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Metastatic Breast Cancer A sub-focus on specific clinical scenarios What to talk about? • Brain Metastatic Disease • CKD inhibition • HDAC inhibition • Androgen Receptor inhibition • mTOR inhibition • Checkpoint Inhibition Case Study • 46 y/o WF • Stage II (3.3cm) ER/PR- HER2+ breast cancer • Treated on protocol • AC->Docetaxel+HP->HP for 1 year • Presented 9 months into adjuvant therapy with intractable headache Your patient has brain metastases • Questions you will get from patients • What do we do next? • How long do I have to live? • Questions for you from me • • • • • • • How do you prognosticate brain metastasis from breast cancer? Who gets surgery? Who gets IT therapy? Whole brain v. SRS? Which phenotype does the best? The worst? Does any group have a median survival over 6 months? Brain Metastases Disease Pattern By Phenotype • TNBC • TNBC has a particular propensity to metastasize to the brain. The interval from early-stage disease to BM diagnosis is short, and de novo brain disease is more common than for the other phenotypes. • BM from triple-negative BC typically occur in the setting of chemoresistance so the effect of further systemic therapy on extracranial disease (ECD) is often poor or of short duration • The median survival of all comers with TNBC BM is approximately 6 months,34 months for poor PS and around 9 months for good PS patients. Disease Pattern By Phenotype • HER2 Positive Disease • HER2BC has a well-described propensity to metastasize to the CNS • The striking success of targeted-HER2 therapies has altered the natural history of the disease by preventing early death from visceral metastases. This ‘allows time’ for the development of CNS disease in a population that would otherwise already have succumbed such that the median survival after a diagnosis of HER2BC is now remarkably long. • In a multivariable model, women with HER2/neu-positive disease who received trastuzumab had a 44% reduction in the risk of death compared with women with HER2/neu-negative disease (hazard ratio [HR] = 0.56; 95% CI, 0.45 to 0.69; P < .0001). • One-year survival rates among patients withHER2/neu-negative disease, HER2/neu-positive disease and trastuzumab treatment, were 75.1% (95% CI, 72.9% to 77.2%), 86.6% (95% CI, 80.8% to 90.8%) [JCO 2010] Disease Pattern By Phenotype • HER2 Positive Disease • HER2+ BM manifest later than triple-negative BC BM and earlier than HR+ BM. • Hormone-negative HER2+ BC may develop BM earlier than hormone-positive HER2+ BC. • BM develop as the first site of metastatic disease in about 2% of patients with metastatic HER2BC. • More commonly, BM arise whilst the patient is receiving HER2-targeted therapy for ECD. • At least one retrospective series suggests that neurologic death, defined as death from uncontrolled metastatic intracranial disease rather than from systemic disease, may be more common in HER2BC than the other phenotypes Disease Pattern By Phenotype • Hormone Receptor Positive Disease • HR+ BC has the least well-defined clinical pattern. • BM tend to occur late in the natural history of this phenotype, some time after extracranial metastatic disease has been treated with one or several lines of endocrine therapy. • May be a very late presentation (many years or even decades after primary disease) • De novo BM are not common. The relatively slow natural history of the HR+ BC phenotype is such that rapid death from CNS disease is unusual. • The median survival of patients with HR+ BC and good PS is 15-17 months Brain Metastases • Treatment• • • • WB-XRT + Valproic Acid Capecitabine + Lapatinib TDM-1 SRS to a possible escape lesion • Scans are 16 months apart • PS =0 Brain Micrometastatic Disease • The risk of occult BM relative to lesion number and by phenotype is unknown. • A retrospective review of 154 cases treated with SRS without WBRT in one institution found that the 12- month rate of failure in the brain (distant from sites of radiosurgery) was • highest in TNBC (79%), • intermediate for HR+ BC (~47%) • least for HER2BC (36%). The rate of failure by lesion number, extracranial disease status and use of systemic therapies was not reported • Median overall survival (OS) was 7, 9, 11 and 22 months for Basal, Luminal A/B, HER2, and Luminal HER2, respectively (p = 0.001), • Median OS was 17 and 8 months for HER2+ and HER(-) patients PMID 23001361 Treatment Modalities • Radiotherapy • WB-XRT • SRS • Neurosurgery • Systemic Therapy • IT Therapy Treatment Modalities - Radiotherapy • WBXRT • WBRT is a regional treatment that delivers a moderate dose of radiotherapy to all of the brain tissue. • WBRT treats known lesions as well as any subclinical disease in the brain. • WBRT plays an important palliative role in treatment of multiple symptomatic brain metastases which are not amenable to stereotactic radiosurgery (SRS) and/or surgery or when extensive leptomeningeal disease is present. • Cognitive changes are real, there are 2 phases to clinical manifestations • Early Changes- Memory impairment - transient, 2-4 months after WBXRT – improves by 1 year • EORTC data did not identify differences at 1 year in regards to grade of toxicity • Alternate data from JHU in SCLC• In a study of prophylactic cranial irradiation for non-small cell lung cancer, a sustained fall in Hopkins Verbal Learning test was observed in the group that received PCI despite a lower rate of tumour progression in the brain. (Approximately 30% at 12 months compared with 7%% in the no PCI arm). However global functioning and QOL were equal. Treatment Modalities – Radiotherapy - SRS • SRS is a specialised radiation technique in which sophisticated technology is used to deliver 1-5 large radiation fractions (daily dose) to small targets. • SRS is best for lesions up to 3.0 cm, but can be used for lesions as large 4.0 cm in some circumstances. • SRS can readily treat lesions at any site in the brain, although special care is needed when treating brainstem lesions. • With careful attention to patient selection, treatment planning and delivery, acute toxicity is minimal. • Edema may develop in the treatment region (days to weeks after SRS) but symptoms from raised intracranial pressure are not common. • The main late effect is radiation necrosis (20-25%), usually seen on magnetic resonance imaging (MRI) anytime from 9 to 12 months after SRS but not always symptomatic. • Symptomatic radionecrosis is uncommon (<10%) • Re-irradiation can be safe, and can be considered after either choice for primary modality • WBXRT following SRS, or SRS following WBXRT as primary therapy Treatment Modalities - Neurosurgery • Studies of patients with BM from unselected primary tumors indicate that microsurgical resection is most likely to benefit symptomatic patients with mass effect or midline shift from large lesions (3 cm diameter) and those with a good PS and well controlled extra cranial disease • In a retrospective review of a BC-specific population, 91% of patients experienced relief of neurological symptoms after surgery • Any changes to the role of neurosurgery in the era of new systemic treatments and targeted agents is yet to be defined. Systemic Therapy • Clinical trials of systemic anticancer agents exclude patients with BM. • This is usually owing to factors including uncertainty regarding blood-brain barrier penetration, difficulties in monitoring the response in the brain, and factors such as the need for corticosteroids and enzyme-inducing anti-epileptic drugs. • Prospective data on the use of systemic agents for BM and which might guide treatment choice are limited. • A few single-arm or small phase II studies and post hoc analyses of retrospective series from large phase III trials have demonstrated that many systemic agents have activity in the brain. • These agents include cytotoxic agents active in breast cancer such as • • • • • capecitabine, platinum agents, microtubule inhibitors, temozolomide, methotrexate. • Targeted therapies with potential CNS activity include • lapatinib in combination with capecitabine, • TDM-I in HER2BC, and • anecdotally, immune checkpoint inhibitors. Intrathecal Chemotherapy • The incidence of leptomeningeal carcinomatosis in breast cancer patients (LC-BC) is increasing. • LC occurs in approximately 5% of all cancer patients • NSCLC, Breast, Melanoma, GI malignancies most common • Median OS of 4 weeks if left untreated • Median OS of 8-16 weeks even with therapy • No standard of care exists • A systematic review of treatment strategies for LC-BC was performed. (n = 173 studies) PMID 27553811 IT therapy summary- from randomized trials only • IT-MTX + XRT significantly increases risk of neurotoxicity compared to IT-MTX alone • MTX dosing? A standard induction regimen consists of a fixed dose of 10 or 12 mg twice a week for four weeks. • DepoCyte (Depo-AraC) produces a response rate comparable to that of MTX and significantly improved time to neurologic progression compared to MTX • Depocyte dosing? Lymphomatous meningitis: Intrathecal: Induction: 50 mg every 14 days for a total of 2 doses (weeks 1 and 3) Consolidation: 50 mg every 14 days for 3 doses (weeks 5, 7, and 9), followed by an additional dose at week 13 Maintenance: 50 mg every 28 days for 4 doses (weeks 17, 21, 25, and 29) To minimize incidence of chemical meningitis,dexamethasone should be administered (4 mg twice daily x 5 days) initiating therapy 1day before and continuing for 4 days after liposomal cytarabine instillation Combining XRT and IT chemo • XRT appears to be more effective at relieving symptoms than does IT chemotherapy. • Treatment for leptomeningeal metastases should consider including palliative RT (30 to 36 Gy in 3 Gy daily fractions) to sites of symptomatic or bulky disease (as seen on MRI). • Also recommend administering RT to sites of obstruction of CSF flow, as demonstrated by a radionuclide CSF flow study, prior to IT chemotherapy. • Shunting can also be considered • Patients with lower extremity weakness, or bladder or bowel dysfunction, generally receive lumbosacral spine irradiation. Intrathecal Trastuzumab • Currently exists only in case reports • Long term survivors have been reported, as has good clearance rates of CSF • Low doses (~20mg) have been used, with reported good improvements in patient symptom complex • Ongoing phase I/2 studies are underway in the US and Europe to define dosing (80mg?) • Phase I study ongoing at Duke for IT Trastuzumab+Pertuzumab Novel Systemic Therapies for Metastatic Disease • CDK4i • Ribociclib (600mg daily x 3w, 1w rest) • Palbociclib – Ibrance (125mg po daily x3w, 1w rest) • [amebaciclib] PMID 27717303 Palbociclib – first or second line • Paloma1 Trial- Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death • Median investigator-assessed PFS was 20.2 months (95% CI 13.8, 27.5) in the palbociclib plus letrozole arm and 10.2 months (95% CI 5.7, 12.6) in the letrozole alone arm [Hazard Ratio (HR) 0.488 (95% CI 0.319, 0.748)] • In subgroup analysis- the difference in PFS for the treatment populations grouped by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, (using the Kaplan-Meier method) • Benefit was seen in all groups analyzed. Palbociclib – first or second line • In combination with Fulvestrant- (PALOMA3) • Patients with endocrine-resistant, HR-positive/HER2-negative MBC (n = 521) were randomly assigned 2:1 to receive fulvestrant (500 mg intramuscular injection) with or without goserelin with oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. • Median progression-free survival was 9·5 months (95% CI 9·2-11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5-5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36-0·59, p<0·0001). PMID 26947331 Cyclin Dependent Kinase 4 – TNBC? • Cyclin-dependent kinase (CDK4) acts as a cancer stem cell regulator and potential novel prognostic marker in triple negative breast cancers. • Cancer Stem Cells (CSCs) are capable of driving not only tumor initiation, but also cancer cell metastasis in various human cancer types • These distinct subpopulations of cancer cells utilize their self-renewal ability to generate and propagate heterogeneous tumors • In breast cancer patients, B-CSCs are frequently detected in metastatic pleural effusions or early-disseminated cancer cells within the bone marrow • Comprehensive analysis of somatic copy-number alterations from thousands of tumor specimens identified the CDK4 gene to be the most frequently amplified in human cancers • CDK4 was also shown to promote normal stem cell expansion and inhibit differentiation of embryonic, hematopoietic, neural and mammary progenitors PMID 27759034 Gene analysis of >1100 breast cancer patients Translational work with CKD4/6i • Suppression of CDK4 expression or kinase activity reverses the basal-B TNBC mesenchymal phenotype to an epithelial- and luminal-like phenotype. • Blocking CDK4 kinase activity leads to inhibition of BCSC self-renewal and significantly reduces cancer stem cell numbers. • Clinical trials ongoing in HER2+ and TNBC with palbociclib mTOR inhibition • BOLERO-2 trial • enrolled 724 women who had progressed on anastrozole. Patients were randomly assigned to treatment with exemestane (25 mg daily) plus placebo or exemestane plus everolimus (10 mg daily) • An improvement in PFS (median, 7 versus 3 months; HR for mortality 0.43, 95% CI 0.350.54) • Higher ORR (9.5 versus 0.4 percent) • No difference in OS (median, 31 versus 26.6 months; HR 0.89, 95% CI 0.73-1.10) • Everolimus use was associated with SAE (grade 3/4), including stomatitis (8 %), dyspnea (4%), noninfectious pneumonitis (3%), and elevated LFTs(3%). • For patients who develop shortness of breath or increase in cough, everolimus should be held and patients assessed for pneumonitis. A brief course of steroids may be necessary. • Everolimus under investigation with chemotherapy in TNBC and others PMID 22149876 HDAC inhibition • Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor (letrozole, anastrozole) were randomly assigned to exemestane 25 mg daily (steroidal AI) plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). • One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). • EE improved median PFS to 4.3 months versus 2.3 months with EP • Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036) PMID 23650416 Entinostat + Exemestane • Compared with the EP group, the EE group had a higher rate of AEs (95%v 85%), grade 3 AEs (44% v 23%), grade 4 AEs (6% v 3%), AEs leading to dose modification (35% v 6%), and AEs leading to study discontinuation (11% v 2%), irrespective of study drug relationship. AEs leading to the majority of EE dose modifications included neutropenia (14%), thrombocytopenia (14%), and fatigue (6%). • Was granted breakthrough status in 2013…. • Is being studied in phase III trials • Is being studied in combination with ICI Androgen Receptor • Of 424 patients with ER/PgR-negative breast cancer, 12% tested ARpositive. • Separate RNA-seq identified AR+ tumors to be more likely in European American patients and not African American patients. (p 0.031) • The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. • The median PFS was 12 weeks (95% CI, 11–22 weeks). • Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. • Multiple studies underway with specific AR inhibitors, bicalutamide, and others Androgen Receptor – Adjuvant? • In some TNBC cases, the androgen receptor constitutes endocrine signaling outside of the estrogen/progesterone pathway • In a retrospective study of 912 patients with (ER)-negative tumors, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14-0.81; P=0.015), • whereas the opposite was seen in the AR(-) group (HR=2.92; 95% CI=1.167.31; P=0.022). • Interaction test was significant P<0.001. • Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression. • No studies underway in the adjuvant setting Immunotherapy • Results have largely been disappointing in breast cancer • TNBC may be a hopeful arena- now in phase III study • Phase I study- Among 111 patients with TNBC whose tumor samples were screened for PD-L1 expression, 58.6% had PD-L1-positive tumors. • Study was of 32 patients with PDL1+ tumors • Among the 27 patients who were evaluable for antitumor activity, the overall response rate was 18.5%, the median time to response was 17.9 weeks (range, 7.3 to 32.4 weeks), and the median duration of response was not yet reached (range, 15.0 to ≥ 47.3 weeks) • five (15.6%) patients with grade ≥ 3 toxicity and one treatment-related death.