breast cancer: a model for treating cancer in the 21st...
TRANSCRIPT
Lowell E. Schnipper,M.D.
Theodore and Evelyn Berenson Distinguished
Professor of Medicine in the Field of Oncology
Harvard Medical School
Chief, emeritus, Hematology/Oncology Division
Beth Israel Deaconess Medical Center
Associate Director, Dana Farber Harvard Cancer Center
Breast Cancer: a model for
treating
cancer in the 21st century
Disclosures
UpToDate Oncology-Co-Editor-in-
Chief
Incidence: Breast Cancer
• Worldwide: 1.7M cases/year; 566,000
deaths/year (2012)
• USA: 266,000 cases/year; 40,000
deaths/year
• 65% ER positive
• 15-20% Her 2 amplified
❖Prevention
❖Risk Reduction
❖Diagnosis/Staging
❖Management: adjuvant and
metastatic
Understanding Contemporary Approaches to Cancer in 2019
Screening: moving towards
risk adjusted screening
Most Common Cancers Among
Gulf Coast NationalsLancet Oncology Volume 16, Issue 5, Pages e246-e257
Most Common Cancers Among GCC Nationals
Global Burden of Cancer
Tumor Type Risk Reduction Prevention
Colorectal Cancer Sig, colonoscopy, FIT, Stool DNA* (not yet-USPTF, ACS-yes)
Polypectomy, NSAIDs
Cervical Cancer Cytology, HPV DNA HPV Vaccine
Hepatocellular CA Treat Hep C Vaccine for Hep B
Breast CA Mammography/MRI/Genetic analyses
SERMs/Surgery
Lung CA Spiral CT screen Eliminate tobacco use
Skin Cancers Reduce UV damage Reduce UV damage
Prostate Cancer PSA Screen Chemo-prevention: 5 alpha reductase inhibitors
Gastric Cancer Treat H. pylori Treat H. pylori
Early Diagnosis & Prevention: Approaches that Can Save
Lives
Screening for Cancer: Advice for High-Value
Care from the ACP (Ann Intern Med 2015;162:718-725)
HARMS
BENEFITS
Mortality benefit/added morbidity/cost
impact
•Over diagnosis: we know that some
tumors will never progress to become
invasive or life threatening
•Over treatment of small tumors that will
never be life threatening
•False negatives
•Psychological harms
•Cost inefficient
Reduce mortality
Reduce morbidity
• Risk Stratification-FHx, Genomics (NCCN.org
for testing criteria)
• Risk Reduction-identify groups for
screening
• Early Detection
Improved likelihood of Cure
Screening for Cancer
A 58 year old woman
-MMG: an area of asymmetry in the upper outer quadrant of the
left breast
-US- 2.7cm hypoechoic mass
-core biopsy: invasive ductal carcinoma, grade III, with lympho-
vascular invasion
-immunohistochemistry: ER-, PR-, Her 2 - (Triple negative)
FHX: positive for mother and sister with breast cancer: gene
testing negative for BRCA 1,2 mutations
After partial mastectomy and sentinel node biopsy she is found to
have pT2pN0Mx disease and is treated with radiation therapy and
chemotherapy.
What is your plan for follow up surveillance?
Question: Breast Cancer Screening
A. Genetic Testing with a broader panel of
genes
B. If a mutation carrier, surveillance should
include bi-annual physical exam, bilateral
mammography and breast MRI alternating at 6
month intervals
C. If no mutation carrier, surveillance should
include annual MMG and MRI
D. All of the above
Breast Cancer Risk Assessmentuse an appropriate tool, i.e., Gail Model or BRAT
• Predisposition genes: BRCA 1,2, p53, AT, CHK2, PALB2, TP53,
PTEN
• Personal history: invasive CA or DCIS
• Family history (maternal or paternal) of breast or ovarian cancer
• History of thoracic radiation age <30
• Lobular carcinoma in situ (LCIS), atypical ductal hyperplasia or
atypical lobular hyperplasia on breast biopsy
• Prior breast biopsy
• Hormonal risk factors: early age at menarche, nulliparity, later age at
first birth, late menopause and >5 years of combined
estrogen/progesterone hormone replacement therapy
Dueling Screening Recommendations
Normal Risk
Experts Cannot Agree!
• USPSTF: against teaching BSE, insufficient evidence for CBE, Digital mammography over film, MRI– Age 39-49: against routine mammography, assess individual risk
and discuss benefits/harms– Age 50-74: biennial mammography– Age >75: insufficient evidence to assess
• NCCN: – Age 20-39: CBE every 1-3 years, “Breast awareness”– Age > 40: Annual CBE, annual mammogram, “Breast
awareness”
• ACS: CBE at least every 3 years age 20-39
• annual mammogram + CBE age 40 on,
• discuss BSE as an option but women should know their breasts and report changes
High Risk Screening Guidelines
NCCN• Women > age 35 with 5 yr risk > 1.7%: Annual mammogram, CBE
every 6-12 months, breast awareness, consider risk reduction with a SERM (Tamoxifen or Raloxifen)
• Lifetime risk >20% based on models largely dependent on family history: Annual mammogram and CBE every 6-12 months starting age 30, breast awareness, consider risk reduction, consider annual MRI age 30 on
• Prior Thoracic Radiation
– Age <25: Annual CBE and “Breast awareness”– Age >25: Annual mammogram, CBE every 6-12 months 8-10 years
following radiation or age 25 (whichever LAST), annual MRI, “breast awareness”
Principles in Diagnosis and Treatment
Of Cancer
Early Stage Cancer
-Diagnosis: Biopsy essential, IHC, Genomics
-Staging: assess tumor burden: biopsy; TNM staging (PET/CT, CT)
-Local-Regional Cancer: Stages I-III potentially curableAnd when appropriate, systemic therapy as adjuvant
Conventional Chemotherapy
Targeted therapy: hormone receptors, or genetic alterations exposing a target
*Immunotherapy: adoptive, immunomodulatory, vaccines (*experimental)
Metastatic Cancer: incurable, palliation often possible-Conventional chemotherapy
-Targeted therapy:
-hormone receptors, or genetic alterations exposing a target
Immunotherapy: adoptive, immunomodulatory, vaccine
-Symptom management: pain, nausea/emesis
-Breaking bad news: hope and reality
Breast Cancer in a Young woman
» 43 yo woman, pre-menopausal, G2P2Ab0, because she palpated a right breast mass
» Strong family hx; menarche 16; no OCP’s, first childbirth at age 33
» Physician’s exam confirms 1.5 cm mass, no nodal enlargement
» Mammo demonstrates linear microcalcs, u/s confirms presence of a solid mass
» Core biopsy confirms IDC (infiltrating ductal adenocarcinoma), extensive DCIS
» Grade III, ER(-), ErbB2 (Her2/neu) 3+ pos.
No formal staging evaluation necessary
» Wide excision; clean margins
» no positive axillary nodes
Copyrights apply
Image Guided Biopsies:
directed by the clinical dataGeneral rule: never treat without tissue diagnosis
Diagnosis- Principles
» Want least invasive method to make an accurate diagnosis
» In most cases in USA core needle biopsy should be the procedure of choice, at times FNA is acceptable
» If pathology results do not correlate with clinical suspicion, surgical biopsy should be performed
Staging Evaluation-a surrogate for tumor burden
The TNM staging system =tumor, node, metastasis
» -correlates with retrospective survival data
» -almost all solid tumors require regional node assessments
» Know when to use systemic staging and when not:
» -local regional breast/prostate cancers-non-symptomatic (no extensive staging)
» -notoriously aggressive diseases: NSCLC, kidney cancer, melanoma require systemic staging
» This relates to Quality of Care and Cost!
Sentinel Lymph Node Biopsy
• 100% concordance between positive sentinel node biopsy (discovered sentinel node), and positive axillary dissection
• 11% false negative (sentinel node found to be negative for tumor, 13/114 w/+ axillary dissection)
• False neg rate varied with surgeon
» Krag et al., NEJM 339:941,1998
Staging: Lung, Colorectal Breast Cancers
» NSCLC
» CT or PET/CT scan: assess for nodal involvement and distant disease
» Mediastinal node sampling for localized lesion
» Adjuvant therapy or not
» CRC
» CT scan ABD/PELVIS
» MR liver if CT result uncertain
» If no distant disease:
» Surgery: removal of at least 16 nodes
» Adjuvant therapy or not?
Breast Cancer
Metastatic work up
only useful for
clinical stage III/IV or
lower stage disease
with worrisome
symptoms
Copyrights apply
Mayo Clinic Newsletter
https://www.mayoclinic.org/tests-procedures/pet-
scan/multimedia/pet-plus-ct/img-20005900
Imaging a Lung Cancer
Local Therapy: Breast Conservationand Mastectomy do not Differ in Overall Survival
• MRM and partial mastectomy followed by radiation: no difference in DFS (local or distant) or overall survival (Early Breast Cancer Trialists' Collaborative Group (EBCTCG) Lancet. 2005;366(9503):2087).
• Decision based on patient choice, anatomic issues such as EIC, clean margins
• Current trials aimed at reducing xrt exposure, i.e., avoiding regional radiation; small Node negative /ER+ cancers in women over 70
Oncologist’s Challenge is
eradicate micro-metastatic disease:
cancer is often metastatic before it can be seen or
cause problems
• Following surgery+/- XRT
• Cytotoxic chemotherapy
• Targeted therapy (hormonal,
small molecules)
• Immune therapies
• ***importance of biomarkers
Breast Cancer in a Young woman» 43 yo woman, pre-menopausal,
G2P2Ab0, because she palpated a right breast mass
» Physician’s exam confirms 1.5 cm mass, no nodal enlargement
» Mammo demonstrates linear microcalcs, u/s confirms presence of a solid mass
» Core biopsy confirms IDC (infiltrating ductal adenoarcinoma), extensive DCIS
» Grade II, ER+/PR+/Her 2 (-)
» No formal staging evaluation necessary
Wide excision; clean margins
» no positive axillary nodes
» Should she receive adjuvant therapy with:
» A. chemotherapy
» B. endocrine therapy
» C. both
» D. neither
Assess Your (lung/breast/crc) Patient’s Risk for Recurrence
(distant or local):
in addition to anatomic stage
Pathology:
• Differentiation, vascular invasion
• Tumor size, nodal involvement?
• Genomic analyses: for recurrence risk
• -oncotype DX - 21 gene assay
• -mammaprint - 70 gene assay
• -Targeted gene sequences: EGFR, EML4/alk, BRCA 1,2,
ATM, CHEK 2, etc
• Biomarkers: PDL-1, PD-1, ER, PR
DeMichele A et al. N Engl J Med 2017;377:2287-2289.
Breast Cancer — Many Tumor Types, Many Outcomes.Breast CA: many tumor types/many outcomes
Gene Expression and Benefit of
Chemotherapy in Women with Node-
Negative, Estrogen Receptor Positive
Breast Cancer
•Paik, S., Tang, G., Shak, S, et al.
•Journal Of Clinical Oncology
•24:3726-3734, 2006
.. J Clin Oncol; 24:3726-3734, 2006
Kaplan-Meier plots for distant recurrence comparing treatment with tamoxifen (Tam) alone versus treatment with tamoxifen plus
chemotherapy (Tam + chemo)
All Pts Low RS
Int RSHigh RS
The Cancer Process: Targets
ReceptorHormone or
Growth Factor
NucleusDNA
RNA
Growth
Metastasis
AngiogenesisLung Ca, Colorectal
Kidney CA
InhibitorI (bcr/abl)
Gleevec(CML)
Or Dasatinib
I
Anti-sense
I
ProteinErlotinib: lung
ca; works on
mutant EGFR
Crizotinib-
eml4-alk
NSCLC
ER inhibitor-
breast
AR inhibitor-Ca P
Benefits of Ovarian Suppression in Pre-menopausal
Women With ER+ Br CA: SOFT and TEXT Trials
Francis, et al., N Engl J Med 2015; 372:436-446
Note:
improvement with OS plus Tam, and further improvement with OS plus Exemestane (AI) when c/w Tamoxifen alone
And And..if she were a 43 y.o. woman with
ER+/PR+/Her 2 amplified breast cancer?
Non-amplifiedAmplified
Perfect clinical scenario for adjuvant treatment with
Her 2 targeted therapy and chemotherapy
And…if she recurs systemically?
Goal is Palliation, no longer cure
• Biopsy the tumor: (solid or liquid biopsy?)
• -confirm breast ca: phenotype ER/PR/Her
2, mutations, NGS?
-ER/PR +: endocrine therapy with a CDK
4/6(palbociclib) inhibitor > ChemoRx
-Her2+: Her 2 directed therapy with ChemoRx
-If this were a BRCA 1 or BRCA 2 associated
cancer-PARPi (polyADP ribose polymerase inhibitor)
Breast Cancer in a Young woman:progressive metastatic disease
» 43 yo woman, pre-menopausal, G2P2Ab0, because she palpated a right breast mass
» Core biopsy confirms IDC (infiltrating ductal adenocarcinoma), extensive DCIS
» Grade III, ER(-), ErbB2 (Her2/neu) 3+ pos.
» Treated: partial mastectomy, radiation, adjuvant chemotherapy and targeted therapy, long term anti-estrogen therapy
» 3 years later: admitted with intractable back pain and weakness
This picture could be NSCLC,
CRC, prostate cancer, kidney
cancer
History is essential, weakness +/-, duration, intensity of pain, complete PE including neurological/? Cord compression
A. Analgesia: NSAIDS, opioids
B. Prophylactic stabilization (hip)
C. Radiation
D. Systemic cancer –directed therapy
E. Bone directed therapy:
Zoledronic acid/denosumab
F. All the above
Which of the following is the appropriate therapy?
Finn RS et al. N Engl J Med 2016;375:1925-1936.
Progression-free Survival: Letrozole +/- Palbociclib
Endocrine Resistance in MBC
Upregulation cyclin dependent kinases (CDKs 4/6)
Phosphorylates Rb: release it’s inhibition of cell cycle progression
Inhibition obviates a resistance pathway
Targeted Therapies
• Breast Cancer: Estrogen, progesterone
receptors + or -? ; Her 2 –amplified or not?
• NSCLC: EGFR mutations, EML4/alk
translocation, ROS, Met gene amplification
• Prostate Cancer: anti-androgens
(castration, inhibitors of the AR)
NSCLC in a Young Man:Targeted Therapy-inhibits a growth promoting gene that is
always “on”
Inevitably, resistance develops: develop new agents that
inhibit the “resistant target”
• Fever, cough, PNA
• CXR: mass LUL, CT confirms ipsilateral
mediastinal lymphadenopathy, bone scan positive-
spine
• Biopsy: NSCLC
• EGFR mutation (T790M)
• Newest targeted therapy: osimertinib (an improvement over
first line therapy-erlotinib)
Osimertinib Improves Progression-free Survival and Overall Survival in EGFR
Mutant NSCLC
Soria J-C et al. N Engl J Med 2018;378:113-125
Major progress in a previously untreatable disease!
Immune Checkpoint Inhibitors: revolutionizing
cancer therapyCancers known to be responsive to immune therapies (kidney
cancers, melanoma), or have high mutation burden (TMB), e.g.,
NSCLC, some colorectal cancers, triple negative breast cancers
Immune Checkpoint
Inhibitors:
high response rate when
biomarker (PD-1, PDL-1,
CTLA-4) present
Some long term survivors
Effect of Inhibition the PD-1 Pathway
For symptom relief while on
cancer-directed therapy
Or
If things don’t turn out well
Palliative Care and the Oncology Patient
The American Society for Clinical Oncology (ASCO) recommends considering the combination of palliative care with standard oncology care early in the course of treatment for patients with metastatic cancer and/or a high symptom burden
When? as a patient's cancer becomes advanced; ideally
within 8 weeks after diagnosis
Care should be available both in and outpatient
WHO Opioid Ladder
Remember: psychosocial support for patient and
family
Temel JS et al. N Engl J Med 2010;363:733-742.
Early Palliative Care:Kaplan–Meier Estimates of Survival According to Study
Group.
Useful Websites
CRICO/Risk Management Foundation
– http://www.rmf.harvard.edu
– Click on Guidelines/Algorithms and then Breast Cancer
– National Comprehensive Cancer Network
– http://www.nccn.org
– National Cancer Institute: nci.gov
https://www.asco.org/practice-guidelines/cancer-care.../palliative-care-oncology