endocrine therapy for breast cancer
TRANSCRIPT
Adjuvant Endocrine Therapy for Invasive Breast Cancer
Providence St. Joseph Medical CenterOctober 2013
No Relevant Disclosures
Adjuvant Endocrine Therapy for Breast Cancer
Adjuvant Endocrine Therapy for Invasive Breast Cancer
• Endocrine therapy choices in pre- and post-menopausal patients
• Optimal Duration of therapy• Side effects and Treatment of side effects - What the literature says - What your patients are saying
Adjuvant Endocrine Therapy for Invasive Breast Cancer
70% of patients with breast cancer are hormone receptor positive and will be advised regarding the risks/benefits of endocrine therapy
Rationale for Endocrine Therapy
• Estrogen promotes the growth of breast cancer by binding to and activating the Estrogen Receptor (ER)
• 3 possible ways to interrupt this process - Interfere with receptor binding - Down regulate receptor - Reduce estrogen production
#1: Drugs that interfere with binding of estrogen to the estrogen receptor
• Tamoxifen: Selective Estrogen Receptor Modulator (SERM), “gold standard” of endocrine therapy that has been used for decades
• Other SERMs– Toremifene (Fareston): not commonly used since It
has no known advantage over Tamoxifen– Raloxifene (Evista): approved for risk reduction but
not treatment of invasive breast cancer
# 2: Estrogen Receptor “down-regulators”
• Work by making less estrogen receptor available for estrogen binding
• Fulvestrant (Faslodex)– Primarily used with metastatic disease– Clinical trials evaluating adjuvant use
#3: Therapy to reduce estrogen productionPremenopausal Patients
• Ovarian Ablation/Suppression (OA/OS)– Medical: LHRH Agonists-- Goserelin (Zoladex)
or Leuprolide (Lupron)• LHRH agonist therapy downregulates pituitary• Decreased production of LH and FSH• Suppression of ovulation and estrogen production.• Potentially reversible; most commonly utilized
– Surgical: Oophorectomy (irreversible)– Radiation: No longer utilized
#3: Therapy to reduce estrogen productionPostmenopausal Patients
• Aromatase Inhibitors (AI)– Reduce circulating estrogen by blocking Aromatase
mediated conversion of androgens to estrogens in peripheral tissues (adipose tissue, and muscle)
– Non-Steroidal AI - reversible binding• Letrozole (Femara)• Anastrozole (Arimidex)
– Steroidal AI - irreversible binding to aromatase• Exemestane (Aromasin)
Definition of menopause?NCCN guidelines, version 2.2013 • Prior Bilateral Oophorectomy
• Age > 60• If Age < 60
– Amenorrheic for 12 or more months (in the absence of tamoxifen, toremifene, or ovarian suppression) with FSH and estradiol levels in post-menopausal range
– If taking tamoxifen or toremifene and age < 60 years, then FSH and plasma estradiol levels in postmenopausal range
Considerations in Premenopausal Patients• Ovary is main source of estrogen• Endocrine therapy choices: - Tamoxifen alone - Tamoxifen with OA/OS
• Aromatase Inhibitors are contraindicated since they will not reduce ovarian estrogen production
Case PresentationPremenopausal Patient
• 36 yo female with a 2.4 cm breast mass on SBE• US Core biopsy positive for grade 2 IDC• ER 80%, PR 80%, Her2/neu 1+
• Left Mastectomy with ALND for a positive SLN• Final pathology: T2 N1; 5/14 nodes; Stage IIIA
• She completed adjuvant chemotherapy and post-mastectomy radiation
• Menstrual cycles resumed during radiation
Case PresentationPremenopausal Patient – Questions
• Should this patient receive adjuvant endocrine therapy?
• If yes, how long (5 or 10 years)?• Should she consider OA/OS?• If yes, should she be switched to an
Aromatase Inhibitor or left on Tamoxifen?
Case PresentationPremenopausal Patient - Decisions
Question # 1 Will she benefit from adjuvant Tamoxifen?
NSABP B-14: Tamoxifen superior to placebo
• Randomized double-blind placebo controlled trial in node negative, hormone positive patients: 2800 patients
• Significant disease-free and overall survival benefits of Tamoxifen regardless of age of patient
• Contralateral breast cancer occurred in 3.7% of Tamoxifen treated patients versus 6.1% on placebo (p=.007)
Oxford Meta-Analysis: Tamoxifen superior to placebo Early Breast Cancer Trialists’ Collaborative Group 2011
• Meta-Analysis 20 trials with patients allocated to Tamoxifen vs placebo or no treatment
• 13-15% reduction in recurrence• 33% reduction in mortality regardless of age
Premenopausal Case Presentation, continued…• Patient was advised to take adjuvant
Tamoxifen
• Question #2:• Should she take Tamoxifen for 5 or 10
years?
Duration of Tamoxifen TherapyWhat we know….• 5 years is better than 2 years
• No clear evidence in favor of Tamoxifen beyond 5 years…
• Until SABCS 2012: ATLAS trial results
ATLAS Trial Adjuvant Tamoxifen Longer Against Shorter
Early stage breast cancer patients who completed 4-5 years of tamoxifen therapy
N = 6846
RANDOM IZE
Discontinue tamoxifen (5 years total therapy)
Continue tamoxifen for10 years total therapy
ATLAS Trial
• 3.7% reduction in recurrence• 2.8% reduction in breast cancer mortality
• Conclusion: Risk of death caused by tamoxifen side effects is greatly outweighed by the reduced breast cancer death provided by 10 years of tamoxifen therapy
Should this patient receive extended duration Tamoxifen therapy?
• YES. If tamoxifen is indicated and tolerated at 5 years, extension beyond 5 years has clear benefits
• Question #3: Should she undergo OA/OS
What is role of OA / OS in Premenopausal Women with Breast Cancer?
ASCO endorsed the Cancer Care Ontario (CCO) guidelines in 2011
However, benefit of OA/OS and patient selection for this therapy remains very controversial…
<40yo may be most likely to benefit from OA/OS
Pending OA/OS Trials
• Trials in progress to answer questions regarding duration, long term sequelae, and clarification of subsets of patients most likely to benefit
• SOFT (Suppression of Ovarian Function Trial) Compares TAM alone to TAM+ OA/OS vs AI/ OAS
• TEXT (Tamoxifen and Exemestane Trial): Treats all patients with OA/OS then randomizes to TAM vs AI
Premenopausal Case Presentation Continued…
You discuss ovarian suppression. She chooses to have laparoscopic oophorectomy. She completes 5 years of Tamoxifen.
Question #4In this patient who was premenopausal at diagnosis but is currently postmenopausal, should you..
Continue Tamoxifen for 5 more years?Switch to an Aromatase Inhibitor?
MA-17: 5 years Letrozole following 4.5-6 years Tamoxifen in Postmenopausal patients**
Tamoxifen for 5 years
Letrozole
Placebo
**883 (out ~ 5000 enrolled) were premenopausal at diagnosis and became postmenopausal (oophorectomy or secondary to chemotherapy) after 5 years of tamoxifen
Results:Significantly improved DFS with Letrozole vs Placebo But - many adverse QOL effects
Premenopausal Case Presentation Continued…
The patient was advised of these results
She decided to continue Tamoxifen rather than switching to an AI due to QoL concerns
Caution: AI in Premenopausal Patients w/ medically induced menopause (Chemo or OA/OS)
• Amenorrhea in perimenopausal women after chemotherapy does not guarantee ovarian suppression
• Aromatase Inhibitors may increase estradiol levels in women with residual ovarian function
• Ovarian suppression needs confirmation by estrogen levels before AI, monitor during therapy
• Use Tamoxifen if not clearly postmenopausal
Considerations in Postmenopausal Patients• Peripheral conversion of androgen to estrogen
by aromatase - main source of estrogen and primary target of therapy
• Questions:– Should she receive an AI or Tamoxifen?– Should she receive monotherapy (AI or
Tamoxifen alone) or sequential therapy using both?
– 5 vs 10 years of therapy?
Case Presentation:Postmenopausal Patient
• 62 year old female with suspicious microcalcifications on screening mammography
• Stereotactic biopsy: grade 2, hormone +, IDC with high grade DCIS. Patient opted for lumpectomy
• Final pathology: 1.2 cm grade 2 IDC with high grade DCIS. SLN 0/1 T1cN0 Stage IA
• Oncotype Dx Recurrence Score – low risk
Postmenopausal Case Presentation, continued…
•Question #1 Should she receive AI or TAM?
•Question #2 Should she receive monotherapy (one drug for five years) or sequential therapy?
ATAC: AI for 5 years is better than 5 years of Tamoxifen
Arimidex, Tamoxifen, Alone or in Combination Tamoxifen x 5y
Anastrozole x 5y
Tam + Anastrazole x 5y Combination arm closed early due to inferiority
- Significantly improved DFS with Anastrozole
- Fewer contralateral breast cancers with Anastrozole
- No significant difference in overall survival
BIG 1 98: 5 years of AI superior to 5 years TamoxifenBIG 1 98 Trial monotherapy arm update*
Tamoxifen 5 years
Letrozole 5 years
Post menopausal women with hormone positive invasive breast cancer
•10 year results
•Improved DFS with Letrozole
•No significant difference in overall survivalNote: After superiority of Letrozole was published in 2005, patients in the Tamoxifen monotherapy arm were allowed to switch to Letrozole (60% switched). Analysis adjusting for this crossover confirmed the superiority of Letrozole* NEJM 2005; 353(26): 2747. NEJM 2009; 361(8): 766
*JCO 2012. 30 (7): 718
Switching to AI after 2-3 years of TAM better than 5 years Tamoxifen
• ABCSG-8 and ARNO 95– Postmenopausal women, ER+ early breast
cancer who completed 2 years of TAM were randomized to receive Anastrozole or Tamoxifen for the rest of their therapy
• Primary endpoint: event-free survival• Result: 40% decrease in the risk of any event
with Anastrozole
Jakesz et al. Lancet 2005.366.455
Switching strategy: starting with Tamoxifen is equal to an upfront AI
No significant difference in DFS between the arms•Median follow up 5.1 years
Exemestane Tamoxifen
Exemestane
TEAM trialTamoxifen Exemestane Adjuvant Multinational Trial
5 y
2-3y 2-3y
Van de Velde et al. Lancet 2011; 377: 321–31
• 9775 postmenopausal hormone positive patients randomized to Aromasin vs sequential TAM/Aromasin
Optimal duration of therapy in Postmenopausal Patients
– MA-17: AI after 5 yrs of Tam is better than placebo – ABCSG-6a: Tamoxifen +/- aminoglutethimide for 2 years,
then randomized to anastrozole or placebo: significant reduction in risk of recurrence for patients who received anastrozole
– NSABP B-33: 5 years TAM randomized to exemestane vs placebo. Accrual terminated early due to publication of MA-17 results. Analysis showed borderline significant improvement in 4 year DFS
Extended duration with AI (>5 years)Pending Trials
• MA17R• LEAD• NSAPB B-42• SALSA• DATA• SOLE
Which AI should be used?
• The benefits of AI therapy appears to be a “class effect”
• The different AIs appear to have equivalent efficacy (MA-27)
• Similar SE profile for all drugs Rao & Cobley. Oncology June 2012;26(6):541-559MA-27: Goss et al. Presented at SABCS December 2012
Question 2/3 Summary: AI vs TAM; Monotherapy vs Sequential…
• 5 yrs of adjuvant AI better than 5 years of TAM (ATAC, BIG 1-98 monotherapy arm)
• Switching to AI after 2-3 yrs of TAM is better than 5 yrs of Tam (ARNO, IES, ABCSG 8)
• Switching to AI after 2-3 years of TAM is equivalent to 5 years of AI (TEAM, BIG 1-98)
• Switching to an AI after 5 yrs of TAM is better than placebo (MA 17)
• Endocrine therapy should include AI but sequencing with tamoxifen is acceptable
Postmenopausal Case Presentation, Continued…• Patient was advised to begin an aromatase
inhibitor
• Decision regarding duration of therapy beyond 5 years deferred pending evaluation of tolerance of the drug and bone density status after 5 years of therapy
Endocrine Therapy Adverse Effects
• AE occur with variable frequency and severity• Early reports suggested no effect on QoL but
later studies 20-50% of patients discontinue therapy – often not disclosed
• More likely if not informed / prepared for AE
• Some evidence that women who experience AE may have the most benefit from treatment
Endocrine Therapy Adverse Effects ASCO Classificationffects
• Cardiovascular• Musculoskeletal• Gynecologic• Climacteric including hot flashes, sexual
dysfunction, and neuropsychological effects
Adjuvant TrialsCardiovascular Adverse EffectsEffects
• Tamoxifen increased venous thromboembolic events 1-2% compared to women on AI
• AI increased cardiovascular disease including ischemic cardiac disease, <1% difference between AI and TAM for serious cardiac disease. Cardiac morbidity not consistently reported among trials
• Tamoxifen has modest lipid-lowering effect (5-30%), possibly one mechanism of reducing risk
• AI effects on lipid profiles inconsistent; studies comparing AI to TAM may be due to lipid-lowering effects of TAM rather than increase due to AI
• Data on stroke inconclusive
Management of Adverse EffectsCardiovascular• No specific recommendations• Counseling on proper diet and exercise,
tobacco avoidance, alcohol in moderation• Manage pre-existing cardiovascular
disease and hypercholesterolemia
Adjuvant TrialsMusculoskeletal Adverse Effects Effects
• AI associated with greater loss of bone mineral density and increased bone fracture compared to TAM, 2-4% on average
• Many trials did not include baseline assessment of BMD or planned BMD monitoring
Management of Adverse EffectsMusculoskeletal – Bone Loss• Check DEXA baseline and annual• Limitation of DEXA: BMD is surrogate measure
for fracture risk - bisphosphonates prevent bone loss but meta analysis suggests might not translate to decreased risk of fractures
• Stopping AI often halts further loss of BMD• Consider tamoxifen if taking an AI• No antiresorptive agents FDA approved
specifically for prevention or treatment of AI-induced bone loss
Management of Adverse EffectsMusculoskeletal – Bone Loss
• Weight bearing exercise, smoking cessation, limitation of alcohol intake
• Calcium and Vitamin D widely recommended but not adequately studied
• BMJ – compared to 600-1000 mg/day, calcium intake above 1400 mg/day associated with higher death rates from all causes, cardiovascular disease and ischemic heart disease but not stroke
• Less effect if primarily dietary sources as opposed to supplements; milk, yogurt, cheese, sardines, salmon, tofu made with calcium sulfate, kale, dark leafy greens
Adjuvant TrialsMusculoskeletal Adverse EffectsEffects
• Arthralgia / myalgia syndrome - pain, stiffness, achiness – symmetric, not associated with signs of rheumatologic disorders
• Variable incidence, up to 50%• More common with AI vs TAM• Most report mild to moderate symptoms
Management of Adverse EffectsMusculoskeletal – Arthralgia/Myalgia• May be self-limited – often improves over time
without intervention
• NSAIDs, heat, exercise, weight loss, physical therapy
• May have benefit from changing AI• Change to tamoxifen • Recent data suggesting glucosamine effective
• Acupuncture
Musculoskeletal AE’sAcupuncture Benefits
• Postmenopausal women with BC, self-reported pain related to AI
• Randomized, Blinded Sham-Control x 6 weeks• Small sample size 51 enrolled, 43 randomized, 38 evaluable
• Significant improvement in joint pain and stiffness• Exact mechanism unclear: increase in opioid
peptides and anti-inflammatory cytokines
Crew, LD., et al J Clin Oncol 2010
Management of Adverse EffectsMusculoskeletal – Arthralgia/Myalgia• Bisphosphonates not proven efficacy for pain• Topical agents - temporary palliation• Under study – high dose Vitamin D• Treatment of sleep disturbance may help• Discontinuation of medication usually relieves
symptoms within 8-10 weeks
• More objective measures – vitamin D metabolite levels, inflammatory and rheumatologic markers - under development
Adjuvant TherapyGynecologic Adverse Effects Effects
• All adverse events more common on TAM• Uterine cancer <1%• ATLAS Uterine Cancer Incidence / Mortality Extended Therapy: 3.1 / 0.4% Control: 1.5 / 0.2%• TAM Hysterectomy for benign disease ~5%• Hysterectomy in ATAC 5% TAM vs 1% AI
• TAM vaginal discharge more common• AI vaginal dryness and irritation more common
Management of Adverse EffectsGynecologic• Vaginal bleeding – workup and evaluation• Endometrial ultrasound, biopsy, switch to
AI (postmenopausal)
• Vaginal Discharge – antibiotics, antifungal as indicated
Adjuvant TherapyClimacteric Adverse Effects – Hot Flashes
• Vasomotor symptoms involving vasodilatation and drop in core body temperature
• Reported in 30-50% of patients regardless of treatment. Improved after treatment but sleep disturbance often continues
• Estrogen withdrawal rather than absolute circulating level of estrogen
• Changes in estrogen levels affect functioning of thermoregulatory centers in hypothalamus
Adjuvant TherapyClimacteric Side Effects - Libido• Similar AI vs TAM – variable rates but can
be as high as 50%
• In Intergroup Exemestane Study: post treatment libido did not recover to baseline. At 60 months 32% in exemestane and 32.5% in tamoxifen reported considerable loss of libido
Management of Adverse EffectsClimacteric
• Dress in layers (!)• SSRI’s, other antidepressants Norepi and serotonin involved in thermoregulation• CYP2D6 – part of Cytochrome P450 mixed function
oxidase system
• Tamoxifen is metabolized to Endoxifen – active metabolite - variability in metabolism may affect serum levels of active metabolite
• Unknown if variations in CYP2D6 genotype accounts for difference in treatment outcomes
Tamoxifen InteractionsCommon CYP2D6 Inhibitors• Strong Inhibitors• Bupropion (Wellbutrin) Fluoxetine(Prozac) Paroxetine(Paxil) Venlafaxine (Effexor) Quinidine No Interaction• Moderate Inhibitors• Duloxetine (Cymbalta) Sertraline (Zoloft)• Weak Inhibitors• Amiodarone CimetidineASCO – urges caution with use of inhibitors although evidence
linking interactions to breast cancer outcomes remains limited and indirect
Management of Adverse EffectsClimacteric• Gabapentin – some efficacy• Clonidine - <50% efficacy in placebo controlled
trials
• Estring• Progestins, Androgens – effective to reduce hot
flashes but no data on long term safety in women with breast cancer
• Acupuncture
Walker, et al J Clin Oncol 2009Acupuncture vs Venlafaxine
• 50 patients randomized:12 weeks acupuncture or venlafaxine, outcomes measured for up to one year post-treatment
• Both groups: significant improvement in hot flashes, depressive symptoms, o
• Venlafaxine group 18 adverse effects – nausea, dry mouth, dizziness, anxiety
• Acupuncture group no adverse effects• Acupuncture group: increased libido in some
women; most - improvement in energy, clarity of thought, sense of well-being
Walker, et al J Clin Oncol 2009Acupuncture vs Venlafaxine
• Many women don’t want additional medication due to potential adverse effects but 50% of patients feel they need treatment
• Conclusion - Given results of small randomized study feel that integrative therapies have a role in improving QoL and should be explored further
Management of Adverse EffectsClimacteric
• Recommended but not proven benefit: Smoking cessation, relaxation techniques, massage, reflexology, yoga
• No proven benefit: Vitamin E, Black Cohash
Management Adverse EffectsClimacteric - Cognitive Dysfunction, Fatigue• Has received limited attention compared to
chemotherapy; recent studies suggest “endocrine brain” is real
• Effects from endocrine therapy vs. chemotherapy difficult to separate; also effects of surgery/anesthesia, cancer-induced stress
• When cognitive problems reported, comprehensive review to rule out potential causes, treatment of depression and fatigue can help
• ?Accupuncture based on “chemobrain” studies
Management of Adverse EffectsClimacteric - Sexual• Significant impact on QoL, primarily seen with AI
• Dryness – lubricants, moisturizers, olive oil
• Estring, vaginal suppository – controversial; allowed in placebo controlled MA.17 without seeming to interfere with efficacy
Management of Adverse EffectsClimacteric - Sexual• 30+% does not return to baseline after
stopping therapy• Counseling, better physician-patient
communication• Antidepressant (if indicated)• Testosterone(controversial)• Trials evaluating pelvic floor relaxation exercises
and other modalities
• Likely to be unreported or underreported
Other Side Effects and Conclusions
• No major differences in incidence or severity: Skin rash, eye symptoms, neurologic function, headache, fatigue, GI symptoms, psychiatric conditions, cognitive dysfunction• No direct data that changing drug agents or
classes alleviates treatment-related symptoms
• ASCO Update Committee favored switching drugs if needed to promote compliance with therapy among patients whose treatment related symptoms were intolerable
Adverse Effects – What patients say
Adverse Effects - What patients say
• Information requested via Facebook, Twitter, and Blog Post – asked for AE’s and Treatments
• 90 responses – only 10 were by email – most posted on public forum
• Approximately 75% premenopausal, initially started on tamoxifen
• 5% had minimal / tolerable / manageable symptoms
• Highly selected group; biased towards discussing treatment and SE’s
Tamoxifen AE
• Hot flashes – mild to “ungodly”• Endometrial thickening (uterus “went crazy” required
hysterectomy), vaginal discharge• Bone / Joint pain – mild to “bone splitting”• Weight gain (average 10 lbs); nausea, loss of appetite• Increased body and facial hair; scalp hair thinning / loss• Cataracts• Sleep disturbance, nightmares, severe mood swings
(“murderous rage”), migraine headaches• Severe anxiety, depression, “life was gray”Anxiety / depression over treating one cancer but causing
another, or at least needing multiple tests
Tamoxifen AE Treatments
• Joint pains – regular moderate exercise - walking, biking, swimming, yoga; massage• HF’s – peppermint oil on back of neck, effexor• Mood – effexor• Nausea – prevacid• EPO, Resveratrol, Curcumin / Turmeric, Fish oil• Intentional weight loss of 15 lbs due to regular
exercise and changing diet• HF’s reduced by avoiding alcohol, caffeine and
increased hydration
Aromatase Inhibitor AE
• Vaginal dryness, dyspareunia, hot flashes• Joint pain mild to severe/progressive, stopped
therapy• Hair thinning• Migraine headaches
• Cognitive decline affecting job performance, depression, anxiety, brain fog
AI SE Treatments
• Estring for vaginal symptoms – with oncologist approval
• Glucosamine-chondroitin for joint paints• Regular moderate exercise (joint pains,
mood, sleep disturbance)• Write everything down (cognitive
dysfunction)• Stopping therapy -> severe anxiety
Complaints
• Doctor acknowledges side effects but does not make any suggestions
• Doctor does not ask about side effects, especially sexual side effects
• Doctor says side effects are not related to medications, but when stopped, symptoms resolve
• Potential benefit of drugs is overplayed - % risk reduction, but what is my actual recurrence risk
Complaints
• Anger that tamoxifen is not viewed as a drug with side effects that can be as serious as chemotherapy
• “Are side effects tolerable?” – loaded question – tolerable compared to recurrence…
• Damned if I do, if I don’t• Relieved to have oncologist blessing to stop due to
low risk, devastated not to have that extra layer of protection
• Felt like a failure because I couldn’t finish treatment
Complaints
•When you go all guns blasting at cancer you have to accept some terrible barbaric compromises
Conclusions:What the Literature Says• Endocrine therapy reduces recurrence and
improves survival• Adverse effect profiles of tamoxifen (TAM) and
aromatase inhibitors (AI) are distinct and are relevant to individualizing therapy
• Intensity and severity of most common AE’s are mild to moderate for the majority of women
• Serious, life threatening adverse effects are rare• Compliance issues are often larger than
recognized
Conclusions:What Your Patients are Saying• Approximately 50% of patients stopped therapy
whether or not physician agreed• Many women are miserable – ask
• Women are talking to each other – ask questions so they get information and guidance from you
• More research is needed both for other mechanisms to reduce recurrence risk as well as better side effect treatments
Thank You!
www.DrAttai.com