lung cancers were enrolled. Vaccines were composed of peptides derived from potential T-helper epitopes of the HER-2/neu protein admixed with granulocyte-macrophage colony-stimulating factor and administered intradermally. Peripheral-blood mononuclear cells were evaluated at baseline, before vaccination, and after vaccination for antigen-specific T-cell immunity. Immunologic response data are presented on the 38 subjects who completed six vaccinations. Toxicity data are presented on all 64 patients enrolled. RESULTS: Ninety-two percent of patients developed T-cell immunity to HER-2/neu peptides (stimulation index, 2.1 to 59) and 68% to a HER-2/neu protein domain (stimulation index range, 2 to 31). Epitope spreading was observed in 84% of patients and significantly correlated with the generation of a HER-2/neu protein-specific T-cell immunity (P =.03). At 1-year follow-up, immunity to the HER-2/neu protein persisted in 38% of patients. CONCLUSION: The majority of patients with HER-2/neu-overexpressing cancers can develop immunity to both HER-2/neu peptides and protein. In addition, the generation of protein-specific immunity, after peptide immunization, was associated with epitope spreading, reflecting the initiation of an endogenous immune response. Finally, immunity can persist after active immunizations have ended.

SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer.

PURPOSE: To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. PATIENTS AND METHODS: A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. RESULTS: Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 (HER2) -negative tumors (P = .067), with no differences seen with hormone receptor-positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). CONCLUSION: Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors.

[Tc-99m]-sestamibi uptake and washout in locally advanced breast cancer are correlated with tumor blood flow.

OBJECTIVES: To determine the influence of breast tumor blood flow on MIBI kinetics, we compared MIBI uptake and washout to [O-15]-water PET estimates of blood flow in patients with locally advanced breast cancer. METHODS: Prior to therapy, 37 patients underwent MIBI and [O-15]-water PET imaging; 22/37 also had MIBI washout analysis. Twenty-five patients underwent serial imaging over the course of chemotherapy. RESULTS: MIBI uptake and blood flow had a significant positive correlation pre-therapy. The change in MIBI uptake over the course of therapy also correlated with the change in blood flow. The half-time of MIBI washout inversely correlated with blood flow, indicating faster MIBI washout with higher blood flow. CONCLUSIONS: Blood flow strongly influences early MIBI uptake and can be a factor affecting the rate of MIBI washout in breast tumors. We present a model of MIBI kinetics in tumors which forms a hypothesis for further mechanistic studies of MIBI uptake and washout in breast cancer.

Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy.

RATIONALE AND OBJECTIVES: The authors performed this study to determine the feasibility of using quantitative 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to monitor the response of breast cancer bone metastases to therapy. MATERIALS AND METHODS: Twenty-four women with stage IV bone-dominant breast carcinoma were included in this study. Whole-body FDG PET imaging was performed at serial time points during the course of therapy. FDG PET scans were interpreted quantitatively by using the maximum standard uptake value (SUV) of the most conspicuous bone lesion at baseline FDG PET. PET results were compared to the overall assessment of response (response, stable disease, progressive disease) with a combination of conventional imaging, change in tumor marker values, and subjective symptom changes by experienced medical oncologists blinded to the findings at FDG PET. Changes in FDG SUV were also correlated quantitatively to the changes in a particular tumor marker (CA 27.29). RESULTS: The changes in FDG SUV with therapy showed correlation with the overall clinical assessment of response (P < .01). The percentage change in FDG uptake with therapy showed strong correlation with the percentage change in tumor marker value (P < .01). CONCLUSION: Preliminary results indicate that serial whole-body FDG PET can help quantitatively assess the response of breast cancer bone metastases to therapy. Prospective trials are needed to further investigate its accuracy.

A phase I trial of immunotherapy with lapuleucel-T (APC8024) in patients with refractory metastatic tumors that express HER-2/neu.

PURPOSE: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu-expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor. EXPERIMENTAL DESIGN: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. RESULTS: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-gamma enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting > 48 weeks. CONCLUSIONS: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu-expressing breast, ovarian, and colorectal cancer are warranted.

Delayed type hypersensitivity response to recall antigens does not accurately reflect immune competence in advanced stage breast cancer patients.

The development of delayed-type hypersensitivity (DTH) response to recall antigens has long been utilized as a measure of immune competence. It is assumed that because patients with advanced stage cancers exhibit multiple immune system defects they may not be responsive to immunization. We pre-selected patients with advanced HER-2/neu (HER2) overexpressing breast and ovarian cancers for enrolment into a phase I trial designed to evaluate the immunogenicity of a HER2 peptide vaccine based on the patient's immune competence as assessed by DTH skin testing to common recall antigens (Multitest CMI, Institut Merieux, Lyon, France). At the time of a positive DTH response to tetanus toxoid (tt) peripheral blood was obtained to measure T cell responses to tt. Of 53 patients evaluated, 38 (72%) were not anergic. Among the 15 (28%) who were, seven patients with advanced stage breast cancer were re-tested a median of 26 days (range 12-150 days) after receiving a tt bopster vaccination. Five of the seven had positive DTH responses when re-challenged with tt and six had peripheral blood tetanus specific T cell response with stimulation index >2.0. Thus, the majority of patients studied with advanced stage breast or ovarian cancer were able to mount a DTH response to common recall antigens. Moreover, a negative response by DTH testing to a battery of common recall antigens was not a reflection of the breast cancer patient's ability to mount a cell-mediated immune response to a vaccinated antigen, tt.

Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu-overexpressing cancers.

Dendritic cells (DCs) are potent antigen-presenting cells and have shown promise to function as "natural" vaccine adjuvants. Currently, most cancer vaccine trials using DCs generate autologous DCs ex vivo for each patient. Systemic treatment with Flt3 ligand (FL) results in a marked increase of DCs in tissues such as spleen and lymph nodes in mice and in the peripheral blood and skin of humans. In light of these observations, we questioned whether FL could be used systemically as a vaccine adjuvant to stimulate DC mobilization in vivo, circumventing the need to generate DCs ex vivo. Ten patients with HER-2/neu-overexpressing cancer were enrolled in a phase 1 study to receive a HER-2/neu peptide-based vaccine targeting the intracellular domain of the HER-2/neu protein. All patients received 20 microg/kg FL per day subcutaneously for 14 days. Five patients received the HER-2/neu peptide-based vaccine alone on day 7 of the 14-day cycle, and 5 patients received the vaccine admixed with 150 microg granulocyte macrophage-colony-stimulating factor (GM-CSF) on day 7 of the FL cycle. T-cell proliferative responses to HER-2/neu peptides and intracellular domain protein suggest that vaccine regimens including FL as an adjuvant were not effective in eliciting a significant HER-2/neu protein-specific T-cell proliferative response. However, including FL as a vaccine adjuvant was effective in boosting the precursor frequency of interferon-gamma-secreting HER-2/neu-specific T cells. The small sample size of each group, however, did not allow a statistically significant comparison of immune responses between the FL alone and FL with GM-CSF arms. Finally, vaccine regimens including FL as a vaccine adjuvant were associated with the development of apparent autoimmune phenomena in some patients.