Transcript Ovarian Cancer

Ovarian Cancer
A LITTLE HISTORY, A LITTLE SURGERY,
A LITTLE GENETICS
Jerry Perez, M.D.
United States Statistics


In 2015

22,280 new cases

14,240 deaths
Lifetime risk

1 in 75 women will develop Ovarian Cancer

1 in 100 women will die of ovarian cancer

8th most common cause of Cancer among women

5th most common cause of cancer death
SEER Cancer Statistics Factsheets: Ovary Cancer.
National Cancer Institute. Bethesda, MD
Ovarian Development
Three main cell types of ovary: Coelomic epithelium, Germ Cells, Sex Cords
Types of Ovarian Cancer




Germ Cell Tumors

Cells that will become the eggs of the ovary

When fertilized become embryos

Think stem cells
Sex Cord Stromal Cell Tumors

Derived from the mesoderm

Produce hormones that support the eggs
Epithelial Cell Tumors

Outer coating of the ovary

Gets injured every month with ovulation
Each can be benign or malignant
Germ Cell Tumors

Benign and malignant account for 20% of all
ovarian neoplasms, only 3-5% are malignant.

Benign version is the Mature Teratoma

Little monster

Contains all germ cell layers


Hair, teeth, sebum, bone, neural tissue most common,
eyes not uncommon
Thyroid Tissue Stoma Ovarii
Teratoma Imaging
Malignant Germ Cell Tumors

Rare tumor accounting for 5% of ovarian Cancers

Usually girls and young women peak incidence is 13 to 20 years of
age.

Good prognosis with overall survival of 93%


Most retain normal menstrual cycles and fertility rates.
Think pregnancy

Rapidly growing

Tumor markers: BHCG, AFP, LDH,

Treatment: Fertility sparing cyto-reductive surgery

Chemotherapy; Bleomycin, Etoposide, Cisplatin

Lance Armstrong Tumor
Malignant Germ Cell Tumors
13 y/o with a Bhcg of 1359, LDH 4682, Final path: 32 cm missed germ cell tumor 80% dysgerminoma
And 20 % Yolk Sac tumor
Sex Cord Stromal Cell Tumors

Comprised of granulosa cel, theca cells, sertoli cells and Leydig
cells, pure or in any combination.

Benign or malignant

Granulosa Cell Tumors Adult (peak 50 -55 Y/O) or Juvenelle

Secrete estrogen so precocious puberty in prepubetal girls and
hyperestrogen symptoms in menopausal women. Menstrual irregularities
and breast enlargement


25% have AIN and 5% have endometrial cancer
Sertoli-Leydig Cells

AKA androblastomas

Testosterone Virilzation
Virilization
Epithelial Cell Tumors

Most Common

Arise from the outer layer of the ovary or the epithelium

Malignant or benign

Benign mostly cystic with a normal or low CA-125

Malignant mostly complex often with an elevated CA-125
Benign
Malignant
Epithelial Ovarian Cancer

Represent 90% of ovarian cancers

50% occur in women over the age of 65

Ethnically Diverse

Dramatic rise in incidence at age 55

Most common cancer after breast cancer in women over 40 years
of age particularly in developed countries
Ovarian Cancer by Age
Median age of diagnosis is 63. Median age of death is 70
SEER 2009-2013,
http://seer.cancer.gov/statfacts/
html/ovary.html
Epithelial Ovarian Cancer Survival by Stage
Stage
Relative 5-Year Survival Rate
I
90%
IA
94%
IB
92%
IC
85%
II
70%
IIA
78%
IIB
73%
III
39%
IIIA
59%
IIIB
52%
IIIC
39%
IV
17%
Catch it early get a cure
Seer Data Base Jan. 2014
Ovarian Cancer Stage and Screening

51% of ovarian cancer patients present with stage 3. and 15 %
present with stage 4. Therefore 66% of patients present with a
horrible prognosis.

Screening: affordable, reproducible, reliable way to detect
pathology (in an asymptomatic patient) at a stage in which
treatment will affect the outcome. (eg: Pap, Mammogram,
colonoscopy)
 For
ovarian cancer there is no reliable
way of screening.
 Silent Killer
Metastasis in Ovarian Cancer

Seeding vs. 3D Growth (Direct extension)

Early spread via peritoneal fluid delivery and implantation
Ovarian Cancer Metastasis
Omentum
Normal
Omentum with Tumor
CA-125

Glycoprotein that is measured from a blood test.

Tumor marker

Only 50% of stage I ovarian cancers will have an elevated CA-125

Non-specific: coelomic epithelium irritation increases CA-125

Endometriosis, diverticulitis, pregnancy, fibroid uterus, peritonitis, Ascities

Does not correlate with volume of disease

Study of 78,216 women randomized to either yearly CA-125 and
pelvic ultrasound versus routine exam showed no survival benefit.
History Ovarian Cancer Treatment

Prior to the 1955 diagnosis to death was 6 months

Chemotherapy discovered

Combination chemotherapy in 1978

Cisplatin approved

Oral Contraceptives found to cut Ovarian Ca risk 1981

Mid 1980s CA-125 discovered

1989 Carboplatin Approved

1992 Taxanes Emerge

Mid-1990s BRCA 1 and BRCA 2

2005 Decoding the Ovarian Cancer Genome

2006 Ovarian Cancer begins in the fallopian tubes

2006 IP Chemotherapy begins

2010 Neo-adjuvant chemotherapy

2010 Bevacizumab approved
Cancerprogress.net
History of Ovarian Cancer Treatment

World War I : Mustard gas invented by Germans . Used in Bari Italy raid with
over 1,000 exposed.

Sr. Francis Alexander performed autopsies showed profound lymphoid and myeloid
suppression. Fast growing cells simply stopped growing.

Too volatile for experimentation so change a nitrogen molecule for sulfur and get
Alkeran (Melphalan) the first chemotherapy. First used for lymphoma Multiple side
effects.
Combination Chemotherapy
Single agent chemotherapy : short lived responses less than 2 years
 TB treatment expanded to multidrug therapy



Alkaran and Cytoxan
1978 Cisplatin approved

Interferes with DNA replication

Causes intrastrand crosslinking with purine bases
Side effects

Renal insufficiency and failure

Hair loss

Hearing Loss

Nausea and Vomiting (one of the most emetogenic agents known)

Hypocalcemia and hypomagnesaemia
History of ovarian Cancer
Treatment


Mid 1980s Oral contraceptive pills found to decrease the risk of
ovarian cancer

Repetitive injury theory

Women, especially young women, who use birth control pills for 5 or
more years have a 50% reduction in ovarian cancer when compared to
women who have never used birth control

Works in BRCA Carriers, but debate regarding increase breast cancer
risk
Stop ovulation decreases risk

Multiparity (up to 5 children) regardless of age of first conception

breastfeeding
Carboplatin approved

Another platinum based chemotherapy


Discovered at Michigan State University
Similar efficacy to Cisplatin but much less side effects

Eliminated nephrotoxicity

Minimal nausea and vomiting

Increase myelosuppression.

Very stable

90% excreted in urine unmetabolized. Need 4X as much as cisplatin
Sparty
Paclitaxel (Taxol)

Most significant chemotherapeutic agent for ovarian and Breast Cancer

Discovered in 1962


Derived from the bark of the Pacific Nortwest Yew Tree (Taxus Brevifolia thus
“Taxol”)

Debarking kills tree. 1990 Robert Holton form Florida State University discovers
how to synthesize it from the needles.

Docetaxel from European Yew tree ( more common)
Highly insoluble so use Cremaphor


Severe anaphylaxis
Abraxane- nanoparticle-albumin-bound paclitaxel

Orphan drug for pancreatic cancer
Ovarian Cancer Resistance

Ovarian cancer is one of the most sensitive solid tumors with
responses of up to 80%

Ultimately develop resistance and die

Minimal survival improvement in 20 years.

Multiple mechanisms


Decreased drug accumulation inside cell

Increased cellular detoxification

Increased DNA repair
Multidrug resistance-associated protein (MRP) gene functions as an
ATP-dependent pump for cytotoxic drugs and MRP plays the
significant role for platinum resistance in ovarian cancer.
Multi Drug Resistance

Mechanisms of MDR towards cancer chemotherapeutic drugs.
Cancer cells can develop resistance to multiple drugs by various
mechanisms as depicted. Mechanisms include (a) decreased
uptake of drug, (b) reduced intracellular drug concentration by
efflux pumps, (c) altered cell cycle checkpoints, (d) altered drug
targets, (e) increased metabolism of drug and (f) induced
emergency response genes to impair apoptotic pathway.
Cytoreductive Surgery

If we know that cancer cells exposed to chemotherapy develop
resistance, then does it follow that the fewer cells that see
chemotherapy the lower the resistance to chemotherapy and the
better the prognosis?

Complete cytoreductive surgery

Often includes splenectomy, diaphragm stripping, partial hepatic
resection, partial bladder or ureteral resection, or bowel resection.

Problem: High morbidity and mortality

Mortality rate quoted at 2%l

Morbidity: transfusion, prolonged hospital stays. DVT’s and embolisms.
Survival advantage of cytoreductive surgery

1994 Dr. Hodkins publishes GOG study 97.


Patients who are reduced down to1.5 cm have a survival advantage
2001 Dr. Chi cytoreduction down to <1cm

282 patients multivariate analysis (18 factors: age ascities, CA-125

56 month survival vs. 31 months (about 2 years)

No difference in survival if over 2 cm of residual disease
Dr. Robert Bristow meta-analysis showed that for every 10% increase in
maximal cytoreduction you get a 5.5% increase in median survival
 Issue: Does the risk of surgery make sense if the morbidity is high and
you might not be able to cytoreduce the patient.


Pre-operative CA-125, and CT scans do not reliably predict which patients
can be optimally cytoreduced.
Neoadjuvant Chemotherapy


European Organization of researchand Treatment of Cancer
(EORTC)

718 patients randomized to either upfront surgery of 3 cycles of upfront
chemotherapy followed by surgery

Survival was 30 months in both groups.

Morbidity was dramatically lower in the Neoadjuvant group
CHORUS Trial (Lancet: Vol 386, July 2015)

87 women in UK and New Zealand essentially same design as EORTC
trial


No difference in survival at 22.6 months
Problem: in US optimal cytoreductive surgery followed by IP
chemotherapy has a median survival of 66months.
Personal approach to treatment of
Ovarian Cancer

Young health patient’s I will almost always operate and be as
aggressive as possible. Includes coon resection, pelvic and aortic
lymph node dissection, hysterectomy, Bilateral salpingooophorectomy, often splenectomy with distal pancreatectomy,
diaphragm stripping or resection and repair

Older than 75 (moving target) clear evidence that mordity of
surgery outweighs the benefits so neoadjuvant

Not sure: Start with laparoscopy if it appears that I can resect
everything will convert to laparotomy. If I can’t place a power port
and disposition the patient to neoadjuvant

Often interval cytoreductive surgery can be done robotically.
Intraperitoneal chemotherapy

Theory: ovarian cancer spreads by putting little seeds throughout the
abdomen. It makes sense that putting chemotherapy (depth of
penetration about 3mm) directly on the tumor should be more
effective.

Published August 3 in the Journal of Clinical Oncology, the
prospective cohort study found that, compared with IV
chemotherapy alone, treatment with both IP and IV chemotherapy
was associated with improved 3-year overall survival in women with
stage III ovarian cancer who, after surgery, had only very small tumor
deposits remaining (1 cm or less in size).

IP and IV chemotherapy extended median overall survival for
patients with ovarian cancer by more than a year, compared with
women treated with IV chemotherapy alone.
IP Chemotherapy
Not sure if the mechanism of action is due to direct application of chemotherapy or to extended pharmacokinetics
More abdominal pain, nausea and vomiting , neutropenia and catheter complications than IV Chemo
Only 40% of IP chemo patients can tolerate all 6 doses, but survival advantage begins after 2 doses.
Risk factors for ovarian cancer
Age: Rare if younger than 40.
 Obesity : 5 point increase in BMI increases ovarian cancer risk by 6%



Responsible for 40% of cancers. Colon, Uterine, esophagus, gallbladder, thyroid
and pancrease.

120,000 cancer cases/year in US
Reproductive History:

Term pregnancy prior oto age 26, multiple pregnancies decrease rik

Nulliparous or first baby after age 35 increase risk
Birth control :decreases risk
 Fertility Drug: Clomid increase risk for LMP tumors after 6 cycles
 Estrogen Replacement:1 additional cancer case per 1,000 users who
have been on estrogen > 5 years
 Genetics: BRCA 1 and 2

American Inst for Cancer Research iand the World Cancer research fund March 2014
BRCA 1 and 2 & Mary-Claire King


Degree in Math form Carleton College
UC Berkley convinced to go into genetics

Proved chimpanzees and humans ore 99% genetically the same

After 17 years discovered a single gene on Chromosome 17
responsible for upto 10% of all breast cancers and upto 19% of all
ovarian cancers

Used LDS genealogy to find families with clusters of breast cancer

Worked with Abuelas de Plaza de Mayo (Grandmothers of Plaza de
Mayo) in Argentina. She used dental genetics to identify missing
persons, ultimately identifying 59 children and helping return them to
their biological families.
BRCA 1 and 2

BRCA1 is a human tumor suppressor gene (to be specific, a caretaker
gene), found in all humans; its protein, also called by the synonym breast
cancer type 1 susceptibility protein, is responsible for repairing DNA.

BRCA 2 is found on Chromosome 13.

Tumor suppressor genes help repair DNA before it becomes cancer

Not every BRCA carrier will develop cancer, but the likely hood of
developing Breast and ovarian cancer is much higher
Risks of BRCA Carriers
Myriad Genetics
BRCA Testing Consider When

Breast cancer diagnosed before age 50 years

Cancer in both breasts in the same woman

Both breast and ovarian cancers in either the same woman or the
same family

Multiple breast cancers

Two or more primary types of BRCA1- or BRCA2-related cancers in a
single family member

Cases of male breast cancer

Ashkenazi Jewish ethnicity
Ovarian Cancer begins in the
Fallopian tubes—WHAT?

10% to 15% of fallopian tubes removed from women with BRCA1/2
mutations have precursor lesions, whereas the ovaries do not. Fifty
percent to 60% of women without a genetic predisposition who
developed sporadic ovarian cancer also have early tubal lesions and
carcinomas. Genetic mutations and characteristics of early fallopian tube
lesions lend further support to the fallopian tube origin of ovarian cancer.
Moreover, studies have "consistently" found that tubal ligation reduces
ovarian cancer risk by 50%,

Jan. 20105 ACOG Committee opinion: he use of salpingectomy for
ovarian cancer prevention in women with population risk already
undergoing routine pelvic surgery for benign disease.

If every patient that has completed childbearing and is undergoing a
gynecologic procedure also has a bilateral salpingectomy,, the
incidence of ovarian cancer should decrease between 20-30%
Cancer Prevention Research, April 2015
Conclusion

Not all Ovarian cancer are the same, but the most common,
Epithelial Cell Cancers are the most lethal

No way to screen for ovarian cancer

Surgery and chemotherapy are the main therapeutic options for
ovarian cancer.

Debate rages on which should come first

Genetic testing of all high rick patients should be performed

Prophylactic salpingectomies at the time of a benign operative
procedure is reasonable

Lifestyle modifications including weight loss is always a good idea
CRISPR and Gene Drive
Technology

https://www.ted.com/talks/jennifer_kahn_gene_editing_can_now_c
hange_an_entire_species_forever?language=en

Jennifer Kahn: Gene editing can now change an entire species -forever