The Link Between Breast Cancer and Hormones_ Kristin Rojas MD

Kristin Rojas, MD
Breast Surgical Oncology and Gynecologic Surgery
Obstetrics and Gynecology Grand Rounds
January 25, 2019
Maimonides Medical Center
The link between hormones and
breast cancer: does staying young
forever come with a price?

Disclosures
• No financial or commercial relationships to disclose

Outline
• Introduction
• Reproductive risk factors
• Systemic hormone replacement therapy
• Local estrogen
• Hormonal contraception
• Conclusion

Introduction: BC Basics
P-1 Trial
NSABP B-14
NSABP B-24
• Invasive breast cancer is a diverse family of tumor
subtypes
• Subtypes grouped into the following:
• Luminal A-like tumors: ER+/Her2-
• Luminal B-like tumors: ER+/Her2+
• Basal-like tumors: ER-/Her2-
• Her2-overexpressing: ER-/Her2+
• Presentation, treatment, and prognosis related to
subtype
• Older literature does not assess risk by subtype
• Convenient, but does not scratch surface of heterogeneity
• Genomic profiling, next-generation sequencing
Rojas K and Stuckey A. Clin Obstet Gynecol (2016)

Estrogen
• Estrogen discovered in 1929, receptor discovered
in 1958 by Elwood Jensen at University of Chicago
• 80% of invasive breast cancers express the estrogen
receptor
• Estrogen blockade reduces lifetime risk in special
populations, decreases risk of recurrence after
primary treatment
P-1 Trial
NSABP B-14
NSABP B-24

The link between breast cancer and
reproductive factors
First evidence of hormonal influence on cancer risk

BC Risk Due to Reproductive Factors
• 1969: Fraumeni observed that nuns had a higher-than-
average risk of breast cancer
• Many attempts to articulate the link between
reproductive factors (endogenous hormone exposure)
and breast cancer risk
• Similar concept later applied to exogenous hormone
exposure
Fraumeni, et al. J Natl Cancer Inst (1969)

Brief Statistics Primer
• Relative risk: Probability of event in group 1 v. probability in group 2
• RR 1 is neutral: chance of event occurring is same for both groups
• Value <1: Group 1 has less of a chance of event
• Value >1: Group 1 has more of a chance of event
• Sometimes expressed as %:
• RR 1.26 means group 1 has 26% higher chance of event occurring
• If 95% CI cross 1= the result is not significant
Fraumeni, et al. J Natl Cancer Inst (1969)

9 studies using data from 1966-2005
Old Data
Ma H, et al. Breast Cancer Res (2006)

Studies with
significant
resultsà
Old Data
Ma H, et al. Breast Cancer Res (2006)

Better Data
21,941 breast cancers and almost 900,000 controls
Lambertini M, et al. Cancer Treat Rev (2016)

Better Data
Conclusion:
• Parity decreases your risk of ER+
tumors (OR 0.75 95% CI 0.70-0.81)
• Does decreased age at delivery?

Better Data
Conclusion:
tumors (OR 0.75 95% CI 0.70-0.81)
• Does decreased age at delivery?
?

Reproductive Risk Factors
• Parity results in 25% risk reduction in only luminal tumors (ER+, Her2-)
• Not Her2-overexpressing or HR negative1,2
• Long-term benefit is preceded by increase in risk the years following deliveryàmore
on this later3
• Recent population-based epidemiological data has failed to demonstrate a
consistent association between breast cancer and…
• Age at menarche4
• Age at first delivery- maybe related to HR+1
• Of note, breastfeeding consistently decreases lifetimes risk of breast cancer
in HR positive and negative groups1,2
• Maybe not Her2+, but not enough data1
1Lambertini, et al. Cancer Treat Rev (2016)
2Ma, et al. Breast Cancer Res (2006)
3Lyons, et al. Nat Med (2011)
4Li, et al. Am J Epidemiol (2013)

Hormone Replacement Therapy and
Breast Cancer Risk
A story of femininity and media sensationalism

Emmenin (1935)
• First commercial preparation of estrogen
• Alcohol-soluble substance derived from human
placentas
• Marketed to treat dysmenorrhea
Watson M. Canadian Med Assoc Journal (1935)

Premarin (1942)
• From pregnant mares’ urine
• Dominated by estrone (50%)
• Equilin (22.5% to 32.5%) with less than 5% estradiol.
• Premarin® approved by the FDA in 1942 to treat
hot flashes
• By 1992, was the number one prescription in
the US, with sales exceeding $1 billion in 1997

Feminine Forever
• In 1966, Dr. Robert Wilson wrote that
by using estrogen, menopause was a
preventable event.
• With this therapy, a woman’s “breasts
and genital organs will not shrivel. She
will be much more pleasant to live
with and will not become dull and
unattractive.”

The Nurses’ Health Study
HRT: hormone replacement therapy
CEE: conjugated equine estrogen
MPA: medroxyprogesterone acetate
• Studies in 1980’s, 1990’s observed HRT may be cardioprotective
• Prospective cohort NHS, published in 1996 followed 60,000 women
through menopause
• Collected data from 1976-1992, found marked decrease in coronary
disease in those taking CEE with progestin (RR 0.39) or alone (RR
0.60) compared to women who did not use hormones
Grodstein F, et al. N Engl J Med (1996)

A Secondary Analysis of the NHS
Colditz, et al. NEJM (1995)

NS

• Does not apply for those
taking E other than oral CEE
• Increase in risk does not
apply to those taking HRT
for <5 years
• Does not apply to past use
of any kind
• Confirmed in the UK’s Million
Women Study
• No increased risk of dying
from breast cancer
NS
NS
Beral, et al. Lancet (2003)

Leading up to the WHI
• NHS (1996) found cardioprotective effect of HRT, but increased risk of
BC in current users >5 years taking CEE with or without progestin
• HERS study (1998) found that CEE + MPA did not decrease CV events
in women with baseline CAD
• Mean age 66.7 years
• Also found increased VTE risk, despite improving lipid profile
• Did not look at BC risk
Hulley S, et al. JAMA (1998)

Leading up to the WHI
• Designed after Public Health Service Task Force found that research
disproportionately focused on white men
• First randomized trial in healthy women, but still older (n=160,000 aged 50-
79)
• Majority of women were >10 years past menopause
• Designed to measure effect of nutrition and HRT on “global health index”
• Included CV disease, breast, endometrial, and colon cancer
• Sought to look at women >10 yrs post-menopause:
• Enrollment had been restricted so that <10% were between 50-54
• Two hormone trials:
• 1) RCT of women without a uterus given CEE 0.625mg v. placebo
• 2) RCT of women with a uterus given CEE + MPA 2.5mg v. placebo
• HT components stopped early (planned 9 year f/u) after 5.2 years in 2002
WHI (2002)

Original Publication (2002)
WHI (2002)

*Remember that
CI that cross 1 are
NOT SIGNIFICANT
WHI (2002)

Risk increase of
breast cancer is
NOT
SIGNIFICANT
WHI (2002)

“Fear and sensationalism over science…
for maximum publicity” – Dr. Robert Langer
• Lead researcher states he was told the CEE + MPA arm was stopped
based on a “finding of likely futility”, not harm
• Small group of study executives wrote initial results paper, press release,
citing increase in breast cancer as main reason for termination
• Clinical site PIs given hours to read article and submit edits, but article already
in print
• USPSTF downgraded HRT from B to D
Langer R. Climacteric (2017)

• Methodology:
• Although designed as RCT- should interpret data as observational
• Women at liberty to decide if they continued assigned treatment, or whether they
should undergo diagnostic procedures
• Previous hormone use not accounted for “3-month washout period”
• Statistics:
• The original paper emphasized relative and not absolute risks
• Results not adjusted for pre-existing diseases, treatments besides hormones,
skewed by unusually low rate of breast cancer in the placebo group
• Aftermath:
• Results incorrectly generalized to women <60 (30% of participants age 50-59)
• 2003 WHI paper emerged with CEE alone group with RR of breast cancer <1
Clark J. Nucl Recept Signal (2006)
WHI (2002)

• Methodology:
• Although designed as RCT- should interpret data as observational
• Women at liberty to decide if they continued assigned treatment, or whether they
should undergo diagnostic procedures
• Previous hormone use not accounted for “3-month washout period”
• Statistics:
• The original paper emphasized relative and not absolute risks
• Results not adjusted for pre-existing diseases, treatments besides hormones,
skewed by unusually low rate of breast cancer in the placebo group
• Aftermath:
• Results incorrectly generalized to women <60 (30% of participants age 50-59)
• 2003 WHI paper emerged with CEE alone group with RR of breast cancer <1
IGNORED
WHI (2002)

• 26% increase in relative risk
(although still not significant)
• Public interpreted this as “I have a
26% risk of breast cancer”
• Absolute risk is 8 additional
cancers per 10,000 patient-
years
Relative vs. Absolute Risk

• 3A: Risk ratios appear to
spike at year 4-5
• 3B: Note the placebo
group drop in rates at
year 4
• THIS led to the
NONSIGNIFICANT
increase in relative risk

• 5A: Women with prior
HRT use: CIs very large,
no real conclusions
here
• 5B: No prior HRT use:
all CI cross 1
Questions

A RR < 3 Probably Doesn’t Mean Much
Pesch, et al. Int J Cancer (2012)
• Male smokers with an average daily
dose of >30 cigarettes:
• RR of squamous cell lung ca: >100

Study after WHI confirms no increased BC risk
• Danish Osteoporosis Prevention Trial (DOPS) RCT of recently-
menopausal women to receive:
• Triphasic estradiol + norethisterone acetate (intact uterus) v.
placebo
• 2 mg of estradiol (prior hysterectomy) v. placebo
• Planned as a 20-year trial, terminated in 2002
• Significant reduction (10 year f/u):
• Breast cancer mortality (HR 0.54; 95% CI 0.32–0.91)
• CV mortality (HR 0.48; 95% CI 0.26–0.87)

Study after WHI confirms no increased BC risk
• Danish Osteoporosis Prevention Trial (DOPS) RCT of recently-
menopausal women to receive:
• Triphasic estradiol + norethisterone acetate (intact uterus) v.
placebo
• 2 mg of estradiol (prior hysterectomy) v. placebo
• Planned as a 20-year trial, terminated in 2002
• Significant reduction (10 year f/u):
• Breast cancer mortality (HR 0.54; 95% CI 0.32–0.91)
• CV mortality (HR 0.48; 95% CI 0.26–0.87)
IGNORED

You do the math…
• Theoretical initiation of malignant breast tumors by HRT and clinical
detection is at least 5 years, maybe longer than 10 years
• HRT cannot plausibly cause increased incidence in invasive breast
cancers in less than 6 years
• Similarly, time from starting HRT to diagnosis was actually 1.2 years in
Million Women Study
• Most HRT-BC risk studies based on short observation periods
Beral, et al. Lancet (2003)
Dietel M, et al. Human Reprod (2005)

So what is true about the WHI study?
• Women taking CEE alone did not have more BC events than placebo
• Using adjusted RR, CEE + MPA group did not have more BC than
placebo
• Only significant findings: decrease in fracture rate, increase in VTE
• Effects of HRT on most organ systems vary by age, time since last
exposure to hormones- newly menopausal women were not
represented in the WHI study
WHI (2002)

Decrease in BC after WHI published
• 2001-2004: 12% decrease in breast cancer incidence in women age 50-691
• Analysis of same SEER registry found that decline started prior to WHI
publication, when HRT was high (as early as 1998) and was present for all types
of cancer2
• Decline in MMG compliance started in 20031
• Women who stop HRT less willing to continue periodic screening, but decline in
incidence was also observed in those who continued screening3,4
• Decline not consistently seen in countries with high cessation rates of HRT
• Norwegian screening data (stable and long-term, with 50% of post-menopausal
women on HRT) found initial increase in diagnosis with initiation of screening
(1996) followed by a continued decrease in incidence, not altered by the
decrease in HRT use in 20025
1Ravdin, et al. N Engl J Med (2007)
2Jemal, et al. Breast Cancer Res (2007)
3Glass, et al. J Natl Cancer Inst (2007)
4Cann, et a. J Natl Cancer Inst (2008)
5Zahl and Maehlen. N Engl J Med (2007)
Questions

The mortality toll of estrogen avoidance
• Estrogen HRT in younger postmenopausal women associated with
reduction in all-cause mortality
• Bone health:
• Significant increase in hip fractures after WHI released
• Cardiac health:
• Increased risk of cardiac death in first year after stopping HRT
• Analysis of excess deaths among hysterectomized women 50-60 yrs
• Excess mortality after decline in E use between 2002 and 2011
• Over 10 years, approx. 40,000 postmenopausal women died
prematurely because of avoidance of estrogen therapy
Karim, et al. Menopause (2011)
Mikkola, et al. J Clin Endocrinol Metab (2015)

What about other routes of HRT?
• Transdermal systemic HRT skips first pass metabolism, has lower rate
of VTE
• No strong evidence of an association of route of estrogen and BC risk has
been found1,2
• Vaginal estrogen has been shown to be more effective than
polycarbaphil-based moisturizers in the treatment of vaginal atrophy
• Although some is absorbed, difficult to discern how much due to issues with
immunoassays and cross-reactivity with other steroid hormones3,4
• Has never been found to increase the risk of breast cancer5, nor increase the
risk of recurrence in women with a history of breast cancer6,7
• Endorsed by ACOG8
1Fournier, et al. Breast Cancer Res Treat (2008)
2Crandall, et al. Menopause (2017)
3Lee, et al. J Clin Endocrin Metab (2006)
4Kushnir, et al. Am J Clin Pathol (2008)
5 Cransdall, et al. Menopause (2018)
6Dew, et al. Climacteric (2003)
7Le Ray, et al. Breast Cancer Res Treat (2012)
8ACOG CO 659 (2016)

HRT Summary
• The WHI data does not demonstrate an increased risk of breast
cancer with CEE alone or CEE+MPA
• HRT started near menopause is probably cardioprotective and
definitely decreases risk of fractures
• Not plausible that HRT caused de novo breast cancers in WHI study
• Transdermal, vaginal E routes have not been shown to increase risk
• The effects of the “spin” of the WHI study may have attributed to a
large number of preventable deaths
OCP

The link between hormones and
breast cancer: does reproductive
freedom come with a price?

What about OCPs and breast
cancer risk?
More mediocre science.

• Research for the pill started when discovered
that Mexican women were eating a certain
wild yam
• 1960- Edovid approved by the FDA
• Edovid: 150mcg estrogen, 10,000 mcg of
progestin
• Today’s doses 20-50 mcg estrogen and 50-150
mcg progestin
Oral Contraception (OC)
Asbell (1995)
Grimes (2000)
“Cabeza de Negra” yam

• Reproductive liberation ensued, but tempered by religious,
societal norms AND published studies linking hormonal
contraception and malignancy
• 1996 pooled analysis of 54 epidemiological studies suggested
small increased risk with current or recent combined oral
contraceptive (COC) use:
• RRcurrent 1.24 (95% CI 1.15-1.33)
• RRrecent 1.16 (95% CI 1.08-1.23)
• Risk absent 10 yrs after cessation
Old Data
CGHFBC (1996)

• Large multicenter case-control studies
• CARE (2002): No association between OC and BC risk found in women aged
35-64
• ORprevious use 0.9 (95% CI 0.6-1.0)
• ORcurrent use 1.0 (95% CI 0.8-1.3)
• Risk did not increase with longer duration of use, higher doses
• Nurses’ Health Study II (2010)
• RRprevious 1.12 (95% CI 0.95-1.33)
• RRcurrent 1.33 (95% CI 1.03-1.73)
• Beaber, et al (2014):
• ORever use 1.0 (95% CI 0.8-1.3)
• OR>15 years’ use 1.5 (95% CI 1.1-2.2) in women aged 40-44 only
• Cases more likely to be nulliparous, have a family history, not have breastfed
• Risk only increased for ER negative, triple negative subtypes
Better Data
Marchbanks, et al. 2002
Hunter, et al. 2010
Beaber, et al. 2014

Is it the contraception or the nulliparity
that led to the increased risk?

Better Data
Conclusion:
tumors (OR 0.75 95% CI 0.70-0.81)
• But increase in risk seen in years
after delivery

Breast Cancer Risk After Delivery

• 15 studies of 19,000 breast cancers in 9.6 million person-years
• Compared with nulliparous women younger than 55, parous women
were more likely to be diagnosed with breast cancer up to 24 years
after giving birth
• This risk higher with family history or multiple deliveries
• Breastfeeding does decrease risk, but does not modify risk < 55
• Oral contraceptive use not found to increase risk for breast cancer
Nichols H, et al. Ann Intern Med (2018)

• CARE (2002): No association between OC and BC risk found in women aged
35-64
• ORcurrent use 1.0 (95% CI 0.8-1.3)
• RRprevious 1.12 (95% CI 0.95-1.33)
• RRcurrent 1.33 (95% CI 1.03-1.73)
• ORever use 1.0 (95% CI 0.8-1.3)
• Cases more likely to be nulliparous, have a family history, not have breastfeed
Better Data
Marchbanks, et al. 2002
Hunter, et al. 2010
Beaber, et al. 2014

• CARE (2002): No association between OC and BC risk found in women aged 35-64
• ORcurrent use 1.0 (95% CI 0.8-1.3)
• RRprevious 1.12 (95% CI 0.95-1.33)
• RRcurrent 1.33 (95% CI 1.03-1.73)
• ORever use 1.0 (95% CI 0.8-1.3)
• Cases more likely than controls to be nulliparous, have a family history, not have
breastfeed
BC Risk Compared: Recent Pregnancy, COC Use
Study Risk Increase Significant? Compared to
recent delivery
Pregnancy (Nichols, et al. 2018) Recent preg: HR 1.8* (95% CI 1.6-1.9)
Recent preg + fam hx: HR 3.53* (95% CI 2.9-4.3)
Yes
Yes
Reference
CGHFBC (1996) Recent use: RR 1.16 (95% CI 1.08-1.2)
Current use: RR 1.24 (95% 1.1-1.3)
Yes
Yes
Lower
Lower
CARE (Marchbanks, et al. 2002) Previous use: OR 0.9 (95% CI 0.8-1.0)
Current use: OR 1.0 (95% CI 0.8-1.3)
No
No
Lower
Lower
NHS II (Hunter, et al. 2010) Previous use: RR 1.12 (95% CI 0.9-1.3)
Current use: RR 1.33 (95% CI 1.03-1.7
No
Yes
Lower
Lower
Beaber, et al. (2014) Ever use: OR 1.0 (95% CI 0.8-1.3)
15 years of use: OR 1.5 (95% CI 1.1-2.2)
No
Yes
Lower
Lower

Study Risk Increase Significant? Compared to
recent delivery
Pregnancy (Nichols, et al. 2018) Recent preg: HR 1.8* (95% CI 1.6-1.9)
Recent preg + fam hx: HR 3.53* (95% CI 2.9-4.3)
Yes
Yes
Reference
CGHFBC (1996) Recent use: RR 1.16 (95% CI 1.08-1.2)
Current use: RR 1.24 (95% 1.1-1.3)
Yes
Yes
Lower
Lower
NHS II (Hunter, et al. 2010) Current use: RR 1.33 (95% CI 1.03-1.7 Yes Lower
Beaber, et al. (2014) 15 years of use: OR 1.5 (95% CI 1.1-2.2) Yes Lower

OC Relative Risk
Pregnancy Relative Risk

• Older data found that current OC use à increased BC risk that
disappears after cessation.
• Increased incidence or increased surveillance?
• Newer data shows maybe increased risk with current use >15 years in
women 40-44
• Not a consistent correlation between ER+ BC and other subtypes
• Recent pregnancy increases your risk substantially more than
current OC use

Other Contraceptives
• Progestin-only pill: Prospective study of Swedish, Norwegian women
(n=103,027) 30-49 y found no increased BC risk, later confirmed by
matched case-control study1,2
• Injected or implanted progestin: Case-control CARE study (n=4575)
did not find increased BC risk in pre- or post-menopausal women who
had ever been exposed3
• What about the levonorgestrel IUD?
1Kumle, et al. Cancer Epidemiol Biomark Prev (2002)
2Marchbanks, et al. N Engl J Med (2002)
3Strom, et al. Contraception (2004)

NO increased risk

NO increased risk
NO increased risk

LNG-IUD
• Two large Finnish, German retrospective case-control studies did not
find an increased risk of BC with LNG-IUD1,2
• Another large case-control Finnish study found LNG-IUD users had
significantly lower risk of endometrial (HR 0.5), ovarian (HR 0.6),
pancreatic and lung cancer3
• Then, in 2017…
1Backman, et al. Obstet Gynecol (2005)
2Dinger, et al. Contraception (2011)
3Soini, et al. Obstet Gynecol (2014)LNG-IUD: levonorgestrel IUD

LNG-IUD
• LNG-IUD users had RR 1.21 (95% CI 1.11-1.33) compared to never users
• Risk did not increase with duration of use
• Risk with progestins with higher dose (injectables) à no increased risk
• Study did not account for breastfeeding, alcohol, physical activity
• In the US (2015), risk of maternal mortality is 26.4 deaths/100,000
• Double the risk of BC than those using contraception in the study
Morch, et al. NEJM (2017)
LNG-IUD: levonorgestrel IUD

More problems with NEJM paper
• Comparing LNG-IUD and Cu-IUD, no difference in risk of breast cancer
(OR 0.99, 95% CI 0.88-1.12)
• Both methods prolong nulliparity, decrease lifetime # of deliveries,
eliminating levonorgestrel as likely cause of increased BC risk seen in
NEJM study
Dinger, et al. Contraception (2011)

More problems with NEJM paper
• Comparing LNG-IUD and Cu-IUD, no difference in risk of breast cancer
(OR 0.99, 95% CI 0.88-1.12)
• Both methods prolong nulliparity, decrease lifetime # of deliveries,
eliminating levonorgestrel as likely cause of increased BC risk seen in
NEJM study
Dinger, et al. Contraception (2011)
LNG-IUD lowers hormonally-
sensitive cancer risk, probably
does not increase BC risk in
normal-risk women

Olufunmilayo I, et al. Clin Cancer Research (2008)
Genetic/Familial Factors

Olufunmilayo I, et al. Clin Cancer Research (2008)
Modifiable Risk Factors for Cancer

Picon-Ruiz, et al. Cancer J Clin (2017)
Lifestyle factors and BC risk
• OBESITY increases breast cancer risk
• Increased risk of aggressive subtypes in
premenopausal women
• Risk of BC greatest in postmenopausal obese
women
• Worsens treatment outcomes
• Weight loss, bariatric surgery associated
with decrease BC, other cancer risk
• Smoking, radiation, physical inactivity,
alcohol also linked to increase BC risk

Conclusion
• WHI data does not demonstrate an increased BC risk with CEE alone or CEE+MPA
• HRT started at menopause probably cardioprotective, decreases risk of fx
• “Spin” of WHI study may have attributed to large number of preventable deaths
• Local forms of estrogen are safe, even in women with a history of breast cancer
• Especially with advances in adjuvant treatment, improvement in outcomes
• Newer data shows maybe inc. BR risk in current OC use >15 yrs in women 40-44
• Increased incidence or increased surveillance?
• Recent pregnancy increases your risk substantially more than current OC use
• Risk of breast cancer is multifactorial
• Probably more related to genetic factors than we know
• Focus on other modifiable risk factors
• Hormones for everyone?
• All women need appropriate risk-adjusted screening regimens

krojas@maimonidesmed.org
KristinRojasMD
Thank you

The Link Between Breast Cancer and Hormones_ Kristin Rojas MD

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