Transcript metastatic-breast-cancer-11-2016

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
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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•
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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
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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.