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Breast Update May 2013 Dr Morag Baruch GPSI – Breast Tauranga Hospital
Breast Update May 2013 Dr Morag Baruch GPSI – Breast Tauranga Hospital
General Practitioner of Special Interest
My special interests include: • Familial and high risk breast cancer assessment and
counselling
• Breast cancer follow-up
• Benign breast disease • Menopause
• Gynecomastia
Breast Update May 2013
• Familial breast cancer – risk assessment and referral
• Menopause after breast cancer • Mastalgia
Familial Breast Cancer Risk and Assessment
Breast cancer is: • Most common cancer diagnosed in NZ women
• 27.4% of all female cancer registration in 2005 • 2759 cases diagnosed 2009, 665 deaths.
• Leading cause of cancer mortality in NZ women • 17.1% of female cancer deaths • NZ has 6th highest death rate from Breast cancer in OECD
• Life time risk is between 1:8 and 1:11 • By age 79, ≈ 10% NZ women will have been diagnosed with Breast Cancer
• Incidence increasing but mortality rate has decreased by 19% in the last decade
• Earlier detection and more effective Rx NZ Guidelines Group 2009
Key Risk Factors
1. Being female • Men only 1% of breast cancers
2. Increasing age • 1: 250 women in 30s rising to 1:30 age 75 • Peak incidence 61yrs
3. Family history / Known genetic mutations • 5-10% of new breast cancers
Approximate risk of developing breast or ovarian cancer in the next 10 years (NBOCC 2005)
If the woman is now aged
Her risk of breast cancer in the next 10 years
Her risk of ovarian cancer in the next 10 years
20 1:2,500 1:3,000
30 1:250 1:2,000
40 1:70 1:900
50 1:40 1:450
60 1:30 1:300
70 1:30 1:200
Age Specific Incidence rates per 100,000 population, Females, UK
Other Factors in Risk Assessment Medical factors
Chest wall radiation exposure prior to age 30 Personal history of breast cancer History of atypia (ADH/ALH or cellular atypia) LCIS/DCIS
Environmental/ lifestyle factors Postmenopausal obesity Alcohol use >1 Std drink/day elevates risk by ≈1.4x
Hormonal factors Age of menarche <12 yrs Age at menopause >55 yrs Nulliparity 1st full term pregnancy after age 35 yrs Use of COC / HRT
Hereditary Breast and Ovarian Cancer Syndromes (HBOCS)
• ~ 5-10% of new breast cancers • BRCA1 and BRCA2 gene mutations are the most
common germline mutation associated with increased risk for breast/ovarian cancer - 15%
• Other high risk genes - <1%
• PTEN, TP53, STK11, ATM • CDH1 gene mutation
BRCA 1 & 2 genes • Normal BRCA genes code for proteins that suppress
tumour growth and repair damaged DNA. • > 2000 distinct mutations and sequence variations
have been described associated with increased lifetime risk of breast and ovarian cancer
• No definitive functional tests for BRCA1 or 2 mutations
• Only 10-15% of all individuals undergoing genetic testing with full sequential testing will be positive
• Autosomal Dominant inheritance
Associated Cancer Risk BRCA 1&2 • Increased lifetime risk of breast cancer
between 40 and 80 % • Increased lifetime risk of ovarian cancer
between 20 and 40% • Risk of second primary breast cancer is
>50% • Risk of other cancers – prostate, male
breast, pancreas, skin etc
Associated Cancer risk Gene Mutation
frequency Major sites at risk
Risk to age 75 in mutation carriers
Other possible sites with up to 10% lifetime risk
BRCA1 ~1/1000
Breast Ovary
40-80% 10-60%
prostate
BRCA2 ~1/1000 Breast Ovary
40-80% 10-40%
Male breast, prostate, pancreas
TP53 (Li-Fraumini syndrome)
~1/10000 Breast (premenopausal) Childhood sarcomas
>50% 10-50%
Brain, lung, adrenal gland, leukaemia
PTEN (Cowden syndrome)
~1/200,000
Breast (young and often bilateral) GI, Uterus
25-50% Skin, neurological, thyroid, multiple hamartomas
Indicators of HBOCS • Multigenerational on same side of family • Early age of onset • Ovarian/ fallopian/ primary peritoneal cancer • Male breast cancer • Breast cancer plus a history of unusual patterns of
cancers associated with the high risk breast cancer susceptibility genes
• Ashkenazi Jewish inheritance • McLeod Whanau (e-Cadherin germline mutation) • Known gene mutations associated with HBOC
(BRCA1/2, PTEN, TP53, STK11) in family
Taking a Family History in Primary Care
• Both maternal and paternal history is important • To be significant all relatives must be on the same
side of the family and be blood relatives of each other
• First degree relatives: Mother, father, sister, brother, daughter, son.
• Second Degree Relatives: Grandparent, grandchild, aunt, uncle, niece, nephew, half-sister, half-brother.
• If possible verify type of cancer, age of affected relatives, age of death.
Risk Assessment tools 1. Drawing a family tree
2. Computerised models
• FRA-BOC • Gail, Claus, Tyrer-Cuzick, BRCAPRO and
BOADICEA –(useful in 2⁰ and 3⁰ care and for assessing suitability for MRI surveillance)
3. Genetic testing
Draw a family tree:
42
55 ? 36
40
45
FRA-BOC Access online at:
www.canceraustralia.gov.au Follow links to familial risk assessment • Max 8 questions to provide risk estimation • Includes information about 1st & 2nd relatives
on both sides of family • Quick and easy to use – places women in 1
of 3 broad risk categories and gives appropriate management guidelines
• Most Appropriate Tool for Primary Care
Average Risk – 95% • No confirmed family history • One first degree relative >50yrs • One second degree relative any age • Two second degree relatives same side >50 • Two first or second degree relatives >50 on
different sides of the family
o As a group lifetime risk of breast cancer is between 1:11 and 1:8
ie no more than 1.5 x population average
Management Plan – Average risk
• Advise that risk is similar to the rest of the population
• Advise Self breast awareness • Advise to attend Breastscreen Aotearoa for
screening mammograms from age 45 yrs. • Discuss modifiable risk factors • Encourage all women to be aware of normal
look and feel of their breasts and promptly report any persistent or unusual change to GP
Moderately Increased risk – 4%
• One 1st degree relative diagnosed with breast cancer before the age of 50 *
• Two 1st degree relatives, on the same side of the family, diagnosed with breast cancer *
• Two 2nd degree relatives, on the same side of the family, diagnosed with breast cancer, at least one before the age of 50*
* (without the additional features of the high risk group)
o As a group lifetime risk is between 1:8 and 1:4, ie 1.5 – 3 x population average
Management Plan – Moderately increased risk
• Advice as for general population
PLUS
• Annual mammography from age 40
Potentially High risk – 1% • 2 or more 1st/ 2nd degree relatives on the same side of the
family diagnosed with Breast/ Ovarian Cancer PLUS 1 or more high risk features on the same side of the family: <40 years of age Bilateral breast cancer Breast cancer in a male relative Breast and ovarian cancer in the same patient Ashkenazi Jewish Ancestry Additional relative with breast or ovarian cancer • One 1st or 2nd degree relative with breast cancer at age 50 or
younger PLUS another 1st/2nd degree relative on the same side of the family with sarcoma (soft tissue /bone) at age 45 or younger • A member of the family in which the presence of a high risk gene
mutation has been established
• As a group lifetime risk is between 1:4 and 1:2.
Ie: Risk may be 2- 3 x the population average (≥ 20% lifetime risk)
Management Plan – Potentially high risk
• Advise that that although there is a potentially high
risk of developing breast cancer, and perhaps other cancers, many women in this group will not develop breast cancer
• General advice re risk modification/ family planning/ lifestyle
• Referral to a breast clinic for risk assessment, and additional surveillance with annual MRI
• Consideration of Referral for genetic screening
MRI and Breast Screening • High Sensitivity (98 - 100% with MMG) • Lower specificity (90% vs. 95% for MMG) resulting in
more call backs, biopsies and anxiety • Therefore indicated for high risk population (≥ 20%
above population baseline) as positive predictive value in this group is 20-40%)
• Is not a substitute for mammography • In high risk groups screening should begin at age 30
or ten years before index member (age 20 for TP53 mutations)
• ???risk of ionising radiation – MMG > 30/ USS <30
Consider Genetic testing for: • Any woman in potentially high risk group with a living
affected relative • Member of a family with confirmed germline BRCA
gene mutation or other known gene abnormality conferring increased risk of breast cancer
• ? Young women diagnosed with triple negative breast cancer (High association with BRCA1 gene mutations)
• Women with a family history of breast cancer and Ashkenazi Jewish Inheritance
• Male breast cancer • High grade serous ovarian cancer
Gene testing referral process • Referrals can be made to Genetic Health Service New
Zealand (GHSNZ), by Specialist, GP, Practice Nurse or by self referral
• The Northern Hub covers the upper half of the North Island. It is based at Auckland Hospital and provides outreach clinics in Whangarei, Hamilton, Tauranga, Rotorua and Gisborne
• Clinics held – Auckland ( weekly ) - Waikato (monthly) - Tauranga – 3-4 a year • Waiting time – months for Tauranga, may be shorter if
can go to Auckland • Cost: free
Contact address: Genetic Health Service New Zealand (GHSNZ) –
Northern Hub Auckland Hospital Private Bag 92024
Auckland Mail Centre, Auckland 1142 Ph. (09) 307 4949 ext. 25870 Fax (09)307 4978
Email: [email protected]
0800 476 123
(Best Practice Journal Issue 47: Oct 2012)
Genetic testing process • First step is Detailed phone/mail interview to collect
details of the family history • Discussion regarding implications of testing / pre-
test counselling • General approach is to test an affected member
(search) • A blood sample is taken and sent to Australia –
takes 3-6 months for result. • If gene mutation is found relatives will be offered
testing after counselling (Predictive testing)
Results Genetic testing does not always supply the answers
Genetic counselling
Mutation Search (Affected relative)
No mutation found in BRCA1 or 2 (~80% of families)
INCONCLUSIVE
Family remains high risk, continue high risk screening including annual MRI
Mutation Found
Predictive testing of at risk relatives
CONCLUSIVE
+ -
High risk screening Refer to discuss prevention/ RRS / trials Offer support – gift of knowledge
Risk as for population average for age.
Screening as for this group
Risk reduction strategies for carriers of breast cancer susceptibility genes.
• Improve modifiable risk factors – family planning/ lifestyle factors/contraception
• Enhanced Surveillance - (Annual MRI + MMG/USS) • Prophylactic Tamoxifen – reduction in breast cancer
rate ≈ 50% in BRCA2 mutation • Prophylactic bilateral salpingo-oophorectomy (BSO)
• similar benefit to Tamoxifen if by age 40. • Reduces risk of ovarian cancer by 80%
• Prophylactic mastectomy and breast reconstruction • Reduction in risk of breast cancer by 90%
Menopause
after Breast
Cancer
Why does the issue of premature menopause warrant increasing
attention?
• 25-30% of new breast cancers occur in women <50yrs of age.
• Treatments have increased survival rate BUT at the
expense of early menopause
Symptoms of Menopause Symptoms in young patients are typically more severe marked by: • Distressing vasomotor symptoms (VMS) • Urogenital symptoms • Sexual dysfunction • Decreased metabolism • Musculoskeletal effects • Cardiovascular effects • Fatigue
How common Is Treatment Induced Menopause and Who is Affected?
Panjari et al: Sexual function after breast cancer. J Sex Med. 2011;8(1):294–302. – A prospective cohort study of 1,011
women treated for breast cancer
• 70% experienced sexual dysfunction • 77% reported severe VMS • Women with VMS were 2x likely to experience sexual
dysfunction • Women with body image issues were 2.5x more likely to
report sexual dysfunction
Causes: 1. Adjuvant Chemotherapy (CXT) • Risk of early menopause with polyagent CXT is in the
range of 26-89% • Extent of CXT induced follicular damage ranges from
preservation of menses, temporary amenorrhoea, irregular menses (perimenopause) to complete ovarian failure (menopause)
• Chemotherapy related amenorrhoea (CRA) varies with
age, cytotoxic agents used and total cumulative dose.
2. Adjuvant Endocrine Therapy (ET) • Compared with placebo Tamoxifen is associated with
significantly more Vasomotor and genitourinary symptoms. (NSABP breast cancer Prevention Trial)
• AIs block peripheral production of oestrogen • The combination of CXT and ET increases the risk for
early menopause and resultant increase in menopausal symptoms
• Risk increases with age o from 5% in normal population to > 40% at age 40 yrs. o from 20% in normal population to ~100% at age 50 yrs. )
Probability of menopause during the first year after diagnosis in women who received no therapy, hormonal therapy, chemotherapy, or both.
Current treatments available to treat menopausal symptoms include:
• Herbal and complementary treatments
• Lifestyle modifications
• Non hormonal pharmaceuticals • Hormonal treatments
Herbal and Complementary Medicines
• Multitude of small trials involving a variety of herbal remedies including Black Cohosh, Dong Quai, phytoestrogens and homeopathic remedies.
• To date no convincing evidence any are better than
placebo • Concerns re estrogenic agonist activity of Dong Quai
and risk of hepatotoxicity in long term use of Black Cohosh.
Lifestyle Modifications • Yoga and relaxation
• reduction in sympathetic activation and psychological distress (common triggers for hot flashes)
• Behavioural and Lifestyle Modification • Wearing lighter clothes, dressing in layers, keeping
the room temperature low, avoiding alcohol and spicy foods and drinking cold beverages have all been shown to improve VMS
• Exercise, Diet and Rest – have a positive impact on psychological well-being as well as decrease in VMS
Non Hormonal Pharmaceuticals
Background Physiology • Hot flashes are the most commonly perceived and
reported menopausal symptom. • Decreased oestrogen levels are believed to cause an
induction in noradrenergic hyperactivity, which leads to a heat loss response and the sensation of warmth throughout the body followed by sweats
• Serotonin may also play an important role in
thermoregulation, as decreased serotonin levels and upregulation of serotonin receptors in the hypothalamus are associated with oestrogen withdrawal
1. SSRIS • Fluoxetine 20 mg/d was associated with a 50% decrease
in hot flash scores at the end of the first 4-week treatment period compared with a 36% decrease in those receiving placebo
• Paroxetine 10 mg/d reduced the frequency of hot flashes by 40.6% compared with 13.7% for placebo (P = .0006) and 20 mg reduced hot flash frequency by 51.7% compared with 26.6% for placebo (P = .002).
• Citalopram 10 mg/d of citalopram reduced frequency of hot flashes by 46% compared to 23% for placebo, and by 55% in those receiving 30mg a day.
• Citalopram is a moderate inhibitor of CYP2D6 and can be given with Tamoxifen
2. Venlafaxine • affects the reuptake of serotonin and noradrenalin. • Reduction in frequency and severity of hot flashes
from 36% to 66% compared to 27% with placebo, depending on dosage ( range 37.5mg to 150mg)
• Side effects dry mouth , sleep disturbances and loss
of libido
• Not currently funded for use in VMS but as mood disorders are a common presentation among breast cancer survivors and antidepressants may provide relief for more than just hot flashes.
3. Gabapentin: • Multiple randomized controlled trials have
evaluated the efficacy of gabapentin for the treatment of hot flashes.
• 45-66% reduction in hot flush frequency and severity compared to placebo (dose 900mg/day)
• 31% reduction at 300mg/day with no reported side effects
• Side effects reported were light-headedness, excessive sleepiness, and rash.
4. Clonidine
• A centrally acting α-agonist that reduces vascular reactivity.
• Reduces the release of adrenalin in the brain, raises the sweat threshold, and may ameliorate hot flashes
• 100μg od → ↓ in VMS by 38% vs. 24% with placebo
• Side effects include sleep difficulties, dry mouth, constipation, postural hypotension and skin reactions
• Thus clonidine currently has only a limited role as a treatment of menopausal VMS.
Hormonal Treatments ?
• WHI and HABITS trial both demonstrated increase in adverse events among women treated with oral HRT
• Based on these studies it is nearly universally agreed that oral
HRT should not be used for treatment of menopausal symptoms in breast cancer survivors
• Includes testosterone replacement (aromatisation to oestrogen),
and Tibolone.
Urogenital Symptoms and Sexual Function Symptoms: • Vaginal dryness (AIs, GnRH analogs – but not
Tamoxifen) • Sexual dysfunction
• Loss libido (SSRIs) • Vaginal myalgia / Vulvodynia
Management of Urogenital Symptoms
• Avoid washing vaginal area with soap, use soap substitutes
• Apply regular moisturisers e.g. sorbolene, vit E cream
• Use water based lubricants during intercourse • Bio-adhesive Vaginal moisturisers – e.g.
Replens™ • If refractive topical oestrogen (lowest dose
required to relieve symptoms)
• Pelvic floor relaxation for vaginal myalgia
• ? Botox to pelvic floor muscles / nerve modulators (TCAs, Gabapentin) for vulvodynia
• Sildenafil (1/2 male dose) for SSRI related loss of libido
Cardiovascular effects
• Potential cardiac effects from RXT, CXT & trastuzamab
• Increased CVD risk associated with postmenopausal Oestrogen decline
• Primary Care CVD risk assessment and treat modifiable factors accordingly
Changes in Metabolism
Weight gain post menopause due to: • Loss of fat-free mass post menopause • Post menopausal women tend to exercise less • Post menopausal women burn fewer calories at rest
than do premenopausal women suggesting oestrogen has role in weight regulation
Treatment: • Moderate intensity aerobic exercise has been shown
to produce favourable changes in body composition, improves long term prognosis, mood disorders and quality of life.
• Induction of premature menopause and use of AIs increases risk of osteoporosis
• Identification and appropriate management of
women at risk is essential to prevent skeletal morbidity from CXT and hormone therapy
• 1/3 of women on AIs suffer joint and muscle pain –
mechanism uncertain but attributable to oestrogen depletion
Musculoskeletal symptoms
Management:
• General lifestyle measures • Regular physical activity including impact and non
impact exercises ( decrease bone loss by 1- 1.6%) • Smoking , caffeine and alcohol ( all have negative
impact on bone loss) • Adequate dietary calcium intake (3 servings dairy as
rule of thumb) • Vitamin D – sunlight exposure, diet or supplement
• No evidence for prophylactic bisphosphonates for
women on AIs with normal bone mass
Vitamin D in Breast Cancer • Epidemiological studies showing inverse relation of
sunlight exposure/ Vit D levels and incidence of breast cancer, tumour growth , metastasis and recurrence
• Extra renal production of 1-α- hydroxylase in breast tissue
• Discovery of Vitamin D Receptors (VDR) in breast tissue
• Vitamin D involvement in Cox2 inhibition and inflammation
• Healthy bone at less risk for metastases
Vitamin D in Breast Cancer • 40-60nmol/L considered optimum level for bone and
breast health • Adverse effects unlikely below 100nmol/L and
toxicity unlikely below 250 nmol/L • Best source is sunlight • Diet alone unlikely to provide sufficient levels • Identify those at risk • Consider supplements in those unable to increase
sun exposure • Consider for those on AIs due to increased risk of
osteoporosis and as Vit D shown to decrease the incidence of MSK symptoms
Summary • Benefit of increased use of CXT and targeted
endocrine therapy in patients with early stage breast cancer on survival and recurrence needs to be balanced with detrimental effects of menopausal complications and quality of life especially in young breast cancer survivors.
• First line treatments should be lifestyle modification and relaxation therapies in mild VMS
• SSRIs, venlafaxine and Gabapentin are most promising first line non- hormonal pharmaceutical agents for VMS
• Clinical evidence for herbal and homeopathic treatments scarce
• Local vaginal moisturisers are useful for urogenital symptoms
• Topical oestrogen in refractory cases
• Standard advice to address CVD risk, metabolic effects and bone health with diet, exercise and smoking cessation
• Consider Vitamin D supplements
Mastalgia
Mastalgia (Breast Pain) • One of the most common breast related complaints
• Nearly 70% of women experience pain at some time in their lives.
• Pain can vary from trivial premenstrual discomfort to severe and debilitating pain persisting throughout the menstrual cycle.
• Pain may occur in one or both breasts and may even extend to the armpit.
• Breast cancer is rarely painful but needs exclusion.
Cyclical Breast Pain • Breast pain seldom occurs at puberty but may be a
significant problem in later teenage years. Breast pain predominantly occurs in the 35-45 year age group
• Rare after menopause unless women are taking hormone replacement therapy (HRT).
• Cyclical breast pain accounts for nearly 76% of all breast complaints.
• Is a response by the breast tissue to the hormones produced by the pituitary gland.
• Starts premenstrually, relieved with menstruation
Non cyclical breast pain
Non-cyclical causes for pain
• True breast pain,
• Chest wall pain
• Referred pain.
• Physical activity
• Costo-chondritis
Investigations • Routine history –duration, timing with cycle, activity,
other associations, bilateral/ unilateral • Physical exam • Imaging if unilateral, palpable lump, other abnormality
*request Mammogram + USS ± Core biopsy if indicated
• Consider FNA
Treatment Options • Reassurance only
• Dietary - limit salt intake, reduce caffeine, alcohol and saturated fats
• Maintain an ideal weight - losing excess weight can stabilise hormone levels and reduces risk for breast cancer later.
• Wear a well fitted bra
• Reduce stress, stop smoking, regular exercise
With this advice and reassurance over 85% of patients will require no special treatment for breast pain.
Herbal treatments
• Flax seed oil – 25g daily as first line treatment (IA) • Evening primrose oil or Star flower oil - presently
insufficient evidence to recommend their use (II-2 C). However some patients may still wish to trial this otherwise safe option. The regime is: o 3000mg (3g) of EPO per day should be taken for the first
6 weeks. Most women will get full or partial relief of breast pain within the second month of treatment.
o Once the pain resolves, reduce the dose of EPO to two thirds or half the dose i.e. 2000mg or 1500mg.
o If there is no improvement after taking EPO 3000mg per day for 6 weeks we should recommend stopping.
Hormonal Treatments Tamoxifen 10mg daily.
• Cheap effective medication • should be avoided in those with a history of
thromboembolic disease.
• Reported incidence of side effects: • Hot flushes 10% • Menstrual irregularity/ amenorrhoea 10% • Weight gain, nausea, vaginal dryness and bloating
5% or less
Danazol 100mg bd. • more expensive drug
• more effective in cyclical Mastalgia but equally effective as Tamoxifen in this setting.
• Reported incidence of side effects; • Weight gain 30% (this can be minimised with
careful advice re diet and salt intake) • Menstrual irregularity/ amenorrhoea or
menorrhagia 50% • Deepening of voice 10% • Hot flushes 10% • To minimise this it can be given in luteal phase
only.
MASTALGIA ALGORITHM
Breast Pain
History & physical examination
+ve findings on exam
? Chest wall pain
Rx as appropriate
Refer to breast service for
further investigation
Treatment options
1. Reassure 2. Firm bra support 3. simple analgesia 4. Lifestyle changes 5. Consider changes to contraception –hormonal/non-
hormonal 6. If on HRT consider regime change
Persistent? Mild
Reassure & educate.
Follow-up prn
Moderate to severe Cyclical Non-cyclical
Trial of:
1. Flax seed oil, 25g/day for 3/12 &/or 2. EPO 3g daily
Severe, persistent & unilateral No
No Yes
Yes No
Effective
No Yes Continue daily or
luteal phase only
or or
Danazol 100mg bd for 3/12 Tamoxifen 10mg daily for 3/12
Effective at 3/12? Continue and reassess after 6/12
yes No
Consider:
1. Bromocriptine 2.5mg bd after gradual increase
2. Psychological/emotional support
Gynecomastia
Gynecomastia: • Is the non-cancerous enlargement of one or both
breasts in a male. • Common, affecting 30-50% of healthy men and
accounting for 60% of disorders of the male breast.
• Clinically defined by the presence of a firm mass under the nipple and extending outward concentrically.
• Is due to proliferation of the glandular tissue of the breast.
• Is not associated with increased risk of breast cancer in men
Pseudo-gynecomastia or lipomastia • Refers to increased deposition of fat in the male
breast without glandular proliferation • Is generally associated with obesity. • Pectoral muscle enlargement can simulate
gynecomastia
Pathophysiology of Gynecomastia • Estradiol in men is derived from peripheral
aromatisation of testosterone and adrenal oestrone • Oestrogen stimulates the proliferation of breast tissue
cf inhibitory effect of androgens • Gynecomastia results from an altered oestrogen-
androgen balance, in favour of oestrogen, or from increased breast sensitivity to a normal circulating oestrogen level
• Oestrogens in males is primarily derived form extra-testicular aromatisation of androgens
• Thus any cause of oestrogen excess from overproduction to peripheral aromatization of androgens can initiate the cascade to breast development.
Extraglandular Tissue Circulation Steroid - Secreting Testis Adrenal Tissue Leydig Cell Pathophysiology of gynecomastia: Estrodiol is the growth hormone of the breast and and excess of estrodiol leads to
Breast Growth
Estrodiol Estrone
Testosterone Androstenedione
Testosterone Androstenedione
Estradiol Estrone
*Predominately aromatisation in fat
Physiological Causes of Gynecomastia Three peaks during life
1. Neonatal period
• 60-90% of infants have transient breast enlargement due to maternal hormones transferred across the placenta.
2. Puberty.
• 48-64% of boys at puberty have gynecomastia. Usually the peak age of onset is 12-14 years, resolving within 2 years and almost always by age 20
3. Late life.
• The highest prevalence of gynecomastia is seen in men aged 50-80 years and is associated with natural decline in testicular function and decreased testosterone production.
Pathological Causes of Gynecomastia Any condition causing an imbalance between production and action of oestrogen and testosterone • Primary Hypogonadism (↑LH, ↓T ), and Secondary
Hypogonadism (↓LH, ↓T) o ≈ 8% and 2% respectively o Congenital, acquired and idiopathic
• Chronic illness, starvation, malnutrition (8%) • Obesity • Medications (10 – 25%) • Testicular - trauma, surgery, irradiation, malignancy
(3%) • Idiopathic (≈ 25%)
Gynecomastia in adults is often multifactorial. • Increased aromatization of testosterone to oestrodiol
in extraglandular tissue (Primarily fat) and the gradual decrease of testosterone production in the aging testes most often account for gynecomastia in adult males.
• Older men are also more likely to take medications associated with gynecomastia than are younger men
• and have associated chronic illnesses o Renal failure o Thyroid disease o Liver Cirrhosis
Some Drugs Cause Awesome Knockers
Medications • 10-25% of gynecomastia is seen as a side effect of
drugs,
• Many - both prescribed and those taken for recreational purposes. o Antiandrogens/inhibitors of androgen synthesis
o Cancer/chemotherapeutic drugs
o Cardiac and antihypertensive medications
o Hormones
o Psychoactive drugs
o Drugs for infectious diseases
o Drugs of abuse
o Others
Approach Considerations • Patients with physiologic asymptomatic or
prepubertal gynecomastia do not require further evaluation - (follow-up 6/12).
• Further evaluation is necessary in patients with the following:
• Breast size greater than 5 cm
• A lump that is tender, of recent onset, progressive, or of unknown duration
• Signs of malignancy (e.g. hard or fixed lump or positive lymph node findings)
Approach Considerations
History
• Duration (and age of onset) family history • Associated symptoms – pain, discharge,
nipple eczema, • Drugs (include alcohol, recreational drugs) • Sexual functioning/ history of testicular
trauma, mumps/ infertility • Weight change • Thyroid
Examination
• Breast - true vs. pseudogynecomastia, uni/bilateral, tenderness, nipple discharge, skin changes
• External genitalia • Abdomen – chronic liver disease, renal
disease, thyroid • Feminisation/ virilisation
Investigations • Laboratory Studies
–FBC, RF, TSH, LFT, FSH, LH, βHCG, estrodiol and testosterone.
• Radiology: If suspect malignancy Mammogram, US plus core biopsy or FNA Testicular USS if indicated
• NB: suspect malignancy if lump >5cm, unilateral,
eccentric, irregular, strong family history suggestive of HOBC, especially BRCA2 gene mutations.
Treatment • Generally no treatment is required for physiological
gynecomastia. • Identifying and correct any underlying abnormality • Medical treatments are unlikely to result in regression of
the breast enlargement if it has been present longer than 12 months.
• Most adolescent gynecomastia resolves spontaneously within 18 months to 2 years without treatment. • If distressing Tamoxifen can be trialled for 3 months. • Most effective for recent onset and tender
gynecomastia. Up to 80% of patients report partial to complete resolution.
Treatment continued:
• Weight loss – decreased aromatisation of androgens to oestrogen
• For drug related gynecomastia, withdrawal of the medication usually leads to regression over a year.
• For men with reduced gonadal function and decreased production of testosterone, testosterone replacement can be considered.
• Testosterone does, however, have the potential to exacerbate gynecomastia.
Surgery • Reduction mammoplasty may be considered for those
with longstanding gynecomastia, in those in whom medical therapy has failed or for psychosocial reasons.
• For patients with pseudogynecomastia or lipomastia, liposuction is the procedure of choice. However this will be less successful in true gynecomastia as it will not remove the glandular tissue.
• Complications of surgery include wound infection, skin or nipple loss due to compromised blood supply, scarring, loss of contour and permanent numbness or altered sensation in the nipple- areolar area.
Vitamin D and Breast Cancer
Vitamin D: Is it the best thing under the sun?
• Explosion of literature regarding the benefits of Vitamin D o 1142 citations of studies in 2000 o 3877 in 2012
• Long known to be important in bone health now increasing evidence that Vitamin D has effects on almost all body systems: o Respiratory o Diabetes o Autoimmune disease o Cancer - breast, colon o CVD o Neurologic function o Etc. etc.. etc..
Vitamin D – the vitamin that isn’t a vitamin • 4th vitamin to be discovered
• A group of secosteroid compounds that include
ergocalciferol (D2) – plant - and cholecaciferol (D3) –animal
• Most circulating Vitamin D is produced when 17-dehyrocholesterol in the skin is exposed to UVB and converted to vitamin D3
• Dietary sources: o Oily fish o Fortified dairy and cereal products o eggs
Vitamin D: metabolism and action
7-dehydrocholesterol in skin
Vitamin D3 (cholecaciferol)
25(OH)D (major circulating metabolite
1,25(OH)2D (Calcitriol = biologically active form)
UVB
25-hydroxylase in liver
1-α- hydroxylase in kidney and extra renal tissue e.g.
breast
Binds to VDR intracellularly in breast epithelium
Regulation of gene expression
Vitamin D receptor (VDR) • Intracellular vitamin D receptor (VDR) first identified in
breast cell lines in 1979
• Activation of VDR maintenance of
extracellular levels of Vitamin D Influences up to 200 genes that mediate cellular growth, differentiation and apoptosis.
Breast cancer and Vitamin D: Epidemiology • 1990 Garland et al noted inverse association with
sunlight and breast cancer in USA
• Subsequent studies have noted inverse association with Vitamin D3 levels and Breast cancer, tumour size, mortality and recurrence in postmenopausal early stage breast cancer
• Suggesting protective role for Vitamin D in Breast Cancer Development
Proposed mechanisms for protective effect of vitamin D in breast cancer
• Growth and arrest apoptosis (VDR) • Inhibition of invasion and metastasis • Anti-inflammation • Oestrogen pathway inhibition
Defining Vitamin D deficiency • Caution in interpreting data • Multiple methodologies used lacking
standardisation across laboratories
• No real consensus but generally <20nmol/L considered deficient
• Optimum level for bone health >30nmol/L • Optimum level for breast cancer prevention 40-
60nmol/L
Recommended Vitamin D levels in NZ - Best Practice June 2011
Table 1: Recommended vitamin D levels7
Vitamin D serum concentration
Vitamin D status
<25 nmol/L Moderate to severe deficiency
25-50 nmol/L Mild deficiency/insufficiency
50-100 nmol/L Optimal range
>100-150 nmol/L Associations with adverse effects
>250 nmol/L Vitamin D toxicity
So should we be doing baseline serum 25(OH)D testing in breast
cancer patients?
• YES? because:
E deficiency down-regulates 1-α-hydroxylase enzyme and ↓levels of VDR thus further depletion of E levels may unmask subclinical vit D deficiency
NO because:
• Expensive test • Lack of consensus regarding optimum level • Unlikely to alter management in those not
considered high risk for deficiency • Vitamin D toxicity rare Therefore identify those at HIGH risk of vitamin D deficiency and manage accordingly
Risk factors for Vitamin D deficiency • Absence of sun exposure (levels lowest in winter) • Dark pigmentation • Older age (>70) • People with a history of hip fracture • Institutionalised/ house bound • Low dietary intake • Obesity • Malabsorption syndromes • Medications affecting absorption – e.g.
anticoagulants, rifampicin, methotrexate etc.. • Oestrogen deficiency syndromes/ AI
Prevention
1.Sunlight – rule of thumb : o short exposure (< burn time) o Direct sunlight (UVB) o Exposing up to 20% of body (shorts and t-shirt
exposes 30%) o Not affected by sunscreen
BUT seasonal variation
Region Dec-Jan
(summer) 10 am or 2 pm
July-Aug (winter) 10 am or 2
pm
July-Aug (winter) Midday
Auckland 6-8 min 30-47 min 24 min
Christchurch 6-9 min 49-97 min 40 min
Recommended daily sun exposure for vitamin D production for people with fair skin - Best Practice 6:2011
2. Diet • Diet is a minor source of vitamin D in comparison to
sunlight. • Supplementation through diet alone is unlikely to
provide adequate vitamin D in order to satisfy daily requirements
• Most people only derive 2.5 µg (100IU) of vitamin D per day from food, which is less than the New Zealand guidelines for vitamin D intake
• However, during winter months, diet can be an important source of vitamin D and increased intake of vitamin D rich foods should be combined with sensible amounts of sun exposure.
Optimal Management of Vitamin D Deficiency
If vitamin D deficiency suspected (based on risk factors) and those who are unable to increase sun exposure or modify diet: • Supplementation
oMonth 1: Stat dose of cholecaciferol 2.5mg ( ii tabs)
Or if severe deficiency 1.25mg od for 10/7 oMonth 2 onwards: 1.25mg cholecaciferol monthly
Vitamin D toxicity • Cannot occur with excess sunlight exposure due to
self regulation • Food and supplements are not naturally regulated • Monthly dose of 1.25mg is safe BUT some OTC
products contain significant levels which may lead to inadvertent toxicity with prolonged intake ( e.g. cod liver oil, multivitamins)
• Toxicity unlikely to occur below serum 25(OH)D levels 250nmol/L
• Care with renal failure, hyperparathyroidism ( monitor Ca levels)
Summary • Emerging evidence of association with vitamin D
deficiency and breast cancer • No evidence for blanket supplementation in general
population • BUT vitamin D is well tolerated • Target at risk group for supplementation • In breast cancer target postmenopausal women with
early stage disease • Especially if on oestrogen suppression therapy / CXT • Important in bone health for those on AIs • May be useful in alleviating MSK side effects of AIs
