Prof. Dr. Engin Oral

1. MHT-Meme Kanseri : Güncel durum
Dr. Engin Oral
İ.Ü. Cerrahpaşa Tıp Fakültesi
Kadın Hastalıkları ve Doğum Anabilim Dalı
Üreme Endokrinolojisi Bilim Dalı
drenginoral@gmail.com

2. • About 1 in 8 U.S. women (about 12%) will develop invasive breast
cancer over the course of her lifetime.
• Breast cancer incidence rates in the U.S. began decreasing in the year
2000, after increasing for the previous two decades. They dropped by
7% from 2002 to 2003 alone.
• One theory is that this decrease was partially due to the reduced use of
hormone replacement therapy (HRT) by women after the results of a
large study called the Women’s Health Initiative were published in 2002.
These results suggested a connection between HRT and increased
breast cancer risk.
• For women in the U.S., breast cancer death rates are higher than those
for any other cancer, besides lung cancer
• Besides skin cancer, breast cancer is the most commonly diagnosed
cancer among American women
2017

3. • A woman’s risk of breast cancer nearly doubles if she has a first-degree relative
(mother, sister, daughter) who has been diagnosed with breast cancer. Less than
15% of women who get breast cancer have a family member diagnosed with it.
• About 5-10% of breast cancers can be linked to gene mutations (abnormal
changes) inherited from one’s mother or father. Mutations of the BRCA1 and
BRCA2 genes are the most common.
• On average, women with a BRCA1 mutation have a 55-65% lifetime risk of
developing breast cancer. For women with a BRCA2 mutation, the risk is 45%.
• Breast cancer that is positive for the BRCA1 or BRCA2 mutations tends to
develop more often in younger women.
• An increased ovarian cancer risk is also associated with these genetic mutations
• About 85% of breast cancers occur in women who have no family history of
breast cancer. These occur due to genetic mutations that happen as a result of
the aging process and life in general, rather than inherited mutations.
• The most significant risk factors for breast cancer are gender (being a woman)
and age (growing older).

4. SEER Incidence & U.S. Mortality 1975-2013, All
Races, Females. Rates are Age-Adjusted.
130.4
136.6

5. 2016

7. Meme Kanseri ve Emzirme
30 Ülkedeki 50,302 Meme Kanserli ve 96,973 Sağlam Kadını Kapsayan
47 Epidemiyolojik Çalışmanın Veri Analizleri
Lancet 2002; 360: 187–95
1 2 3 4 >5
1.1
1.0
0.9
0.8
0.7
0.6
0
Relatif
Risk*
(%95
FCl)
Doğumların Sayısı
Emziren Kadınlar
Hiç Emzirmeyen Kadınlar

8. BMJ: 2000: 321; 624-628

9. Estrogen related risk factors for breast
cancer
E. Amir ,Journal of theNational Cancer Institute 102 (10) (2010) 680–691.

10. APRIL 2017 | VOLUME 13

11. Breast cancer risk can be estimated using the
National Cancer Institute (NCI)-Breast Cancer Risk Equation
(http://www.cancer.gov/bcrisktool/)

12. Breast Cancer with HRT:
Risk Perception vs. Reality
PERCEPTION
Leading causes of death
perceived by women
REALITY
Actual causes of death
among US women
Old age (1%)
Heart
disease
(18%) Other
cancer
(13%)
Breast cancer
(39%)
Lung
cancer
(2%)
Ovarian
cancer (9%)
Stress (2%)
Smoking (1%)
Other/don’t
know (16%)
Heart
disease
(45%)
Other (25%)
Lung
cancer
(5%)
Ovarian cancer (<2%)
COPD (4%)
Pneumonia (4%)
Other
cancer
(11%)
Breast cancer (4%)
KEEPS Study 2012

13. *P < 0,01.
Lancet. 1997;350:1047-59.
Herhangi bir zamanda
kullanmış
Halen Kullanmakta
Geçmişte kullanmış
RR
1.14*
1.21*
1.07
HT Kullanımı
HT – Meme Kanseri
Collaborative Group on Hormonal Factors in Breast Cancer
Meme kanseri olan 52.705 kadın
Meme kanseri olmayan 108.411 kadın
51 çalışma, 21 ülke

14. HRT – Meme Kanseri
(1975-2000 arası çalışmalar)
• ERT ve Meme kanseri riski (45 çalışma)
• % 82 çalışmada risk 1.0 den farklı değil
• % 13 çalışmada risk >1.0 fakat >2.0 den değil
• % 2 çalışmada risk <1.0
• HRT ve Meme kanseri (20 çalışma)
• % 80 çalışmada risk 1.0 den farklı değil
• % 10 çalışmada risk >1.0
• % 10 çalışmada risk <1.0
Bush TL, et al. Obstet Gynecol. 2001;98:498-508.

15. JAMA. 2003;289(24):3243-3253. doi:10.1001/jama.289.24.3243
Plazebo
EPT
Estrogen-Progestin-Therapy: WHI (2003)

16. Incidence of Breast Cancer as a
Function of prior HT
Anderson et al. 2006

17. WHI-Estrogen Arm
Total Breast Ca Invasive Breast Ca in situ Breast Ca
JAMA. 2006 Apr 12;295(14):1647-57

18. WHI Trial
EPT and ET
Follow-up: 12
years
2013

20. Conclusion:
Risk of breast cancer depends on choice of progestin
Risk of Breast Cancer under
different Progestins (E3N-Studie)
Fournier et al 2008
1990 to 2002. During follow-up (mean
duration 8.1 postmenopausal years), 2,354
cases of invasive breast cancer occurred
among 80,377 postmenopausal women
Compared with HRT never-use, use of estrogen
alone was associated with a significant 1.29-fold
increased risk (95% confidence interval 1.02-1.65).
The association of estrogen-progestagen
combinations with breast cancer risk varied
significantly according to the type of progestagen:
the relative risk was 1.00 (0.83-1.22) for estrogen-
progesterone, 1.16 (0.94-1.43) for estrogen-
dydrogesterone, and 1.69 (1.50-1.91) for estrogen
combined with other progestagens.

21. Choice of Progestogen and Breast Cancer
Risk: Finnish Cohort Study
Lyytinen H et al. Obst Gyn 2009;113:65–73.
Estradiol/
MPA
Estradiol/other
progestogens
Standard
incidence
ratio
(95%
CI)
0
0.2
0.4
0.8
1.2
1.6
1.0
2.2
2.0
1.8
1.4
0.6
2.07
2.03
1.64
1.13
Estradiol/
dydrogesterone
Estradiol/
NETA
(0.49–
2.22)
(1.49–
1.79)
(1.88–
2.18)
(1.76–
2.04)
Baseline risk
without HRT
Risk elevation may not be uniform for all progestogens
Risk elevation may not be uniform for all progestogens
N = 50,210 women >50 years of age, treatment duration 5 years

22. MHT and breast cancer risk
Breast cancer risk for users of CHT (CEE+MPA) is higher
than for placebo group
Women’s Health Initiative (WHI) –> HR=1,26
Heart and Estrogen/Progestin Replacement Study (HERSII) -
> HR=1,30
Breast cancer risk in users of MHT is higher than in never
users
Million Women Study (MWS) 2003
Collaborative Group Study 1997–Reanalyzes of 51 studies
Shah Nirav, et al -2005 > estimated the risk of 1,39 fold
increase for observational studies
RCTs
Observational
Studies

23. Long of use of MHT and breast cancer risk
Breast cancer risk for users of CHT (CEE+MPA) is increased
in time against placebo group
1 year – 8 more cases per 10 000 against placebo group
5,2 years – there are expected 46 more cases per 10 000
than in placebo group
Breast cancer risk for users also appeared to depend
on time
MWS -> RR=1,63 (<5 years) and 2,21 (>5 years)
RCTs
Observational
Studies
Breast Cancer
< 5 y
> 5 y
1.15
1.53

24. Continuous or Sequential use of MHT and
breast cancer risk
• Observational data:
• Studies show that women using MHT sequentially (<15 days/mo) present
lower risk against continuous users;
• Others found an increased risk of 30% against non users for both strategies
of use;
After 5 years of discontinuing the hormonal therapy use, past and
current users have the same relative risk.

25. ET and breast cancer risk
Breast cancer risk for users of ET (e.g.: CEE alone)
presented no raise in the risk of breast cancer compared
with placebo WHI –>HR=0,77 (23% decrease)
)
Most of studies show a higher breast cancer risk in users
compared with never users
MWS -> RR=1,30
Collaborative Group Study -> RR=1,34
E3N cohort study-> RR=1,29
Shah Nirav, et al -> estimated the risk of 1,16 fold increase as
a review of observational studies
RCTs
Observational
Studies

26. ET, long of use and breast cancer risk
• Most observational studies found that:
• Breast cancer increases with the course of time for current users;
• Breast cancer has a higher risk for past users;
• After discontinuation of ET, breast cancer risk decreases;
• Breast cancer risk increase for ET is smaller than the risk that these studies
presented for MHT, according with time.
• Other observational studies presented similar results to WHI studies.

27. Histological types of breast cancer, MHT
and ET
MHT
• MHT are associated with 2.0 – 3.9 fold increased risk of ILC, but generally
not with IDC.
ET
• Both ILC and IDC risks remain unaltered, even after prolonged use of 25
years.
Invasive lobular carcinoma (ILC) is more difficult to detect by
mammography but have better prognosis than invasive ductal
carcinoma (IDC) [Christopher I., et al]

28. HT & Breast Cancer
 Diagnosis of breast cancer increases with EPT use beyond 3-5 years
 Unclear whether EPT risk differs between continuous and sequential progestogen
 EPT and to a lesser extent ET increase breast cell proliferation, breast pain, and mammographic density
 EPT may impede diagnostic interpretation
of mammograms
 Breast cancer diagnosis dissipated 3 years post EPT cessation
 Breast cancer mortality higher in women assigned to EPT compared to placebo
 Women starting EPT shortly after menopause experience increased breast cancer risk,
but those with a gap time greater than 5 years do not
 ET arm of WHI showed no increased cancer risk after mean 7.1 years on study
 ET and EPT use in breast cancer survivors may increase recurrence risk
NAMS position statement. Menopause 2012.

29. 1. Routine screening for breast cancer is indicated for midlife women. There is
considerable controversy regarding the age at which breast cancer screening
should begin and end and the frequency of screening. Current guidelines
generally include mammograms every 1 to 2 years, starting at age 40 to 50 years
and continuing until age 70. Magnetic resonance imaging is recommended
for women at high risk for breast cancer. (Level I)
2. Genetic testing for BRCA mutations should be recommended for women at high
risk for breast cancer on the basis of family history. (Level I)
3. Weight gain is associated with an increased risk of breast cancer recurrence,
and a low-fat diet is associated with improved survival in women with certain
types of breast cancer, so weight control and a low-fat diet may be advised for
women with breast cancer. (Level II)
4. Women at increased risk for breast cancer should be counseled regarding the
potential benefits and risks of tamoxifen and raloxifene for breast cancer risk
reduction.
(Level I)
2014

30. 2014

31. 2015

32. WHI (2002) ve MWS (2003) “kombine HRT ile CVD ve meme kanseri arasında ilişki
vardır” dedikten sonra İngilterde HRT kullanımı %50 azaldı..
• NICE’e göre olumsuz etkilerle ilgili korku doktorları HRT vermekten hastaları da
HRT istemekten soğuttuğu için pekçok kadın sessizce menopoz semptomlarına
katlanmakta..
• NICE kılavuzu HRT ile ilgili korkuyu azaltmaya çalışmakta;
Sadece E2 meme ca riski yaratmaz ya da çok düşük risklidir.
Kombine HRT meme ca riskini artırabilir, tedavi bırakıldıktan sonra risk tekrar düşer
Lancet, 21 kasım
2015

33. 2015

35. Breast cancer
Key points
• The risk of breast cancer associated with MHT in women over 50 is complex
• The increased risk is primarily associated with the addition of a synthetic
progestogen to estrogen therapy and to duration of use [B]
• The risk may be lower with micronized progesterone or dydrogesterone [C]
• The MHT attributable risk is small and decreases when treatment stops [B]
• There is a lack of safety data supporting MHT use in breast cancer survivors
• Breast cancer risk should be evaluated before MHT prescription [D]*
• Any possible increased risk associated with MHT may be decreased by selecting
women with lower baseline risk including low breast density and by providing
education on preventive lifestyle measures (reducing weight, reducing alcohol
intake, increasing physical activity) [D]
• Annual mammograms should be proposed in case of high breast density in
women using MHT. [D]

36. Perception
All types of HRT cause an increased risk of breast
cancer within a short duration of use.
Evidence
In the WHI estrogen-only arm, there was no increase in breast
cancer risk for up to 7 years.
However, the risk of invasive breast cancer was significantly lower
in first-time users of estrogen. [A]
In observational studies, a small increase in risk during estrogen-
alone therapy was recorded only after long-term use. [B]

37. Perception
The reported decline in breast cancer rates in the
US following the publication of the WHI data proves
that HRT causes cancer.
Evidence
A decline in the incidence of breast cancer in the USA started
before the WHI publication and can be partially related to fluctuation
in screening.
There has been no decline in breast cancer registration in the UK
following the Million Women Study report, nor in Norway, Canada,
the Netherlands and countries with stable screening programs. [B]

38. Perception
HRT causes an increase in mammographic breast
density. Increase in mammographic breast density is
associated with an increased risk of breast cancer.
Evidence
Increased baseline breast density is a risk factor for breast cancer.
Combined E + P therapy may cause increased breast density in up to 50% of
postmenopausal women, dependent on the regimen (dosage, type of progestogen.
The average increase in breast density with standard dose is up to 10%). The effect
of estrogen alone is smaller.
There are no data to support a direct association between HRT-induced breast
density changes and the risk of developing breast cancer.

39. 2017

40. MHT stimulates the proliferation of occult
breast cancer
Santen et al. 2012

41. Breast cancer, mammography
Abnormal
mammograms
Diagnostic
delay
6,9% raise in
breast cancer
density
MHT
leads
to:
Mammograms
are not
compromised
2,9% raise in
breast cancer
density
ET

42. Patient monitoring during menopausal
hormone therapy administration
• Monitor breast symptoms and schedule annual
mammography.
• Breast tenderness can improve with change in progestogen or
reduction in estrogen dose.

45. Conclusion
• The baseline risk of breast cancer for women around menopausal age varies from one woman
to another according to the presence of underlying risk factors
• Women taking MHT have a high breast cancer risk, compared with non-users;
• The risk is more apparent with continuous MHT ;
• Although the differences between RCTs and observational studies ; ET is associated with less
risk than MHT is
• Any increase in the risk of breast cancer is related to treatment duration and reduces after
stopping MHT
• Replacing MPA for other progestin (micronized progesterone , dydrogesterone) may provide
more safety for users;
• Mortality is still a controversial.