ABSTRACT
PURPOSE OF REVIEW: Leptomeningeal metastasis is a complication of metastatic breast cancer that has a rising incidence likely due to the increased availability of novel systemic therapies, which have improved survival with better extracranial disease control but with limited intracranial efficacy. A poor prognosis of less than 6âmonths has historically been associated with leptomeningeal metastasis and it is often an exclusion factor for enrollment in clinical trials. There are limited evidence-based data supporting use of therapeutics in leptomeningeal metastasis patients and recommendations are largely derived from retrospective reports and small prospective studies. However, in recent years, there has been a surge in effective modern therapeutics with promising intracranial activity. RECENT FINDINGS: The study aims to review the most recent updates in the management of leptomeningeal metastasis in breast cancer. We discuss the effectiveness and limitations of intrathecal administration, predictive biomarkers in the cerebrospinal fluid, proton radiation therapy and promising new systemic therapies such as antibody drug conjugates. SUMMARY: Ongoing development of clinical trials that allow inclusion of leptomeningeal metastasis are essential for establishing efficacy potential and discovering new treatment options in this population of great unmet need.
Subject(s)
Breast Neoplasms , Meningeal Carcinomatosis , Meningeal Neoplasms , Humans , Female , Breast Neoplasms/pathology , Retrospective Studies , Prospective Studies , Meningeal Carcinomatosis/secondary , Meningeal Neoplasms/therapyABSTRACT
Brain metastases (BM) significantly affect the prognosis as well as the quality of life of breast cancer (BC) patients. Although advancements in neurosurgical and radiotherapy techniques improve local control and symptom management, BM remains associated with a poor prognosis. In addition, the efficacy of currently approved systemic therapies in central nervous system (CNS) compartment is still limited, especially after progression on local therapy. The blood-brain barrier (BBB) has been recognized as a mechanism of primary resistance to many chemotherapeutic agents and targeted therapies due to low drug penetration. Other mechanisms of primary and secondary resistance are still unclear and may vary across the BC subtypes. New small molecules have demonstrated efficacy in BM, in particular for the HER2-positive subtype, with a benefit in survival. A new era has begun in the field of BM, and many trials specifically designed for this population are currently ongoing. The BC research community needs to address this call with the final aim of improving the efficacy of systemic therapy in CNS compartment and ultimately preventing the occurrence of BM.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Humans , Female , Breast Neoplasms/therapy , Quality of Life , Brain Neoplasms/therapyABSTRACT
PURPOSE: Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3'deoxy-3'-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases. METHODS: A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study. RESULTS: 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7-10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUVmax of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients. CONCLUSIONS: Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases. TRIAL AND CLINICAL REGISTRY: Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).
Subject(s)
Brain Neoplasms , Breast Neoplasms , Brain/diagnostic imaging , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Breast Neoplasms/drug therapy , Female , Humans , Neuroimaging , Positron-Emission Tomography , SorafenibABSTRACT
Many genomic assays that assess recurrence risk in early breast cancer (EBC) are prognostic, but they differ in risk group stratification, which can affect clinical utility. Prospective outcomes of >60 K patients treated based on the 21-gene assay results have shown that chemotherapy may be safely omitted in EBC patents with low Recurrence Score (RS) results (RS < 18). Because of its extensive validation and wide clinical use, the RS assay is a common comparator in head-to-head studies with other assays. Published/presented studies of the RS assay performed on the same tumor samples with Breast Cancer Index (BCI), EndoPredict (EP) or EP+ clinical features (EPclin), MammaPrint (MMP) and/or Prosigna (ROR) assays were reviewed. Study findings were summarized descriptively.
Subject(s)
Breast Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Breast Neoplasms/pathology , Female , Genomics/methods , Humans , Neoplasm Recurrence, Local/pathology , Prognosis , Prospective StudiesABSTRACT
The increasing incidence of breast cancer brain metastases is a major clinical problem with its associated poor prognosis and limited treatment options. The long-acting topoisomerase-1 inhibitor, etirinotecan pegol, was designed to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. Motivated by improved survival findings from subgroup analyses from the Phase III BEACON trial, this ongoing randomized, Phase III trial compares etirinotecan pegol to drugs commonly used for advanced breast cancer in patients with stable, treated breast cancer brain metastases who have been previously treated with an anthracycline, taxane and capecitabine. The primary end point is overall survival. Secondary end points include objective response rate, progression-free survival and time to CNS disease progression or recurrence in patients with/without CNS lesions present at study entry. Trial registration number: NCT02915744.
Subject(s)
Brain Neoplasms/drug therapy , Breast Neoplasms/drug therapy , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Polyethylene Glycols/administration & dosage , Adult , Aged , Brain Neoplasms/pathology , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Female , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Polyethylene Glycols/adverse effects , Progression-Free Survival , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/adverse effectsABSTRACT
Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with chemotherapy, but researchers rarely study its risk factors, fall risk, and prevalence in long-term breast cancer survivors. We aimed to determine CIPN prevalence, risk factors, and association with psychological distress and falls among long-term breast cancer survivors. We conducted Cross-sectional analyses among postmenopausal women with a history of stage I-III breast cancer who received taxane-based chemotherapy. Participants reported neuropathic symptoms of tingling/numbness in hands and/or feet on a 0-10 numerical rating scale. We conducted multivariate logistic regression analyses to evaluate risk factors associated with the presence of CIPN and the relationship between CIPN and anxiety, depression, insomnia, and patient-reported falls. Among 296 participants, 173 (58.4 %) reported CIPN symptoms, 91 (30.7 %) rated their symptoms as mild, and 82 (27.7 %) rated them moderate to severe. Compared with women of normal weight, being obese was associated with increased risk of CIPN (adjusted OR 1.94, 95 % CI: 1.03-3.65). Patients with CIPN reported greater insomnia severity, anxiety, and depression than those without (all p < 0.05). Severity of CIPN was associated with higher rates of falls, with 23.8, 31.9, and 41.5 % in the "no CIPN," "mild," and "moderate-to-severe" groups, respectively, experiencing falls (p = 0.028). The majority of long-term breast cancer survivors who received taxane-based chemotherapy reported CIPN symptoms; obesity was a significant risk factor. Those with CIPN also reported increased psychological distress and falls. Interventions need to target CIPN and comorbid psychological symptoms, and incorporate fall prevention strategies for aging breast cancer survivors.
Subject(s)
Accidental Falls , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Cancer Survivors/psychology , Peripheral Nervous System Diseases/epidemiology , Taxoids/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Breast Neoplasms/psychology , Cross-Sectional Studies , Female , Humans , Middle Aged , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/psychology , Postmenopause , Prevalence , Risk Factors , Taxoids/therapeutic useSubject(s)
Breast Neoplasms , Diagnostic Tests, Routine , Gene Expression , Genomics , Humans , Neoplasm Recurrence, LocalABSTRACT
In two randomized phase III trials of patients with metastatic breast cancer (MBC), gemcitabine-docetaxel (GD) and capecitabine-docetaxel (CD) had similar efficacy, but distinct safety profiles. Methods. Data from two GD versus CD studies were pooled; overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were determined. Cox proportional hazards models identified prognostic factors associated with improved OS and PFS. Using a multivariate prognostic model incorporating identified adverse prognostic factors, we grouped MBC patients into low-, intermediate-, and high-risk categories. Hazard ratios (HRs) of GD over CD for OS and PFS were determined for subsets of patients. Results. Baseline demographics of the pooled population were mostly well balanced. In the pooled population, there were no significant differences between GD versus CD for OS (HR = 1.02; p = .824), PFS (HR = 1.15; p = .079), and ORR (p = .526). In the pooled crossover population, there were trends toward improved OS (HR = 0.82; p = .171) and PFS (HR = 0.93; p = .557) with GD. Several prognostic factors (including prior adjuvant taxane) for improved OS or PFS were identified; however, there were no significant interactions between treatment arms and prognostic factors for PFS or OS, except number of metastatic sites. In the prognostic model, median OS and PFS were numerically lower in the high-risk group versus the intermediate- and low-risk groups. Conclusion. This analysis confirms the lack of efficacy difference between GD and CD in the pooled population, crossover population, and almost all subpopulations. Several prognostic factors were associated with improved outcomes in the pooled population.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Deoxycytidine/analogs & derivatives , Fluorouracil/analogs & derivatives , Taxoids/therapeutic use , Aged , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Disease-Free Survival , Docetaxel , Female , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Prodrugs/adverse effects , Prodrugs/therapeutic use , Proportional Hazards Models , Taxoids/adverse effects , Treatment Outcome , Tubulin Modulators/adverse effects , Tubulin Modulators/therapeutic use , GemcitabineABSTRACT
BACKGROUND: Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) are recommended 1st line treatments in HR+HER2- metastatic breast cancer. However, the impact of prior CDK4/6i on the natural history of brain metastases (BM) is not well described. MATERIALS AND METHODS: We reviewed retrospective data for 363 patients with HR+HER2- BM who received a CDK4/6i (CDK-Y) between 1 Jan 2015 to 31 July 2021 and 299 patients with HR+HER2- BM who did not receive a CDK4/6i (CDK-N) between 1 Jan 2010 to 31 Dec 2014. CNS PFS and OS were assessed in patients who received CDK4/6i after BM. OS from the time of BM development was assessed between patients who received CDK4/6i before BM and the CDK-N cohort RESULTS: In the CDK-Y cohort of 363 patients, 203 (56 %) received a CDK4/6i before BM, 133 (37 %) received a CDK4/6i only after BM and 27 (7 %) received a CDK4/6i both before and after BM. Median CNS PFS was 21.4 months for patients receiving a CDK4/6i only after BM and 9.4 months for patients who received CDK4/6i both before and after BM (p = 0.006). Median OS was 24.9 months for patients receiving a CDK4/6i only after BM and 12.1 months for patients who received CDK4/6i both before and after BM (p = 0.0098). Median OS from time of BM development for patients receiving a CDK4/6i before BM versus the CDK-N cohort was 4.3 months and 7.7 months respectively (p = 0.0082). CONCLUSIONS: CDK4/6i exposure prior to BM may lead to development of resistance mechanisms which in turn reduces CNS PFS and OS upon rechallenging with a CDK4/6i after BM development. This motivates investigation of biomarkers for patient selection.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Protein Kinase Inhibitors , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Brain Neoplasms/secondary , Brain Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Retrospective Studies , Protein Kinase Inhibitors/therapeutic use , Middle Aged , Aged , Adult , Aged, 80 and overABSTRACT
The HER2-directed antibody-drug conjugate trastuzumab deruxtecan is active against lower levels of HER2 expression than prior-generation therapies. The rate of HER2 expression in brain metastases among patients with initially HER2-null breast cancer is undefined, and receptor discordance in advanced breast cancer with brain metastases may underestimate CNS response potential in the absence of brain metastasis sampling. In this cohort study including 136 patients with 401 samples scored according to ASCO/CAP guidelines, 15/28 patients (54%) with HER2-null primary breast cancer have detectable HER2 expression in subsequently resected brain metastases, a significant discordant population.
ABSTRACT
BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.
Subject(s)
Breast Neoplasms , Meningeal Neoplasms , Receptor, ErbB-2 , Trastuzumab , Female , Humans , Ado-Trastuzumab Emtansine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Prospective Studies , Randomized Controlled Trials as Topic , Receptor, ErbB-2/antagonists & inhibitors , Trastuzumab/administration & dosage , Trastuzumab/therapeutic use , Meningeal Neoplasms/secondaryABSTRACT
BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.
Subject(s)
Breast Neoplasms/mortality , Pregnancy Complications, Neoplastic/mortality , Pregnancy , Adolescent , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Pregnancy Complications, Neoplastic/metabolism , Pregnancy Complications, Neoplastic/pathology , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Young AdultABSTRACT
Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.
Subject(s)
Brain Neoplasms/mortality , Brain Neoplasms/secondary , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Aged , Aged, 80 and over , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , Female , Follow-Up Studies , Humans , Meningeal Neoplasms/diagnosis , Middle Aged , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective Studies , Survival Rate , Time Factors , Young AdultABSTRACT
A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Transcriptome , Chemotherapy, Adjuvant , Female , Gene Expression Regulation, Neoplastic , Genetic Testing , Humans , Neoplasm Micrometastasis , Neoplasm Staging , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Sentinel Lymph Node BiopsyABSTRACT
Importance: Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician's choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM. Objective: To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician's choice in a confirmatory trial. Design, Setting, and Participants: This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019. Interventions: Patients were randomized to receive etirinotecan pegol, 145 mg/m2, every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). Main Outcomes and Measures: The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate. Results: A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non-central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable. Conclusions and Relevance: The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research. Trial Registration: ClinicalTrials.gov Identifier: NCT02915744.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Breast Neoplasms/pathology , Female , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Middle Aged , Polyethylene Glycols/adverse effectsABSTRACT
The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients' selection.
ABSTRACT
PURPOSE: Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT. PATIENTS AND METHODS: We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs). RESULTS: Between April 16, 2020, and October 11, 2021, 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS PFS was observed with pCSI (median 7.5 months; 95% CI, 6.6 months to not reached) compared with IFRT (2.3 months; 95% CI, 1.2 to 5.8 months; P < .001). We also observed OS benefit with pCSI (9.9 months; 95% CI, 7.5 months to not reached) versus IFRT (6.0 months; 95% CI, 3.9 months to not reached; P = .029). There was no difference in the rate of grade 3 and 4 TAEs (P = .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months). CONCLUSION: Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Craniospinal Irradiation , Lung Neoplasms , Meningeal Carcinomatosis , Proton Therapy , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Protons , Craniospinal Irradiation/adverse effects , Lung Neoplasms/drug therapy , Proton Therapy/adverse effects , Meningeal Carcinomatosis/radiotherapy , Meningeal Carcinomatosis/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic useSubject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms , Cytotoxins/therapeutic use , Postmenopause , Receptors, Estrogen/metabolism , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Administration Schedule , Female , Humans , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Patient SelectionABSTRACT
Knowledge of estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor-2 (HER2) status is necessary for determining the optimal treatment of breast cancer patients. At the same time, the discordance between marker profiles (ER/PR and HER2) of primary and metastatic breast cancer is well documented. Whether discordant cases are secondary to "clonal selection" in the face of targeted anti-estrogen or anti-HER2 therapy or whether they are a laboratory artifact is still debated; both scenarios are likely. This article outlines current modalities for ER, PR, and HER2 testing in primary breast carcinoma and its metastases and reviews prospective and retrospective studies that have addressed these issues, as well as recent advances in the field.
Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/therapy , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Biopsy/methods , Breast Neoplasms/metabolism , Disease Progression , Female , Humans , Prospective Studies , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective StudiesABSTRACT
OBJECTIVE: This retrospective observational study described baseline characteristics, real-world treatment patterns, and outcomes among patients with metastatic breast cancer treated with abemaciclib in the United States. METHODS: De-identified electronic health record-derived data were used to describe patients who began abemaciclib treatment on or after 30 June 2016 and ≥4 months before data cutoff (31 December 2018). Real-world response (rwR) and real-world progression assessments were abstracted from clinical documentation. Descriptive statistics were used to calculate the real-world best response. The Kaplan-Meier method estimated real-world time to first response (rwTTFR) and real-world progression-free survival (rwPFS). RESULTS: The median age of 118 female patients at abemaciclib initiation was 66.5 years (interquartile range, 57.0, 73.0). The breakdown of patients who received abemaciclib in first, second, third, or later lines was 28.8%, 21.2%, 20.3%, and 29.7%, respectively. Patients received abemaciclib as monotherapy (12.7%) or in combination with endocrine therapy: fulvestrant (59.3%); aromatase inhibitor (22.9%); aromatase inhibitor and fulvestrant (5.1%). There were 68 patients (57.6%) with ≥1 rwR assessment: 41.2% with a real-world complete response or real-world partial response. Median rwTTFR was 3.6 months (95% confidence interval, 3.5, 5.2). Twelve-month rwPFS probability was 61.7%. CONCLUSIONS: This study represents utilization and outcomes associated with abemaciclib approximately 1 year following FDA approval. Treatment patterns demonstrated heterogeneity and, as in clinical trials, patients appeared to benefit from abemaciclib treatment in the real world. More research investigating outcomes associated with abemaciclib treatment is needed, with larger samples and longer follow-up to enable closer evaluation by subgroup, regimen, and line of therapy.