Breast and Ovarian Cancers Learning Objectives Katherine D. Crew

Katherine D. Crew
Breast and Ovarian
Cancers
Learning Objectives
• Epidemiology and Risk Factors
• Cancer Screening
Katherine D. Crew, MD MS
Division of Hematology/Oncology
Columbia University
College of Physicians and Surgeons
• Staging, Prognosis, and Treatment
Epidemiology
Cancer Trends
Siegel et al. CA:Cancer J Clin 2012
Incidence
Mortality
Case #1
• A healthy 27-year-old white woman of Ashkenazi
Jewish descent comes to establish care. Her age at
first menstrual period was 13 and she has no
children. She has been on birth control pills for
several years. She notes a family history of a mother
with ovarian cancer at age 40 and a maternal
grandmother with breast cancer in her 40s. She has
a normal clinical breast exam.
• She undergoes genetic testing and is found to have a
deleterious mutation in the BRCA2 gene.
Siegel et al. CA:Cancer J Clin 2012
Incidence
Mortality
Question #1
• Which of the following are appropriate
for screening and prevention?
a) Annual mammography and breast MRI
b) Risk-reducing surgeries (mastectomies,
BSO)
c) Tamoxifen for chemoprevention
d) All of the above
Katherine D. Crew
Hereditary Syndromes
• Breast-Ovarian Cancer Syndrome
– DNA repair
– BRCA1 (17q12)
– BRCA2 (13q112)
• Hereditary Non-polyposis Colorectal Cancer
Syndrome (HNPCC, Lynch II)
– DNA mismatch repair
– MSH2, MLH1, MSH6
Indications for Genetic Testing
USPSTF, Ann Intern Med 2005; Bellcross et al. CEBP 2013
• Non-Ashkenazi Jewish:
– 2 first-degree relative with breast cancer, 1 diagnosed at
age≤50
– 3 or more first/second-degree relatives with breast cancer
– Both breast and ovarian cancer among first/second-degree
relatives
– First-degree relative with bilateral breast cancer
– 2 or more first/second-degree relatives with ovarian cancer
– First/second-degree relative with both breast and ovarian
cancer
– Male relative with breast cancer
BRCA1/BRCA2 Genetic Testing
Risch et al. JNCI 2006; Pal et al. Cancer 2005;
Nelson et al. Ann Intern Med 2005; Chen et al. JCO 2007
• Account for 2-7% of breast cancers, 10-15%
of ovarian cancers
• Prevalence is 1:400 in the general population,
1:40 in Ashkenazi Jews
• Lifetime risk of breast cancer 40-60%,
ovarian cancer 20-40%
Ovarian Cancer Screening
• Serum tumor markers
• Pelvic examination
• Transvaginal ultrasound
• Serum proteomics
• Ashkenazi Jewish: any first/second-degree relatives with
breast or ovarian cancer
CA-125 Tumor Associated Antigen
• Membrane glycoprotein
• Elevated in 80% of epithelial ovarian tumors
(primarily serous)
• Reliable index of response to therapy or
progression of disease
• Threshold is 35 U/ml
– Sensitivity 78% Specificity 77%
– NPV 72-82%
Elevated CA-125 Differential Diagnosis
Gynecologic Tumors
Epithelial ovarian cancer
Sertoli-Leydig tumors
Granulosa tumors
Fallopian tube carcinomas
Endometrial carcinomas
Endocervical carcinomas
Benign Gynecologic Conditions
Endometriosis
Adenomyosis
Leiomyomas
Pregnancy
Ectopic pregnancy
Pelvic inflammatory disease
Nongynecologic Tumors
Pancreatic carcinoma
Lung carcinoma
Breast carcinoma
Colon carcinoma
Lymphoma
Nongynecologic Conditions
Pancreatitis
Cirrhosis
Laparotomy
Peritonitis
Tuberculosis
Congestive heart failure
Katherine D. Crew
Ovarian Cancer Screening
Signs and Symptoms
Jacobs et al. Lancet 1999
• Randomized controlled trial of sequential CA125/TVUS (n=10,958) vs no screening (n=10,977)
• 468 elevated CA-125, 29 referred after TVUS (23 FP,
6 cancers)
– PPV 21%
• 20 cancers in control group vs 10 additional cancers
in screened group
• Survival higher in screened group (73 months vs 42
months) (p=0.01)
• Number of deaths similar between groups (18
controls vs 9 screened) (RR 2, 0.78-5.1)
•
•
•
•
•
•
Abdominal mass
Pelvic mass
Pleural effussion
Ascites
Ventral hernia
Inguinal adenopathy
Germ cell tumors
Sex cord stromal tumors
Metastatic
Serous
Mucinous
Endometrioid
Clear cell
Transitional cell
Undifferentiated
Dysgerminoma
Yolk sac tumor (EST)
Immature teratoma
Mature teratoma
Embryonal carcinoma
Choriocarcinoma
Gonadoblastoma
Granulosa cell tumor
Sertoli-stromal cell tumors
Steroid cell tumors
Gynandroblastoma
Numerous
Abdominal pain
Early satiety
Nausea and vomiting
Abdominal distension
Constipation
Vaginal bleeding
Dyspnea
FIGO Staging
Classification
Epithelial tumors
•
•
•
•
•
•
•
Stage I
IA
Growth limited to the ovaries
One ovary, no ascites, no tumor on the surface with capsule intact
IB
Both ovary, no ascites, no tumor on the surface with capsule intact
IC
Stage IA or IB with tumor on the ovarian surface, capsule ruptured or
ascites with malignant cells
Stage II
IIA
Growth involving one or both ovaries with pelvic extension
Extension to the uterus and/or tubes
IIB
Extension to other pelvic tissues
IIC
Stage IIA or IIB with tumor on the ovarian surface, capsule ruptured or
ascites with malignant cells
Stage III
IIIA
Peritoneal implants outside the pelvis, positive
retroperitoneal or inguinal nodes, superficial liver
metastases
Microscopic seeding of abdominal peritoneum
IIIB
Abdominal implants < 2 cm in diameter, nodes negative
IIIC
Abdominal implants > 2 cm in diameter, positive retroperitoneal or inguinal
nodes
Stage IV
Distant metastasis, parenchymal liver disease, cytologically
pleural effusion
Stage Distribution
Survival by Stage
Siegel et al. CA:Cancer J Clin 2012
Siegel et al. CA:Cancer J Clin 2012
Katherine D. Crew
Current Standard of Care
• Early stage disease
– Surgery
– Potentially chemotherapy
• Advanced stage disease
– Surgery
– Chemotherapy
Early Stage Ovarian Cancer
• Surgery
– Diagnosis and staging
– TAH/BSO, lymphadenectomy,
omentectomy, peritoneal biopsies
• Adjuvant treatment
– Stage IA, IB (grade 1 and 2)-observation
– Stage IC, any grade 3-chemotherapy
Surgical Cytoreduction
Advanced Stage Disease
• Surgery
– Surgical cytoreduction
• Adjuvant chemotherapy
– Platinum based therapy
– Intraperitoneal chemotherapy
• Possible consolidation
therapy
Based on GOG 52 and 97
•
•
Optimal-residual disease < 1 cm
Suboptimal-residual disease > 1 cm
Adjuvant Chemotherapy
Adjuvant Chemotherapy
McGuire et al. N Engl J Med 1996
Ozols et al. J Clin Oncol 2003
• Cyclophosphamide/cisplatin vs
cisplatin/paclitaxel
• Cisplatin/paclitaxel vs carboplatin/paclitaxel
Katherine D. Crew
Intraperitoneal Chemotherapy
Trial
Agents
Recurrent Ovarian Cancer
Outcome
SWOG 8501
Cis/Cyclophosphamide (IV) vs
Cis (IP)/Cyclophosphamide
Improved survival with IP
(41 vs 49 months)
GOG 114
Cis/taxol (IV) vs
Carbo (AUC 9)/taxol/cis (IP)
Improved PFS and
borderline OS with IP (63 vs
52 months)
Severe toxicity
GOG 172
Cis/taxol vs
Cis/taxol (IP)
Improved OS with IP
(66 vs 50 months)
• 70-80% of patients respond to primary
therapy
• 80% of patients with stage III/IV tumors
ultimately relapse
Recurrent Ovarian Cancer
Treatment of Recurrence
• Cytotoxic agents
– Carboplatin, cisplatin, topotecn, liposomal
doxorubicin, gemcitabine, etoposide, vinorelbine,
docetaxel, cyclophosphamide, doxorubicin,
trabectadin, pemetrexed
• Hormonal agents
– Progestins, GnRH agonists, SERMs
• Targeted therapy
– Bevacizumab, PARP inhibitors, HER2/neu
inhibitors, EGFR inhibitors, mTOR inhibitors, other
VEGF inhibitors
Control Disease: SD, TTP
GOALS
Maintain
Quality of Life
Extend Survival
Selection of Treatment
•
•
•
•
•
•
•
Type and number of prior regimens
Prior toxicity
Current symptoms and disease volume
Performance status/co-morbidities
Treatment free interval
Social/quality of life
Schedule
Platinum Free Interval
P
R
E
V
I
O
U
S
T
R
E
A
T
M
E
N
T
Time to recurrence, months
0
3
6
12
18
24
Refractory
Resistant
Sensitive
Very sensitive
Katherine D. Crew
Ovarian Cancer: Summary
Case #2: Breast Cancer
• Surgical therapy should consist of
complete staging and cytoreduction
• Standard front line therapy should
contain platinum and taxane
• Treatment of relapsed ovarian cancer is
based on patient specific variables with
the goal of extending survival and
maximizing quality of life
• 49-year-old African American woman with suspicious
calcifications on a screening mammogram.
• Breast biopsy revealed
invasive ductal
carcinoma. She is s/p
lumpectomy → poorly
differentiated, 1.8 cm,
negative lymph nodes,
ER/PR+, HER2-.
Risk Factors for Breast Cancer
Singletary, Ann Surg 2003
Question #2: Breast Cancer
• Which of the following factors does
NOT affect breast cancer prognosis?
a)
b)
c)
d)
Age
Family history
Tumor hormone receptor status
Tumor molecular profiling
Breast Cancer Screening
• Self Breast Examination
• Clinical Breast Examination
Risk Factor
Relative Risk
Alcohol intake (>2 drinks/day)
Body mass index
HRT use (>5 years)
1.2
1.2
1.3
Early age of first menstrual period (<12 years)
Late menopause (>55 years)
Age at first birth (>30 years or no children)
Current age (≥ 65 years)
1.3
1.2-1.5
1.7-1.9
5.8
Benign breast disease
Prior breast cancer
5-20
6.8
Family history
2nd degree relative with breast cancer
1st degree relative, age>50
1st degree relative, age<50
1.5
1.8
3.3
BRCA1/2 mutation carrier
15-200
Breast Cancer Staging
• Stage 0: Non-invasive or ductal carcinoma in situ
(DCIS)
• Stage I: Tumor < 2 cm, negative lymph nodes
• Mammogram
• Breast Ultrasound
• Breast MRI
• Stage II: Tumor 2-5 cm or 1-3 positive lymph nodes
• Stage III: Tumor > 5 cm or ≥ 4 positive lymph nodes
• Stage IV: Distant metastases
Katherine D. Crew
Breast Cancer Treatment
Local Therapy
Systemic Therapy
• Surgery
• Radiation Therapy
• Chemotherapy
• Hormonal therapy
• Biologic therapy
Choice of Adjuvant Therapy
EVALUATION OF RISK
OF RECURRENCE
CHOICE
OF
ADJUVANT
THERAPY
CONSIDERATION OF
ACUTE AND LATE
SIDE EFFECTS
PATIENT'S PREFERENCE
Prognostic Factors
Patient-Related
Factors
Tumor-Related
Factors
•
•
•
•
•
•
•
•
•
Adjuvant Systemic Therapy
Age
Race
Obesity
Lymph node status
Tumor size
Tumor grade
Hormone receptor status
HER2 expression
Tumor molecular profiling
(Oncotype DX, MammaPrint)
NODE
NEGATIVE
NODE
POSITIVE
ESTROGEN
RECEPTOR
POSITIVE
Hormonal
Therapy +/Chemotherapy
Chemotherapy +
Hormonal
Therapy
ESTROGEN
RECEPTOR
NEGATIVE
Chemotherapy
Chemotherapy
Oncotype DX
Paik et al. NEJM 2004
Chemotherapy
Chemotherapy
Drugs
Benefits
Adriamycin
(AC)
20-30% ↓ in
recurrence risk
Risks
Cardiac toxicity
Cyclophosphamide
Acute leukemia,
Ovarian failure
Taxanes (T)
Neuropathy
Katherine D. Crew
Trastuzumab
Trastuzumab
Romond et al. NEJM 2005; Piccart-Gebhart et al. NEJM 2005
• HER2/neu
overexpression
in 20-25% breast
cancer
• Benefits:
~50% ↓ in
recurrence risk
AC→TH
AC→T
• Humanized mAb
directed against
the extracellular
domain of HER2
• Risks: Cardiac
toxicity
Recurrence Ratio=0.45
Hormonal Therapy
Baum et al. Lancet 2002; Goss et al. NEJM 2003; Coombes et al. NEJM 2004
Hormonal Therapy
Hormonal
Agents
Benefits
Risks
Tamoxifen (premenopausal)
50% ↓ in
recurrence risk
Uterine cancer
Clot formation
Aromatase inhibitor
(postmenopausal)
- anastrozole (Arimidex)
- letrozole (Femara)
- exemestane (Aromasin)
60-65% ↓ in
recurrence risk
Osteoporosis
Joint symptoms
↑ Cholesterol
Conclusions
• Cancer screening has led to improvements in
survival.
• A proper staging work-up is essential for prognosis
and treatment management.
• Understanding of prognostic factors and long-term
side effects of treatments to guide follow-up care
in cancer survivors.
Thank You!