ABSTRACT
Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC. SIGNIFICANCE: Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.
Subject(s)
Breast Neoplasms , Inflammatory Breast Neoplasms , Humans , Female , Inflammatory Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Signal Transduction , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Stem Cells/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
BACKGROUND: Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. METHODS: The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. RESULTS: A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. CONCLUSIONS: Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.
Subject(s)
Breast Neoplasms , Central Nervous System Neoplasms , Inflammatory Breast Neoplasms , Humans , Female , Inflammatory Breast Neoplasms/epidemiology , Inflammatory Breast Neoplasms/therapy , Incidence , Retrospective Studies , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/therapy , Central Nervous System/pathologyABSTRACT
BACKGROUND: HER2)-low expression is a predictive biomarker for novel anti-HER2 antibody-drug conjugates. However, little is known about its clinical significance in inflammatory breast cancer (IBC). METHODS: Patients diagnosed with HER2-negative IBC between December 1999 and December 2020 were identified from the Dana-Farber Cancer Institute IBC registry. Patients were divided into HER2-low (IHC 1+ or 2+/ISH-) and HER2-zero (IHC 0), comparing clinicopathologic features and disease outcomes between the two subgroups. RESULTS: The study included 276 patients. Among patients with stage III (n = 209) and stage IV (n = 67) IBC, 54% and 39% had HER2-low tumours, respectively. Oestrogen receptor (ER)-expressing tumours were more common in patients with HER2-low versus HER2-zero stage III IBC (65% versus 38%, p < 0.01). Among stage III patients undergoing surgery (n = 182), pathologic complete response (pCR) rates were higher for HER2-zero versus HER2-low IBC (11% versus 6%, OR: 1.8, 95%CI:0.6-5.3), but minimal differences persisted when separately analysing pCR by ER status. Similar invasive disease-free survival (iDFS) outcomes were observed among ER-positive HER2-zero versus HER2-low IBC (48-month iDFS: 63% versus 63%, HR: 1.10, 95%CI:0.57-2.13) and ER-negative HER2-zero versus HER2-low IBC (48-month iDFS: 28% versus 25%, HR: 1.19, 95%CI:0.69-2.04). Differences in overall survival (OS) were small, both among ER-positive HER2-zero versus HER2-low IBC (48-month OS: 80% versus 81%, HR: 0.82, 95%CI:0.39-1.73) and ER-negative HER2-zero versus HER2-low IBC (48-month OS: 34% versus 47%, HR: 1.34, 95%CI: 0.74-2.41). CONCLUSIONS: Marginal differences in clinicopathologic features and outcomes were observed in HER2-low versus HER2-zero IBC when controlling for ER status, not supporting the definition of HER2-low as a distinct subtype of IBC.
Subject(s)
Inflammatory Breast Neoplasms , Receptor, ErbB-2 , Female , Humans , Immunoconjugates , Inflammatory Breast Neoplasms/genetics , Inflammatory Breast Neoplasms/metabolism , Inflammatory Breast Neoplasms/pathology , Prognosis , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolismABSTRACT
OBJECTIVES: Dermal lymphatic invasion (DLI) with tumor emboli is a common pathologic characteristic of inflammatory breast cancer (IBC), although its presence is not required for diagnosis. We examined whether documented DLI on skin biopsy was associated with survival and time to recurrence or progression in IBC. MATERIALS AND METHODS: A total of 340 women enrolled in the IBC Registry at Dana-Farber Cancer Institute between 1997 and 2019 were included in this study. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for associations of DLI and overall survival, time to locoregional recurrence/progression, and distant metastasis by stage at presentation. RESULTS: DLI was detected in 215 (63.2%) of IBC cases overall. At disease presentation, IBC with DLI had a higher prevalence of de novo metastases (37.7% vs. 26.4%), breast skin ulceration (6.1% vs. 2.4%), and lymphovascular invasion within the breast parenchyma (52.9% vs. 25.5%) and a lower prevalence of palpable breast mass (48.2% vs. 70.6%) than IBC without DLI. Over a median follow-up of 2.0 years, 147 deaths occurred. DLI was not associated with survival or recurrence in multivariable models (all P ≥0.10). For example, among women with stage III disease, hazard ratios (95% confidence intervals) for DLI presence was 1.29 (0.77-2.15) for overall survival, 1.29 (0.56-3.00) for locoregional recurrence, and 1.71 (0.97-3.02) for distant metastasis. CONCLUSION: Although the extent of tumor emboli in dermal lymphatics may be associated with biological features of IBC, DLI was not an independent prognostic marker of clinical outcomes in this study.
Subject(s)
Inflammatory Breast Neoplasms/mortality , Inflammatory Breast Neoplasms/pathology , Biopsy , Combined Modality Therapy , Female , Humans , Inflammatory Breast Neoplasms/therapy , Lymphatic Metastasis/pathology , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local , Proportional Hazards Models , Survival AnalysisABSTRACT
PURPOSE OF REVIEW: Inflammatory breast cancer (IBC) is an uncommon but highly aggressive subtype of breast cancer that contributes significantly to breast cancer-related mortality. In this review, we provide an overview of the clinical and molecular characteristics of IBC, and highlight some areas of need for ongoing research. RECENT FINDINGS: The disease is characterized by florid tumor emboli that obstruct dermal lymphatics, leading to swelling and inflammation of the affected breast. Recent studies have focused on tumor cell intrinsic features, such as signaling through pathways involved in growth and stem-like behavior, as well as extrinsic features, such as the immune system, that can be leveraged to develop new potential therapies. Key efforts have led to an increase in awareness of the disease as well as new insights into IBC pathogenesis. However, there is a strong need for new therapies designed specifically for IBC, and many unanswered questions remain.
Subject(s)
Inflammatory Breast Neoplasms/pathology , Inflammatory Breast Neoplasms/therapy , Female , Humans , Inflammatory Breast Neoplasms/classification , PrognosisABSTRACT
BACKGROUND: Inflammatory breast cancer (IBC) is an uncommon and aggressive subtype of breast cancer associated with early disease recurrence and short survival. The prevalence of germline variants in cancer predisposition genes has not been systematically evaluated in women with IBC. METHODS: Among 301 women enrolled in the clinical IBC registry at a single institution between 2010 and 2017, 168 had documented genetic testing. A second cohort of 200 IBC cases who had panel-based germline testing performed through a commercial testing laboratory from 2012 to 2017 was added to the analyses. Personal and family cancer histories and genetic testing results were evaluated when they were available for both cohorts. RESULTS: Among 501 IBC cases, 368 had documented genetic testing. Germline mutations (56 total) were identified in 53 cases (14.4%). BRCA1 or BRCA2 mutations were found in 7.3% of the subjects, 6.3% had a mutation in other breast cancer genes (PALB2, CHEK2, ATM, and BARD1), and 1.6% had mutations in genes not associated with breast cancer. The prevalence of mutations was 24% (22 of 92) among women with triple-negative IBC, 13% (13 of 99) among women with estrogen receptor- and/or progesterone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 9.3% (10 of 108) among women with HER2-positive IBC. CONCLUSIONS: The prevalence and diversity of germline genetic mutations among patients with IBC suggest that further studies should be performed to assess the role of inherited mutations in IBC carcinogenesis in comparison with non-IBC breast cancer. Since IBC has a high metastatic potential associated with poor prognostic outcomes, proposed future studies may also inform targeted treatment options.
Subject(s)
Biomarkers, Tumor/genetics , Genetic Predisposition to Disease , Germ-Line Mutation , Inflammatory Breast Neoplasms/epidemiology , Inflammatory Breast Neoplasms/genetics , Adult , BRCA1 Protein/genetics , Checkpoint Kinase 2/genetics , Fanconi Anemia Complementation Group N Protein/genetics , Female , Follow-Up Studies , Humans , Massachusetts/epidemiology , Middle Aged , Prevalence , Prognosis , Retrospective Studies , Survival RateABSTRACT
PURPOSE: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). METHODS: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method. RESULTS: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8). CONCLUSION: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.
Subject(s)
Breast Neoplasms/therapy , Neoplasm Recurrence, Local/epidemiology , Paclitaxel/administration & dosage , Receptor, ErbB-2/metabolism , Trastuzumab/administration & dosage , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Female , Humans , Lymphatic Metastasis , Mastectomy, Segmental , Middle Aged , Neoplasm Staging , Paclitaxel/therapeutic use , Prospective Studies , Radiotherapy, Adjuvant , Receptor, ErbB-2/antagonists & inhibitors , Survival Analysis , Trastuzumab/pharmacology , Treatment OutcomeABSTRACT
Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression-free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar-plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response. IMPLICATIONS FOR PRACTICE: Triple-negative breast cancer (TNBC)-a disease with a dearth of effective therapies-often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways-alone or in combination-have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.
Subject(s)
Anilides/administration & dosage , Proto-Oncogene Proteins c-met/genetics , Pyridines/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Vascular Endothelial Growth Factor Receptor-2/genetics , Adult , Aged , Anilides/adverse effects , Biomarkers, Tumor/blood , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Molecular Targeted Therapy , Neoplasm Metastasis , Placenta Growth Factor/blood , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Pyridines/adverse effects , Triple Negative Breast Neoplasms/blood , Triple Negative Breast Neoplasms/pathology , Vascular Endothelial Growth Factor D/blood , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitorsABSTRACT
Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.
Subject(s)
Amenorrhea/epidemiology , Amenorrhea/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/complications , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/diagnosis , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant/adverse effects , Clinical Trials, Phase II as Topic , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Grading , Neoplasm Staging , Paclitaxel/administration & dosage , Trastuzumab/administration & dosage , Tumor BurdenABSTRACT
Brain metastases are associated with significant morbidity. Minimal research has been conducted on the risk factors for and incidence of brain metastases in women with inflammatory breast cancer (IBC). 210 women with Stage III or IV IBC diagnosed from 1997-2011 were identified. Competing risk analysis and competing risks regression were used to calculate the incidence of brain metastases and identify significant risk factors. After a median follow-up in surviving patients of 2.8 years (range 0.6-7.6) and 3.3 years (range 0.2-14.5) in the 47 and 163 patients with (MET) and without (non-MET) metastatic disease at diagnosis, 17 (36 %) and 30 (18 %) developed brain metastases, respectively. The cumulative incidence at 1, 2, and 3 years was 17 % [95 % confidence interval (CI), 8-30], 34 % (95 % CI, 20-48), and 37 % (95 % CI, 22-51) for the MET cohort. The corresponding non-MET values were 4 % (95 % CI, 2-8), 8 % (95 % CI 5-13), and 15 % (95 % CI, 10-22). Once non-MET patients developed extracranial distant metastases, the subsequent 1, 2, and 3 years cumulative incidence of brain metastases was 18 % (95 % CI, 10-28), 25 % (95 % CI, 15-36), and 31 % (95 % CI, 20-43). On multivariate analysis, brain metastases were associated with younger age [hazard ratio (HR), 0.73; 95 % CI, 0.53-1.00; P = 0.05] and distant metastases at diagnosis (HR, 2.33; 95 % CI, 1.11-4.89; P = 0.03). The incidence of brain metastases is high in women with IBC. Particularly for patients with extracranial distant metastases, routine screening with magnetic resonance imaging should be considered.
Subject(s)
Brain Neoplasms/epidemiology , Inflammatory Breast Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/secondary , Estrogen Receptor alpha/genetics , Female , Humans , Inflammatory Breast Neoplasms/genetics , Inflammatory Breast Neoplasms/pathology , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging , Receptor, ErbB-2/genetics , Receptors, Progesterone/genetics , Risk FactorsABSTRACT
BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive subtype. This study analyzes the patterns of failure in patients with IBC treated at our institution. METHODS: We retrospectively analyzed the records of 227 women with IBC presenting between 1997 and 2011. Survival analysis was used to calculate overall survival (OS) and disease-free survival. Competing risk analysis was used to calculate locoregional recurrence (LRR). RESULTS: A total of 173 patients had locoregional-only disease at presentation (non-MET). Median follow-up in the surviving patients was 3.3 years. Overall, 132 (76.3 %) patients received trimodality therapy with chemotherapy, surgery, and radiotherapy. Three-year OS was 73.1 % [95 % confidence interval (CI) 64.9-82.4]. Cumulative LRR was 10.1, 16.9, and 21.3 % at 1, 2, and 3 years, respectively. No variable was significantly associated with LRR. Fifty-four patients had metastatic disease at presentation (MET). Median follow-up in the surviving patients was 2.6 years. Three-year OS was 44.3 % (95 % CI 31.4-62.5). Twenty-four (44.4 %) patients received non-palliative local therapy (radiotherapy and/or surgery). For these patients, median OS after local therapy was 2 years. Excluding six patients who received local therapy for symptom palliation, the crude incidence of locoregional progression or recurrence (LRPR) was 17 % (4/24) for those who received local therapy compared with 57 % (13/23) for those who did not. CONCLUSIONS: For non-MET patients, LRR remains a problem despite trimodality therapy. More aggressive treatment is warranted. For MET patients, nearly 60 % have LRPR with systemic therapy alone. Local therapy should be considered in the setting of metastatic disease to prevent potential morbidity of progressive local disease.
Subject(s)
Carcinoma/secondary , Carcinoma/therapy , Inflammatory Breast Neoplasms/pathology , Inflammatory Breast Neoplasms/therapy , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Carcinoma/chemistry , Chemotherapy, Adjuvant , Disease Progression , Disease-Free Survival , Female , Humans , Inflammatory Breast Neoplasms/chemistry , Lymphatic Metastasis , Mastectomy, Modified Radical , Middle Aged , Radiotherapy, Adjuvant , Receptor, ErbB-2/analysis , Retrospective Studies , Survival Rate , Treatment FailureABSTRACT
BACKGROUND: No single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab. METHODS: We performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease. RESULTS: The median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption. CONCLUSIONS: Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).
Subject(s)
Adenocarcinoma/drug therapy , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/administration & dosage , Adenocarcinoma/chemistry , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Follow-Up Studies , Humans , Infusions, Intravenous , Mastectomy, Segmental , Middle Aged , Neoplasm Recurrence, Local , Paclitaxel/adverse effects , Radiotherapy , Receptor, ErbB-2/analysis , Receptor, ErbB-2/immunology , Survival Rate , TrastuzumabABSTRACT
There are ethical concerns regarding the performance of biopsies in patients for research purposes. We examined our single-institution experience regarding acceptance, safety, and success rate with research biopsies in patients with breast cancer. Among patients with data from paired samples, receptor status agreement between primary and metastatic samples was examined, either on first recurrence or after progression on one or more lines of therapy. An IRB-approved prospective study at the Dana-Farber Cancer Institute collects research biopsies as additional passes at the time of a clinical biopsy (AB, additional biopsy) or as a separate procedure for banking purposes (RPOB, research purposes only biopsy). Biopsies are not linked to a specific therapeutic or correlative trial. Grade 2-5 adverse events are prospectively collected. 151 patients were included in the analytic cohort (total procedures = 161); 80.8 % underwent AB, 17.2 % underwent RPOB, and 2.0 % underwent both AB and RPOB. Most patients were white (88.7 %) with a performance status of 0-1 (94.0 %). 96.0 % of patients underwent a biopsy in the setting of known or suspected metastatic disease. Receptor status between primary cancer and recurrent research biopsies differed in 43.2 % of patients with available data (18.8 % among patients who underwent the research biopsy before any systemic treatment, 48.1 % after treatment). Tissue was successfully collected in 92.3 % of patients undergoing AB and 100 % patients undergoing RPOB. Only three (2.0 %) patients had adverse events ≥ grade-2: one grade-2 pain; one grade-2 pneumothorax; and one grade-3 pain. Our experience suggests research biopsies can be performed safely with a high rate of successful tissue collection. Consistent with previous reports we found a high rate of discordance between primary and metastatic samples, which was even higher among treated patients. This supports continued efforts to study tissue samples at multiple points in a patient's disease course.
Subject(s)
Biopsy , Breast Neoplasms/pathology , Research , Adult , Aged , Aged, 80 and over , Biopsy/adverse effects , Breast/pathology , Female , Humans , Middle Aged , Prospective Studies , Risk Factors , Young AdultABSTRACT
BACKGROUND: Contemporary clinical outcomes of microinvasive breast cancer (MIBC), defined as no focus >1 mm, are not well characterized. We document the immunophenotype, incidence of axillary metastases, and rate of recurrence in a well-defined case series. METHODS: We reviewed 83 consecutive patients with MIBC from 1997 to 2005. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2/neu) receptor status were assessed. The cumulative incidence of local recurrence (LR) and nodal/distant recurrence was calculated. Predictors of recurrence were identified and effect estimates determined. RESULTS: Fifty-two patients (63%) underwent breast-conserving therapy (BCT) and 31 (37%) underwent mastectomy. Sixty-one percent had ER-positive disease and 49% had HER-2/neu-positive disease. Three (4%) of 68 patients with sentinel node mapping or axillary dissection had single node micrometastases, and none had macrometastases or multiple nodes involved. Median follow-up was 6.4 years, with 6 LRs, 2 regional nodal recurrences, and 2 concurrent local/distant recurrences. The 5-year cumulative incidence of recurrence (local, nodal, or distant) was 5.3% (95% confidence interval [CI] 2.0-13.4) for all patients, and among BCT patients, the 5-year cumulative incidence of LR was 4.2% (95% CI 0.7-12.7). HER-2/neu overexpression was not associated with recurrence (P = 0.46). Close/positive margins (≤2 mm) were significantly associated with an increased risk of LR after BCT or mastectomy (hazard ratio 8.8; 95% CI 1.6-48.8; P = 0.003). CONCLUSIONS: MIBC has a favorable prognosis, and HER-2/neu overexpression, although highly prevalent, is not significantly associated with recurrence. Axillary metastases at diagnosis are small and infrequent. The cumulative incidence of LR after BCT is acceptable; however, our data confirm that negative margins (>2 mm) are required for optimal BCT outcomes.
Subject(s)
Breast Neoplasms/pathology , Mastectomy, Segmental , Mastectomy , Neoplasm Recurrence, Local/diagnosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Adult , Axilla , Breast Neoplasms/metabolism , Breast Neoplasms/surgery , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Intraductal, Noninfiltrating/surgery , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Lymph Node Excision , Lymphatic Metastasis , Middle Aged , Neoplasm Invasiveness , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Prognosis , Survival RateSubject(s)
Breast/pathology , Carcinoma, Ductal, Breast/pathology , Inflammatory Breast Neoplasms/pathology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Ductal, Breast/therapy , Diagnosis, Differential , Female , Humans , Inflammatory Breast Neoplasms/diagnostic imaging , Inflammatory Breast Neoplasms/therapy , Mammography , Middle AgedABSTRACT
The treatment of inflammatory breast cancer (IBC) has been hampered by the diagnostic rarity of the disease and its consequent inclusion in clinical trials of preoperative treatment for the more indolent locally advanced breast cancer (LABC). Patients with IBC have a 2-fold greater probability of dying of their disease compared with patients diagnosed with LABC. The aggressive clinical portrait of IBC supports the recent investigative focus on determining molecular changes specific to IBC and developing novel systemic therapies that will favorably affect its poor disease prognosis. A significant amount of laboratory research has been involved in defining a specific "inflammatory signature" for IBC, denoting molecular changes consistently found in IBC. This work has involved human IBC tissue and cell lines and has demonstrated overexpression of several molecules governing metastatic dissemination, such as overexpression of E-cadherin concurrent with a dysfunctional mucin 1. An increased prevalence of mutant TP53, overexpression of RhoC, and vascular endothelial growth factor-A has been found to contribute to the dominant influence of angiogenesis in this disease. A greater understanding of the molecular mechanisms governing the pathophysiology of IBC has led to the development and clinical application of novel targeting agents for preoperative therapy. This study reviews the advances in molecular understanding of IBC and focuses on the efficacy of therapies that target the epidermal growth factor pathway and angiogenesis as well as early investigational therapies involving RhoC and TP53.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Neoadjuvant Therapy/methods , Breast Neoplasms/pathology , Clinical Trials as Topic , Epidermal Growth Factor/drug effects , Epidermal Growth Factor/genetics , Female , Humans , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/geneticsABSTRACT
PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the combination of weekly oxaliplatin x 4, weekly irinotecan x 4 and capecitabine Monday through Friday for 4 weeks of every 6 week cycle in patients with solid tumors; to determine the pharmacokinetic profile of these agents in this combination; to observe patients for clinical anti-tumor response. METHODS: Twenty-two patients with metastatic solid tumors received oxaliplatin 60 mg/m(2) weekly x 4, irinotecan beginning at a dose of 40 mg/m(2) weekly x 4, and capecitabine Monday through Friday for 4 weeks of every 6 week cycle, initially at 1,000 mg twice daily (bid). RESULTS: The MTD was oxaliplatin 60 mg/m(2) weekly x 4, irinotecan 50 mg/m(2) weekly x 4 and capecitabine 450 mg bid Monday through Friday for 4 weeks of every 6 week cycle. One of six patients at this dose level developed DLT of nausea, vomiting, and diarrhea. Among patients treated with a constant capecitabine dose of 450 mg bid, there was a higher mean AUC of 5-FU in women than in men (mean +/- SD: 892 +/- 287 nM h vs. 537 +/- 182 nM h; Mann-Whitney two-tailed, P = 0.02). There was one complete response in a patient with gastric cancer. CONCLUSION: The novel schedule of weekly oxaliplatin, weekly irinotecan, and capecitabine Monday through Friday, all administered for 4 weeks of every 6 week cycle, evaluated in this phase I trial is well-tolerated and demonstrated activity in a patient with gastric cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Area Under Curve , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Capecitabine , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Humans , Irinotecan , Male , Maximum Tolerated Dose , Middle Aged , Organoplatinum Compounds/administration & dosage , OxaliplatinABSTRACT
Rapid sequential delivery of doxorubicin 75 mg/m2 q 2 weeksx3 cycles followed by docetaxel 100 mg/m2 q 2 weeksx3 cycles, with filgrastim support was evaluated in patients with inoperable and large operable breast cancers who were not initially candidates for breast conservation therapy. Postoperative CMF chemotherapy and/or radiation were administered based on surgical findings. Median age of the 39 enrolled patients was 47 (range 27-59), stage IIA (6 patients), IIB (14 patients), IIIA (10 patients), IIIB (9 patients), and 23 patients (59%) had clinical nodal involvement. The average bidimensional tumor size before treatment was 30 cm2. Clinical responses included 13 (33%) complete responses, 23 (59%) partial responses, 1 stable disease, and 2 progressive disease, for an overall response rate of 92%. Clinical response rate was 11/13(85%) in HER2/neu positive patients compared to 25/26 (96%) in tumors that did not express HER2/neu. Twenty patients (51%) underwent breast conservation surgery. Pathologic tumor response at the time of definitive surgery included 4 pathologic CR (pCR, 10%), 4 microscopic invasion (pINV), and 14 (36%) pathologically negative axillary nodes. pCR was not observed in any HER2/neu positive patients. 5/39 patients were unable to complete all cycles of docetaxel and 8 patients required dose reduction of docetaxel due to development of grade 3-4 mucositis and hand-foot syndrome. This observation prompted a protocol change requiring 3 weeks between doxorubicin and docetaxel. Primary chemotherapy with dose-dense doxorubicin and docetaxel given sequentially is well tolerated and allows a high rate of breast sparing in patients with large breast cancers.