• Endocrine manipulation in breast cancer 1stintroduced by BEATSON in1896 → Demonstrated objective regression of breast cancer afteroophorectomy.[Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma:Suggestions for a new method of treatment with illustrative cases. Lancet 2:104-107,1896.]• Hormone therapies now used : For palliative treatment of metastatic or very elderly hormone sensitivebreast cancer patients. Adjuvant therapy in hormone sensitive early breast cancer cases.• Goal of hormone therapy is either to reduce synthesis of estrogen orblocking estrogen receptors in hormone dependent tumours.
All estrogens produced by action of AROMATASE enzyme. Aromatase present in high concentration in granulosa cells of ovariesof pre-menopausal women; and produces 90% of plasma estrogens. In post-menopausal women who are devoid of ovarian aromataseproduction, (only 10% of pre-menopausal levels), stromal andepithelial cells of breast cancers contain measurable amount ofaromatase. Virtually all breast cancers that respond to hormonal therapy expresssignificant levels of ESTROGEN RECEPTOR ALPHA (ER) whichincreases with age (upto 80% ER positive above 65 yrs age).
Unconjugated estrogen crosses the cell membrane and binds to theER, leading to various changes like dissociation from heat shockprotein, homodimerization, phosphorylation and conformationalchange in activating factor (AF-2) domain. This leads to production of mRNA and DNA sequences to withsubsequent trancriptional and translational changes. This leads to formation of specific protein sequences which bringabout various actions.
ACTIVATION OF HORMONE RECEPTOR
MECHANISM OF HORMONE ACTION
Thus in breast cancers in post menopausal women, the smallamount of estrogen produced by the breast tissue is still sufficient topromote tumour growth. Hormonal therapy thus aims either in preventing the formation ofhormones by blocking of the action of aromatase or to preventupregulation of receptors by blocking the formation/release ofregulatory hormones. According to EBCTCG-1996; adjuvant ovarian ablation resulted in18% reduction in risk of death in women less than 50 years age withearly breast cancer.
SURGICAL OVARIAN FUNCTION SUPPRESSION First report of surgical oophorectomy for the treatment of advanced breastcancer published by Dr. George Beatson in 1896 who saw a younglactating woman with advanced breast cancer and had tumor regressionafter removing both her ovaries. Oophorectomy reliably and promptly reduces circulating estrogens topostmenopausal levels in nearly 100% of women, and has the advantageof simultaneously reducing ovarian cancer risk. It is also the most cost-effective method of ovarian ablation. But oophorectomy may require hospitalization and carries potentialoperative and anesthesia-related morbidity and mortality. It alsoirreversibly induces premature menopause with sequelae includingosteoporosis, an increased risk of coronary artery disease and permanentloss of fertility.
OVARIAN FUNCTION SUPPRESSION BY RADIATION Ovarian ablation by radiation therapy has been used for over 50years. The obvious advantage over oophorectomy is to avoidinvasive surgery; however, radiation therapy may be lessefficacious than surgery in permanently ablating ovarian function. Ultrasound guidance to ascertain correct ovarian position forsimulation has been utilized to improve the results of radiationablation. Doses range from a single 450 cGy fraction up to 1,000-2,000cGy divided in five or six fractions.
TYPES OF DRUGS FORMEDICAL OVARIANSUPPRESSIONLHRH ANALOGUESNON SELECTIVEAROMATASEINHIBITORSESTROGENRECEPTORDOWNREGULATORSSELECTIVEAROMATASEINHIBITORSExample:Gosserelin,Example:Anastrozole,Letrozole,Exemustane,FadrozoleExample:Aminoglutethimide,FormestaneExample:Tamoxifen, ToremifenFulvestrant,Arzoxifene HCl
HORMONE RECEPTOR STATUS ANDPROBABILITY OF RESPONSE TO THERAPYEstrogen ReceptorStatusProgesterone ReceptorStatusResponse ProbabilityPositive Positive High (50-70%)Positive Negative Intermediate (33%)Negative Positive Intermediate (33%)Negative Negative Low (Less than 10%)
ANTIESTROGENSTAMOXIFEN Has been the standard of care in endocrine therapy for the last 35-40years. Is recommended as 1stline therapy for metastatic breast cancer in pre-and post-menopausal women and as adjuvant therapy in patients withnode – positive or node – negative hormone receptor positivedisease irrespective of menopausal status. Also approved for chemoprevention of women at increased risk whohave DCIS. This drug is metabolized by demethylation and hydroxylation; and is astrong anti-estrogen and weak estrogen receptor agonist. In tumoursthat express Her-2, tamoxifen acts as weak agonist leading to poorresponse to treatment. Response rates in pre-menopausal women with hormone responsivedisease vary from 15-53%. The benefits of adjuvant hormonal treatment with tamoxifen were firstdemonstrated in theNational SurgicalAdjuvant Breast and BowelProject (NSABP) B-14 trial.
ANTIESTROGENS (contd)TOREMIFENE Is a triphenylethylene analogue of tamoxifen. Is approved as 1stline therapy for metastatic breast cancer in ERpositive or unknown ER status tumours. Action and sequelae profile is similar to tamoxifen.FULVESTRANT Is an ER downregulator and pure ER antagonist with affinity 50 timesthat of tamoxifen. Administered as a monthly 250 mg IM injection. In randomized phase III trials it has been found to have similar efficacyto Anastrozole (Howell et al 2005), and to Tamoxifen (Howell et al2004). Is presently FDA approved for post-menopausal hormone receptorpositive breast cancer progressing on other anti-estrogen therapy. Safety profile similar to tamoxifen.
AROMATASE INHIBITORS Two types of Aromatase inhibitors (AIs): Suicidal (type 1) orirreversible inhibitors and Competitive inhibitors (type 2). Type 1 or suicidal inhibitors are steroidal drugs (Aminoglutethimideor testolactone) which bind to catalytic site of aromatase enzymeand cause permanent blockage. They also block other enzymes inCyP-450 family and alter other steroid hormone levels therebycausing side effects. They had been used in metastatic breastcancer, but are now replaced by competitive blockers. Type 2 or competitive inhibitors bind to the active enzyme sitereversibly and their continued activity depends on their serum levels.These drugs alter only estrogen levels. These drugs can used only in women with no ovarian function; eitherin post-menopausal women or pre-menopausal women having hadovarian ablation.
FORMESTANE Was the 1stselective AI. Also has weak androgenic properties. Found to be superior to aminoglutethimide. Given as IM injection.ANASTROZOLE This drug has rapid oral absorption with peak plasma levels within 2hrs. Was found to be superior to tamoxifen in reducing recurrences at 5yrs (ATAC). A higher fraction of women with ER positive tumoursshow benefit with anastrozole. Is FDA approved for 1stor 2ndline therapy for post-menopausalwomen with hormone sensitive tumours. Side effects includes arthralgias, increased risk of fractures, risk ofischaemic events; but decreased risk of vaginal bleeding/ hotflashes/ mood changes/ DVTs compared to tamoxifen. Recommended dose is 1 mg/day for 3-5 years.
LETROZOLE Another selective AI which has been approved as 1stor 2ndlinetherapy in post-menopausal women with hormone receptor positivedisease. It markedly suppresses estradiol, estrone levels within 2 weeks ofstart of therapy. Is associated with lower risk of thromboembolic events, vaginalbleeding or endometrial cancer risk compared to tamoxifen; but hashigher incidence of cardiac risk and hyperlipidemia. Recommended dose is 2.5 mg / day for 3-5 years.EXEMUSTANE Is a steroidal androgen derivative and a selective AI. It suppresses estradiol and estrone levels similar to those ofanastrozole and letrozole. Is presently FDA approved for 2ndlinetherapy of hormone sensitive metastatic breast cancer. If given ih high doses (upto 200mg/day), may cause androgenic sideeffects like alopecia, hoarseness.
FADROZOLE Is a competitive inhibitor more selective than aminoglutethimide butless than letrozole. No significant difference in response comparedto megestrol acetate, but lesser incidence of weight gain andthrombo-embolic events.
LHRH AGONISTS Used increasingly for ovarian ablation. Also called GnRH agonists. They reduce the release of estrogen by providing a constant highlevel of pituitary-releasing hormones leading to stopping ofgonadotropin release. Chronic use results in estrogen levels similar to post oophorectomypatients. Gosserelin approved for use in pre-menopausal women. Administration initially results in “Flare” symptoms due to initial risein gonadotropin levels.
EVIDENCES ON ADJUVANTHORMONE THERAPY IN BREASTCANCER
IN PRE-MENOPAUSAL WOMEN Data from EBCTCG (2005) indicate that patients whose tumours arepotentially responsive to endocrine therapy achieve a reduction inrisk of relapse and death from breast cancer from treatmentstrategies that reduce the levels, or block the action, of circulatingoestrogens. In premenopausal women with oestrogen receptor alpha (ER)positive tumours, ovarian ablation or suppression is associated witha reduction in risk of relapse and death from breast cancer. Whether younger women, not rendered menopausal as aconsequence of adjuvant chemotherapy gain additional benefit fromovarian suppression remains a subject of continuing research. Menopausal symptoms following ovarian ablation/suppression areworse than after chemotherapy.
In 2000, the National Institutes of Health (NIH) recommended thatadjuvant chemotherapy should be offered to the majority ofpremenopausal women with early breast cancer, and that tamoxifenshould be given to ER-positive patients for 5 years. The panel didnot recommend the use of ovarian suppression in patients who werereceiving both chemotherapy and tamoxifen for 5 years, but its usecould be considered instead of tamoxifen in selected patients. In contrast, the St. Gallen panel in 2003 highlighted the primacy ofendocrine therapy in the management of premenopausal womenand recommended the combination of tamoxifen for 5 years as anacceptable alternative to chemotherapy in ERpositive women
Ovarian ablation or suppression versus none: in premenopausalwomen with breast cancer that is ER-positive or with unknown ERstatus, ovarian ablation or suppression is beneficial compared to noovarian treatment in terms of recurrence (respective rates 47% and52%, p<0.0001) and breast cancer mortality (respective rates 40%and 44%, p<0.004), both assessed at 15 years follow-up (EarlyBreast Cancer Trialists Collaborative Group, 2005). Ovarian ablation and the role of chemotherapy: the most recentevidence from a meta-analysis of individual patient data suggeststhat ovarian ablation has benefit in terms of recurrence and survivalover no ablation in premenopausal women, with or withoutchemotherapy (EBCTCG, 2005). LHRHa versus no systemic therapy: Premenopausal women withoperable breast cancer showed a 5 and 10 year disease-free survivaland overall survival rates were significantly improved followingadjuvant oophorectomy and tamoxifen (Love et al., 2008).
The ZEBRA trial showed that 2 years of Gosserelin treatment wasequivalent to 6 cycles CMF chemotherapy for ER positive tumoursat 6 years follow up. ABCSG 05 trial showed that gosserelin plus tamoxifen wassuperior to CMF chemotherapy in increasing relapse free period. Role of aromatase inhibitors is not indicated till complete ovarianablation is achieved with use of LHRH agonists. In this subset ofpatients, AIs do not show benefit over tamoxifen. Low levels of either ER or PR correlated with a shorter time torecurrence but hormone status did not predict the superiority ofanastrazole over tamoxifen that had been found in a large multi-centre RCT (Dowsett et al., 2008). Positive hormone receptor status (either estrogen or progesterone)was associated with significantly longer relapse-free survivalcompared with negative receptor expression whilst those with ER-ve status had a poorer relapse-free survival (Dowsett et al., 2006).
SIDE-EFFECTS Ovarian ablation, ovarian suppression and chemotherapy eachhave adverse side effects and each can induce menopausalsymptoms, including amenorrhoea (Brunt et al., 2004a; Groenvoldet al., 2006; Schmid et al., 2007; Love et al., 1999; Sharma et al.,2007 and Celio et al., 2002). A Cochrane Review cited trials which found that side effects aremore severe following LHRHa plus tamoxifen compared totamoxifen alone (Sharma et al., 2007). Health-related quality of life tends to favour ovarian ablation orsuppression over chemotherapy, wherein acute adverse effectsappear to be worse following chemotherapy. In contrast,menopausal symptoms (for example hot flushes) appear to beworse following ablation or suppression, than after chemotherapy,and with earlier onset. Amenorhoea can be longer lasting following chemotherapycompared with LHRHa (Brunt et al., 2004a; Groenvold et al., 2006;Sharma et al. 2007 and Schmid et al. 2007).
POST-MENOPAUSAL PATIENTS The aromatase inhibitors (anastrozole, exemestane and letrozole),are alternative options to tamoxifen for ER-positive invasive breastcancer in postmenopausal women. (ATAC, BIG-98, ITA, ARNO-95trials) The risk of disease recurrence is significantly reduced withanastrozole and is reported to be independent of nodal status,tumour size or prior chemotherapy. All ER-positive patients showeda benefit but there was no statistical difference between theprogesterone receptor (PR)-positive or PR-negative subgroup( Buzdar et al., 2006; Dowsett et al., 2005; and Kaufmann et al.,2007b). When patients who were disease-free at the end of receiving 5years of adjuvant tamoxifen were randomly assigned to receiveeither 3 years of anastrozole or no further treatment; the disease-free survival was statistically improved with significantly fewerrecurrences.
The risk of contralateral breast cancer is significantly reduced only ifanastrozole is given as first line adjuvant treatment; it is notsignificantly different if given after tamoxifen. In the BIG-98 trial letrozole when compared to tamoxifen showedimproved DFS than with tamoxifen alone. In the IES trial, exemustane after 2-3 years of tamoxifen showedimproved DFS with lower incidence of side effects. In the ARNO trial anastrozole after 2-3 years of tamoxifen improvedrelapse free intervals. Hence the recommendations were to shift to aromatase inhibitorsafter 2-3 years of tamoxifen.
EXTENDED ADJUVANT HORMONALTHERAPY MA.17 was a phase III,randomized, double-blind, placebocontrolled trial of letrozole asextended adjuvant therapy inpostmenopausal women withprimary breast cancer who hadcompleted approximately 5 yearsof adjuvant tamoxifen therapy Letrozole significantly improvedDFS in all patients, irrespective ofnodal status.
Letrozole significantly improved OS in patients with node-positivetumors (hazard ratio = 0.61; 95% CI 0.38, 0.98; P = 0.04) The risk of disease recurrence increased over time in the placebogroup, whereas in patients receiving letrozole, risk appeared to peakat around 2 years of treatment and decrease thereafter. On the basis of this trial, letrozole was approved as extendedadjuvant therapy, and it is currently the only AI approved for thisindication MA.17 demonstrated that extended adjuvant therapy with letrozoleprovides women further protection against relapse after thecompletion of tamoxifen. Also women in all risk categories benefitedin terms of reduced risk for recurrence of their cancer. This could mean that distant micrometastases that have survived 5years of tamoxifen therapy remain highly estrogen-sensitive andresponsive to extended adjuvant letrozole treatment. Extended therapy with adjuvant letrozole should therefore beconsidered for all women completing tamoxifen.
NEOADJUVANT HORMONE THERAPY Two trials (IMPACT and PROACT) evaluated Anastrozole andtamoxifen in post-menopausal women with locally advancedinoperable tumours. A comparative analysis (Smith et al 2004)showed better response with anastrozole but no statisticallysignificant difference. P024 trial (Eiermann 2001) evaluated Letrozole and found thatLetrozole made breast conserving surgery more possible thantamoxifen. Exemustane also been evaluated and results are promising. Optimal neoadjuvant hormone therapy recommendations areawaited.
RECOMMENDATIONS• Hormone therapy results in disease palliation in 50-60% of hormonesensitive tumors.• Alone or with chemotherapy, it significantly reduces diseaserecurrence.• Tamoxifen is standard adjuvant endocrine therapy in pre-menopausal women.• Aromatase inhibitors now recommended in adjuvant treatment ofpost-menopausal hormone sensitive breast cancers.
Do not offer adjuvant ovarian ablation/suppression topremenopausal women with ER-positive early invasive breastcancer who are being treated with tamoxifen and, if indicated,chemotherapy. Offer adjuvant ovarian ablation/suppression in addition to tamoxifento premenopausal women with ER-positive early invasive breastcancer who have been offered chemotherapy but have chosen not tohave it. Postmenopausal women with ER-positive early invasive breastcancer who are not considered to be at low risk should be offered anaromatase inhibitor, either anastrozole or letrozole, as their initialadjuvant therapy. Offer tamoxifen if an aromatase inhibitor is nottolerated or contraindicated.
Offer an aromatase inhibitor, either exemestane or anastrozoleinstead of tamoxifen to postmenopausal women with ER-positiveearly invasive breast cancer who are not low-risk and who havebeen treated with tamoxifen for 2–3 years. Offer additional treatment with the aromatase inhibitor letrozolefor 2–3 years to postmenopausal women with lymph node-positive ER-positive early invasive breast cancer who have beentreated with tamoxifen for 5 years. Following drugs were recommended:a) Anastrozole for primary adjuvant therapyb) Exemestane for adjuvant therapy following 2–3 years of adjuvanttamoxifen therapyc) Letrozole for primary adjuvant therapy and extended adjuvanttherapy following standard tamoxifen therapy.