Breast Cancer: a model for treating cancer in the 21st...

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