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Hereditary Breast Cancer in 2017: What’s New for Metastatic Breast Cancer Treatment
June 10, 2017
Payal D. Shah, MD Basser Center for BRCA Abramson Cancer Center University of Pennsylvania
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Disclosures
Research funding: - TESARO - Astra Zeneca
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Outline w Background:
• What is MBC • MBC treatment and biomarkers • Cancer genetics • Landscape of hereditary breast cancer • Clinical trial basics
w Recent updates in breast cancer care • Cell cycle inhibitors (palbociclib, ribociclib) • Pembrolizumab • PARP inhibitors
w Approaches under investigation • Immunotherapy • Targeted therapy • PARP inhibitors beyond olaparib, beyond BRCA!/2
w Expanded access programs w Quality of life for MBC survivors w Survival and prognosis
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Outline w Background:
• What is MBC • MBC treatment and biomarkers • Cancer genetics • Landscape of hereditary breast cancer • Clinical trial basics
w Recent updates in breast cancer care • Cell cycle inhibitors (palbociclib, ribociclib) • Pembrolizumab • PARP inhibitors
w Approaches under investigation • Immunotherapy • Targeted therapy • PARP inhibitors beyond olaparib, beyond BRCA!/2
w Expanded access programs w Quality of life for MBC survivors w Survival and prognosis
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What is metastatic breast cancer (MBC)?
w Breast cancer that has spread outside of the breast to a distant area
w Treatable, not curable
w Goals of treatment: prolong life, delay tumor growth or reduce tumor burden, ease symptoms, maintain quality of life
w General approach: sequential treatments, lifelong
w Each drug until • Too many/intolerable side effects • Drug stops working (scan shows progression)
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Why is this an important topic?
w MBC accounts for the vast majority of breast cancer related deaths
440 2600 Men
40,450 246,660 Women
Deaths New Cases
ACS, 2016
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But we do relatively well overall… w Breast cancer: 249,000; 41,000 deaths
w NSCLC: 221,000; 158,000 deaths
w Colon cancer: 90,000; 49,000 deaths (colon + rectal)
w Pancreas cancer: 53,000; 42,000 deaths
w Ovarian cancer: 22,000; 14,000
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Biomarkers
Anti-estrogen therapies
HER2-targeted agents
ER/PR positive
HER2 positive
TNBC
60-70%
15-20%
15-20%
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ER and PR
w HR-Positive: if either ER or PR >1%
w HR-positive tumor uses hormones as food to grow w The stronger the HR positivity, the more benefit the
patient will get from endocrine therapy w Tamoxifen, anastrozole, letrozole, exemestane,
fulvestrant
w HR+ = good prognostic feature
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HER2
w A protein on the surface of cells
w Too much on some cancer cells drives growth
w Unfavorable prognostically
w HER2-targeted therapies altered the natural history of these tumors
B
C
Proliferation, cell survival
A
HER2
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HER2
w A protein on the surface of cells
w Too much on some cancer cells drives growth
w Unfavorable prognostically
w HER2-targeted therapies altered the natural history of these tumors
B
C
Proliferation, cell survival
A
HER2
Trastuzumab (Herceptin)
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MBC Treatments - 1
w For HR+ disease, prefer to start with endocrine therapy when appropriate
w For HER2+ disease, include HER2-targeted antibodies
w For TNBC, chemotherapy
w For all breast cancer, CLINICAL TRIALS
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MBC Treatments - 2
w Monitoring: clinical visits, labs, and imaging periodically (q3-6 mo)
w Bone health (x-geva or zometa if bone mets)
w Other palliative measures when needed • Radiation (for pain or instability) • Symptom control • Psychosocial assistance
w Goals of care/hospice discussions when appropriate
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Biomarkers
Anti-estrogen therapies
HER2-targeted agents
ER/PR positive
HER2 positive
TNBC
60-70%
15-20%
15-20%
w Genomics (somatic, germline)
w Immune biomarkers w Much more!
Impact on treatment?
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A Word About Cancer Genetics
Germline mutation Hereditary cancer Inherited cancer
Somatic mutation Tumor mutation
w What one is born with w Blood / Saliva test w Can be passed down w Can sometimes also be
in tumor
w NOT necessarily what one is born with
w Tumor test w Can NOT be passed down unless
also germline
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A(nother) Word About Cancer Genetics
Germline genetics Somatic/Tumor genetics
w Traditionally used for screening, risk reducing strategies, risks to family members
w Now can have implications on treatment too
w Traditionally used for treatment (trial eligibility, hypotheses re: what might make sense)
w Can lead to germline testing
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Landscape of Hereditary Breast Cancer
w Until 2008: BRCA1 and BRCA2
w Multiple commercial companies have multiple panels with multiple genes
w Some customizable, some fixed
Next-generation sequencing aka Multiplex panel testing aka Multi-gene testing
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Gene name
Ambry
BreastNext
Myriad
MyR
isk
Ambry
CancerNext-‐Ex
Uwash
BROCA
# of genes 17 25 48 61 APC * * * BMPR1A * * * EPCAM * * * SMAD4 * * * FCLN * * FH * * GREM1 * * MAX * MEN1 * * MITF * MLH1 * * * MSH2 MSH6 PMS2 * * * POLD1 * * POLE * * RB1 * RET * * SDHA * SDHAF2 * SDHB * * SDHC * * SDHD * * SMARCA4 * * TMEM127 * TSC1 * TSC2 * VHL * *
Gene name Am
bry
BreastNext
Myriad
MyR
isk
Ambry
CancerNext-‐Ex
Uwash
BROCA
# of genes 17 25 48 61 BRCA1 * * * * BRCA2 * * * * CDH1 * * * * PTEN * * * * STK11 * * * TP53 * * * *
ATM * * * * CHEK2 * * * * NBN * * * *
NF1 * * * PALB2 * * * *
AKT1 * ATR * AXIN2 * BARD1 * * * * BAP1 * * BLM * BRIP1 * * * * CDK4 * * * CDKN2A * * * CTNNB1 FANCC FANCM FAM175A * GEN1 * HOXB13 * MRE11A * * * MUTYH * * * * PALLD * PIK3CA * PPM1D RAD50 * * RAD51C * * * * RAD51D * * * * RINT1 * XRCC2 *
Multiplex panel testing for germline cancer susceptibility
Established high risk breast cancer
susceptibility genes
Established moderate risk breast cancer
susceptibility genes
Possible breast or other cancer
susceptibility genes with varying levels of support (case reports, cohort studies, exome sequencing studies)
Variably established risks for other cancers. No
association or proposed or controversial
association with breast cancer.
Breast Cancer Gene classification as per Easton et al NEJM 2015 Slide courtesy of Kara N. Maxwell, M.D., PhD.
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Landscape of Hereditary Breast Cancer • BRCA1 and BRCA2: tumor suppressor genes involved in DNA repair.
When they don’t work, DNA is error-prone and cancer risks are higher.
• Breast, ovarian, prostate, pancreas
• Now we appreciate that there is MUCH MORE to the story than just BRCA1/2
• ATM, PALB2, CHEK2 • P53 – Li-Fraumeni syndrome • PTEN – Cowden syndrome • Many, many more
• Specific risk reduction, management/screening, treatment strategies
• SO MUCH work ongoing and so much more to do.
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Recommendations exist for other genes
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Recommendations exist for other genes
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Recommendations exist for other genes
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Clinical trials: What are they?
w Therapeutic clinical trials involve: 1) treatment of some sort 2) usually, scientific studies alongside treatment that may require biopsies, blood draws 3) monitoring for safety and effectiveness of drug
w Overarching goal: advance the care of pts with cancer w For an individual patient, we hope for therapeutic
benefit, but this is never certain w Provide access to drugs in development that may be
active w Side effects may be less well delineated than for
approved drugs
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Clinical trials: Phases w Phase 1 – traditional goal is safety / toxicity, but based
on a scientifically promising principle
w Phase 2 – traditional goal is to get a sense of efficacy
w Phase 3 – compare to gold standard and get approval
w Sometimes a really promising phase 2 can lead to accelerated approval
w Lines are becoming more blurred
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Clinical trials: Basic concepts
w Informed consent
w Eligibility
w Dynamic slot availability
w Study requirements regarding visits, tests and procedures
w Clinicaltrials.gov allows one to search for trials by keywords
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Clinical trials: When to think of them? w Upfront, and at every occasional that a treatment change
is needed or upcoming
w Some trials have an upper limit of # lines prior therapy
w Some trials exclude pts with certain prior treatments
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Clinical trials can also be non-therapeutic
w Some trials examine side effects (cognition, mood)
w Some trials track blood or other markers without any specific therapy being administered
w Some trials look at new imaging modalities (PET studies, etc.)
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Outline w Background:
• What is MBC • MBC treatment and biomarkers • Cancer genetics • Landscape of hereditary breast cancer • Clinical trial basics
w Recent updates in breast cancer care • Cell cycle inhibitors (palbociclib, ribociclib) • Pembrolizumab • PARP inhibitors
w Approaches under investigation • Immunotherapy • Targeted therapy • PARP inhibitors beyond olaparib, beyond BRCA!/2
w Expanded access programs w Quality of life for MBC survivors w Survival and prognosis
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Recent advances in MBC w Cell cycle inhibitors
• Palbociclib + AI: PALOMA1/2 – Accelerated approval 2/2015 – Regular approval 3/2017
• Palbociclib + Fulvestrant: PALOMA 3, approved 2/2016 • Ribociclib + AI: MONALEESA-2, approved 3/2017 • Abemaciclib + Fulvestrant – presented ASCO 2017
w Immunotherapy • Pembrolizumab tissue agnostic approval** • KEYNOTE-12 and KEYNOTE-86 studies
w PARP inhibitors • OlympiAD – ASCO plenary, Mark Robson, MD
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Cell cycle inhibitor + endocrine therapy
w Preclinical data that CDK4/6 inhibitors block growth of ER+ breast cancer cells
w Preclinical data that CDK4/6 inhibitors are synergistic with anti-estrogen therapy
Finn et al., Lancet Oncol, December 2014; Finn et al., NEJM, November 2016
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Cell cycle inhibitor + endocrine therapy
w 2 major cell cycle inhibitors currently approved: • Palbociclib (Pfizer) • Ribociclib (Novartis)
w Abemaciclib (Lilly) – not yet approved but looked promising with fulvestrant at ASCO 2017
w Approvals are with endocrine therapy • Fulvestrant (SERD) • Letrozole + AIs
Finn et al., Lancet Oncol, December 2014; Finn et al., NEJM, November 2016
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Palbociclib + Letrozole: PALOMA-1
w Proof-of-concept Phase 2 study w Women with ER+ MBC and no prior treatment received
letrozole + placebo or letrozole + palbociclib w N=165 w PALOMA-1 showed significantly longer PFS with
combination (10.2 months letrozole, versus 20.2 months palbociclib + letrozole)
w Toxicity tolerable: Cytopenias, with 54% of pts having neutropenia, but no neutropenic infections
w Led to accelerated FDA approval of combined letrozole + palbociclib
Finn et al., Lancet Oncol, December 2014
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Palbociclib + Letrozole: PALOMA 2
w Phase 3, double-blind study w Patients with HR+ MBC who had not received prior
treatment for advanced disease w letrozole + palbociclib vs. letrozole + placebo (2:1) w N=666 w Manageable toxicity:
• Neutropenia, still with low rate of neutropenic fever • Mild increases in fatigue and nausea • No increase in risk for PE
w 36% of pts required dose reduction
Finn et al., NEJM, November 2016
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Finn RS et al. N Engl J Med 2016;375:1925-1936
Finn et al., NEJM, November 2016
Palbociclib + Letrozole: PALOMA 2 w Median PFS better
with palbo + letrozole than with placebo + letrozole
w Top panel, investigator assessment: 24.8 months vs. 14.5 months
w Bottom panel, independent central review: 30.5 months vs. 19.3 months
w Benefit seen across subgroups, performance status, visceral involvement
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Palbociclib + Fulvestrant: PALOMA-3
w Phase 3 w 521 women with ER+ MBC and prior progression on
endocrine therapy w Randomized to fulvestrant + placebo versus fulvestrant +
palbociclib w Toxicity mainly neutropenia w Led to FDA approval of combined fulvestrant + palbociclib
after prior POD on endocrine therapy
Cristofanilli et al., Lancet, March 2016
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Palbociclib + Fulvestrant: PALOMA-3
w Median PFS better with palbo + fulvestrant than with placebo + fulvestrant
w 9.5 months versus 4.6 months
Cristofanilli et al., Lancet, March 2016
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Palbociclib + endocrine therapy w Approved in the first line with letrozole
w Approved in endocrine resistant disease with fulvestrant
w Relatively well-tolerated, requiring blood count monitoring
w Retains efficacy despite dose interruptions and reductions
w Improves QOL despite adverse events
w No perfect biomarkers exist
Sunil Verma et al., The Oncologist 2016; Harbeck et al., Ann Oncol 2016
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Ribociclib + Letrozole: MONALEESA-2
w Phase 3 w 668 women with ER+ MBC and no prior treatment for MBC w Randomized to letrozole + placebo versus letrozole +
ribociclib w Toxicity again mainly neutropenia w Led to FDA approval of combined ribociclib + AI
Hortobagyi et al., NEJM, November 2016
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Hortobagyi GN et al. N Engl J Med 2016;375:1738-1748
Ribociclib + Letrozole: MONALEESA-2
Hortobagyi et al., NEJM, November 2016
w After 18 months, PFS rate was 63.0% with letrozole + ribociclib and 42.2% with letrozole + placebo.
w Median PFS was 19.3 months-not reached in the ribociclib group and was 14.7 months in the placebo group.
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Pembrolizumab: Tissue Agnostic Approval
• Based on 149 patient across 5 trials, over half had colon cancer
• Questions remain: best test? IHC, MSI?
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OlympiAD: ASCO 2017 Plenary
w First completed phase III trial of PARP inhibition (olaparib) versus chemotherapy for patients with HER2-negative MBC and a germline BRCA mutation
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OlympiAD: ASCO 2017 Plenary
w Olaparib better than chemotherapy in BRCA-associated MBC
w ORR 59.9% w PFS 7 months, versus 4.2 months with chemo w Pending approval - First non-chemotherapy agent in
any kind of TNBC!
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Outline w Background:
• What is MBC • MBC treatment and biomarkers • Cancer genetics • Landscape of hereditary breast cancer • Clinical trial basics
w Recent updates in breast cancer care • Cell cycle inhibitors (palbociclib, ribociclib) • Pembrolizumab • PARP inhibitors
w Approaches under investigation • Immunotherapy • Targeted therapy • PARP inhibitors beyond olaparib, beyond BRCA!/2
w Expanded access programs w Quality of life for MBC survivors w Survival and prognosis
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Approaches under study w Far more than I can cover here!
w Immunotherapy: harness immune system to target cancer • PD1/PDL1 (nivolumab, pembrolizumab, atezolizumab) • CAR-T therapy
w Molecularly targeted therapy (genomically-directed)
w PARPi plus therapy
w PARPi in patients with mutations other than BRCA
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Immunotherapy in breast cancer:
Nanda et al., JCO, July 2016; Adams et al., presented at ASCO 2017
w KEYNOTE-012, Phase Ib trial of pembrolizumab • Pembrolizumab IV 10 mg/kg q2 weeks to patients with
advanced PD-L1 ≥ 1% TNBC + others • RR 18%
w KEYNOTE-086, Phase 2 of pembrolizumab 200mg IV q3 weeks in TNBC presented at ASCO 2017 by Dr. Sylvia Adams • 2nd line treatment • 4% ORR, some are durable • PFS 2 months • However, response rate 23% in 52 pts without prior
treatment
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Immunotherapy in breast cancer:
Nanda et al., JCO, July 2016
w For this and other immunotherapies, research ongoing, mostly in combinations with other immunotherapies, chemotherapy, radiation, targeted agents
w Immunotherapy in breast cancer sounds very appealing, but some limitations • Small minority of pts respond, though may have a
durable response • Toxicity – immune activation against normal tissues
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Tumor genomic sequencing w Certainly important
w Certainly becoming more common
w Some significant limitations: turnaround time, minority of pts have actionable mutations, even smaller minority then are able to receive the molecularly targeted agent matched to the mutation
w Some “basket” trials – NCI Match, ASCO TAPUR
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Cha
nge
in s
um o
f tar
get l
esio
n di
amet
er
(bes
t ass
essm
ent;
%)
20
–20
–70
–10
–30
10
0
–50
–40
–60
ER+ breast
Cervix Colon Lung Other** Ovary Endometrial Prostate Thyroid
TNBC
*
*
Best % change in tumor
Early clinical activity in a heavily pretreated patient group (median no. of priors=7)
Example of genomically targeted therapy Targeting cancers with an AKT1E17K mutation using an AKT inhibitor
Hyman et al., JCO May 2017; Slide courtesy of Dr. Lilllian Smyth
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PARP inhibitors
w Talazoparib
w Niraparib
w Olaparib / Rucaparib w Veliparib
Most potent
Least potent
• Potency less a/w enzyme inhibition and more associated with the ability to trap PARP on DNA at the site of ss breaks
• Potency does not necessarily correlate with clinical efficacy
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Talazoparib phase 2: ASCO 2017
w Talazoparib phase 2 data in heavily pretreated gBRCA1/2m pts with MBC - presented by Nicholas Turner at ASCO 2017
w ORR: 28% overall, 37% in pts with at least 3 prior chemotherapy lines, no prior platinum chemotherapy
w Median duration of response: 4.9mo w Increased activity with longer platinum-free interval
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Olaparib Expanded: PARPi beyond BRCA1/2 w Multicenter Phase II study, initiated by Nadine Tung and
colleagues at BIDMC/DF-HCC
w Phase 2 study of olaparib in pts with germline mutations in DNA repair genes other than BRCA1/2
w Based on the principle that if olaparib works through synthetic lethality due to DNA repair defect from BRCA1/2 mutation, it may have activity in the setting of other mutations that also confer DNA repair defects
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Outline w Background:
• What is MBC • MBC treatment and biomarkers • Cancer genetics • Landscape of hereditary breast cancer • Clinical trial basics
w Recent updates in breast cancer care • Cell cycle inhibitors (palbociclib, ribociclib) • Pembrolizumab • PARP inhibitors
w Approaches under investigation • Immunotherapy • Targeted therapy • PARP inhibitors beyond olaparib, beyond BRCA!/2
w Expanded access programs w Quality of life for MBC survivors w Survival and prognosis
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Expanded access programs
w Expanded access aka “compassionate use” aka using a drug that has not been approved by the FDA, not as part of a clinical trial
w Ultimately at the discretion of the drug company w Requires that:
• Pt and physician both willing to participate • Physician determines that there is no comparable/satisfactory
alternative • Pt unable to get the drug any other way • FDA decides sufficient safety and effectiveness exists • FDA decides giving the pt drug will not interfere with trials to support
marketing approval • Physician has to submit a clinical protocol that is ultimately
approved
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QOL: symptom reporting
w Ethan Basch and colleagues, ASCO 2017 Plenary + JAMA publication
Basch et al., JAMA June 2017
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QOL: bone pain & bisphosphonates
w Zoledronic acid or denosumab are given to reduce skeletal related events including bone pain and fracture
w Zoledronic acid may be given less frequently without compromising efficacy
w NCCN: annually x 12, then q12 weeks
Hortobagyi et al., JAMA Oncology 2017
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Prognosis
Mariotto et al., Cancer Epidemiology, Biomarkers & Prevention, June 2017
w Median ~2-3 years
w 5-year relative survival rate ~22% (ACS) but per Mariotto et al., 2-fold increase from 18% to 36%
w 11% of women diagnosed between 2000-2004 <age 64 lived 10+ years
w Younger women diagnosed with de novo MBC have a higher survival than women diagnosed older
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Prognosis: WIDE variation
Mariotto et al., Cancer Epidemiology, Biomarkers & Prevention, June 2017
• Patient – Age – Comorbidities – Personal preferences/wishes regarding cancer-
directed treatment or palliative care
• Tumor – Subtype – Responsiveness to therapy – Extent of organ involvement
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Prevalence of MBC
Mariotto et al., Cancer Epidemiology, Biomarkers & Prevention, June 2017
w Patients with MBC are living longer => w There are more and more pts with MBC out there
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Patients & Families
Acknowledgments
Mentors, Colleagues: Susan Domchek Kara Maxwell Katherine Nathanson Genetic counselors: Amanda Brandt Dana Clark Jessica Long Danielle McKenna Jacqueline Powers Collaborators: Mark Robson Nadine Tung
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Questions?
