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Endocrine therapy in MBC
DR K V Pradeep babu
Metastatic Breast Cancer
• Breast cancer is one of the leading cancer throughout the world
• Upfront presentation of breast cancer as metastatic disease is found in 5 to 10% of cases
• More incidence of such cases are because of effective screening measures
It was seen that there are no changes in HR status of triple
negative cancers
Tumor burden/ Site of metastasis
• If tumour burden is high and/or there is visceral site of metastasis Chemotherapy is preferred
• If the site of metastasis is bone and/or soft tissue, hormonal therapy can be given
• In case of visceral crisis, chemotherapy is always instituted
Oligo metastatic disease
• The definition of oligometastatic disease (see next section) has been enlarged to encompass low volume metastatic disease, i.e. limited number and size of metastatic lesions (up to five and not necessarily in the same organ) and potentially amenable for local treatment which is aimed at achieving a complete remission
The beginning of Hormonal Rx
• Historic observations on the regression of breast cancer following oophorectomy over 100 years ago provided the first insight into the estrogen-dependent nature of breast cancer.
• Since then, estrogen deprivation therapy has become a principle component in the treatment of hormone-sensitive metastatic breast cancer
Tumor flare reactions
• Characterized by an increase in pain or cutaneous and soft tissue disease after initiation of endocrine therapy.
• 0ccurs in 3 to 15 %of patients anywhere from three days to three weeks after starting tamoxifen
• Serologic flare is defined as an increase in serum tumor markers, alkaline phosphatase, or calcium .
• Metabolic flare has been defined as increased tumor uptake of FDG on PET imaging
Tumor flare reactions Management : Consists of aggressive treatment of pain and hypercalcemia.
• If symptoms are mild, tamoxifen therapy can be continued, but in more severe cases, it should be stopped and then reintroduced once symptoms have improved.
• A transient phenomenon and symptoms should resolve within four weeks
• If symptoms continue beyond this point, objective evidence of disease progression should be sought .
HISTORICAL PERSPECTIVE
OVARIAN SUPPRESSION OR ABLATION
• Pharmacologic-induced ovarian suppression (ie, use of [GnRH] agonists) and ovarian ablation (by oophorectomy appear to be effective –RR from 30 to 75 percent.
• In one trial, 136 premenopausal women were randomly assigned treatment with the GnRH agonist goserelin or oophorectomy .
• Similar overall survival (OS) compared with oophorectomy
SERM – TAMOXIFEN
• In a 1991 review that included seven phase II trials of tamoxifen in premenopausal women, the overall RR were 32-45 % in confirmed ER positive cases.
TAMOXIFEN VERSUS OVARIAN ABLATION
• The activity of single-agent tamoxifen appears to be equivalent to ovarian ablation in premenopausal women .
• In a 1997 meta-analysis of four studies (n = 220), there were no statistically significant differences in women who took tamoxifen and those undergoing ovarian ablation in either the risk of disease progression (odds ratio [OR] 0.86) or in risk of death (OR 0.94) .
TAMOXIFEN PLUS OVARIAN SUPPRESSION
• Benefit of combined treatment was demonstrated in 2001 meta-analysis of four randomized trials (n = 506) that compared GnRH agonist plus tamoxifen with GnRH agonist alone (64 and 90 % were chemotherapy and endocrine therapy-naïve, respectively).
• Compared with ovarian suppression alone, combined therapy significantly improved both PFS (HR 0.70, p = 0.0003) and OS (HR 0.78, p = 0.02).
Tamoxifen• Postmenopausal women with HR +VE MBC had ORR of 30
to 40 %, premenopausal women had lower response rates.
• AIs have supplanted tamoxifen as first-line treatment for postmenopausal patients.
• Tamoxifen remains as a first-line option for premenopausal
patients and as a second-line treatment after an AI and high-dose fulvestrant.
• A single daily 20 mg dose is recommended; higher doses are no more effective and are more toxic .
• Duration of response is typically between 6 to 12 months, but may last for several years for some patients .
Tamoxifen• Inhibits the growth of BC cells by competitive antagonism
of estrogen at its receptor.
• Also has tissue-specific partial estrogen agonist activity.
• Agonist effects can be both: -beneficial (prevention of bone demineralization) and
- detrimental (thromboembolic events, cataracts, endometrial cancer, hot flashes, and vaginal discharge, ovarian cysts).
Tamoxifen : MOA
Toremifene• A nonsteroidal antiestrogen and a selective estrogen
receptor modulator (SERM).
• Individual trials and a meta-analysis comparing toremifene vs tamoxifen in patients with untreated MBC have demonstrated that both agents have comparable activity and a similar toxicity profile
• An alternative to tamoxifen, although it provides no specific advantage over tamoxifen.
• Toremifene and other SERMs (idoxifene and droloxifene) are cross-resistant with tamoxifen .
• Ineffective as sequential therapy in patients refractory to tamoxifen
Single or combination therapy??
• Premenopausal metastatic breast cancer can be effectively managed through the use of ovarian ablation plus tamoxifen.
Evidence for medical vs surgical oophorectomy
• Oophorectomy is one of the treatments of choice for premenopausal women with advanced breast cancer.
• However, LH-RH analogs have replaced surgical castration (or ovarian irradiation) on the basis of the comparable therapeutic activity shown by these drugs in phase II studies.
• Moreover, the combination of tamoxifen and LH-RH analogues has gained popularity among clinicians attempting to obtain a ‘total estrogen blockade’ according to the same rationale previously proposed for advanced prostatic cancer.
• Eighty-five perimenopausal patients with estrogen receptor or unknown positive metastatic breast cancer were randomly allocated to receive one of the following treatments:
• Surgical castration (or ovarian irradiation);• Goserelin;• Surgical castration (or ovarian irradiation) plus tamoxifen; • Goserelin plus tamoxifen. • The study was performed according to a 2 × 2 factorial
randomised design.
Results:• With no significant difference in the response rates observed, a
trend did favour oophorectomy (or ovarian ablation) with respect to treatment activity.
• In fact, the best response rate was observed in patients allocated to oophorectomy(46.6% OR ) while the lowest rate was ob- served in patients treated with oophorectomy plus tamoxifen (11.1% OR).
• Response to goserelin and goserelin plus tamoxifen was 27.2% (± 18.6) and 45% (± 21.8), respectively.
• Tamoxifen did not improve the efficacy of gonadal ablation, although it did enhance the activity of goserelin treatment.
Goserelin Vs Goserelin + Tamoxifen
• Jonat et. al conducted a randomized trial of 318 pre- and peri-menopausal advanced breast cancer patients, comparing goserelin with or without tamoxifen.
• Both arms exhibited similar response rates (complete response + partial response) (31% versus 38%, respectively; p = 0.24)
• However, a significantly longer median time to progression was demonstrated in the combination arm (23 versus 28 weeks; p = 0.03)
AROMATASE INHIBITORS :Efficacy
• A meta-analysis of randomized trials of AIs compared with tamoxifen as first-line therapy showed a significantly superior OS (relative hazard 0.89, 95% CI 0.80-0.99) favoring treatment with a third generation AI
As second-line and subsequent-line therapy when
compared with progestin, third generation AIs also showed superior OS(relative hazard 0.86, 95% CI 0.79-0.94)
Other meta-analyses which found no benefit for AIs included trials with first and second generation AIs
MODE OF ACTION OF AI
AROMATASE INHIBITORS • Decrease circulating levels of estrogen by blocking action
of enzyme aromatase, which converts androgens into estrogens.
• When compared to tamoxifen for first-line treatment of postmenopausal patients with HR +ve MBC, AIs have shown superior efficacy
• Steroidal (eg, exemestane) and nonsteroidal (eg,
anastrozole and letrozole) AIs differ in their mechanism of interaction with aromatase enzyme (ie, irreversible or reversible inhibition).
Working mechanism of action for anti-aromatase agents
Type I inactivators (steroidal)target the substrate-binding site
Type II inhibitors (nonsteroidal) target the
cytochrome P450 ‘aromatase’
Aromatase molecule
OestrogenAndrogen
Cytochrome P450
NADP+NADPH
Textbook of Breast Cancer. A Clinical Guide to Therapy; 1997
Differences observed b/w anastrozole and letrozole in BIG-198 and ATAC
• In subgroup analyses of the ATAC trial, the benefit of anastrozole was seen predominantly in patients who had not received adjuvant chemotherapy and those with node-negative disease.
• In BIG 1-98 trial, the greatest benefit of letrozole was in patients who had received chemotherapy and in those with node-positive disease.
• All patients with estrogen-receptor–positive tumours had a similar reduction in the risk of a disease-free–survival event associated with letrozole irrespective of their progesterone-receptor status.
• In ATAC trial,it was shown that beneficial effect of anastrozole mainly in patients with estrogen-receptor–positive and progesterone-receptor–negative tumors.
2nd line therapy
BOLERO-2
• Everolimus — Studies show that the mechanistic target of rapamycin (mTOR) inhibitor everolimus (incombination with endocrine therapy) is an option for postmenopausal women for the treatment of AI resistant advanced ER+ breast cancer.
• Inclusion criteria allowed disease recurrence during or within 12 months after completion of adjuvant endocrine therapy, one prior line of chemotherapy for advanced breast cancer, and disease progression within 1 month after treatment for advanced breast cancer
Results • At the final analysis after a median follow-up of 18
months, median PFS based on investigator assessment was 7.8 months in the everolimus plus exemestane arm and 3.2 months in the placebo plus exemestane arm.
• Secondary end points from BOLERO-2 also favored everolimus plus exemestane therapy.
• ORR [complete response (CR) or partial response (PR)] was 12.6% in the everolimus plus exemestane arm and 1.7% in the placebo plus exemestane arm (P < .0001).
• Median duration of overall response was 10.5 months (95% CI, 8.2-21.9) in the everolimus plus exemestane arm and 6.9 months (95% CI, 4.2-6.9) in the placebo plus exemestane arm
• Median overall survival was 31.0 months with everolimus plus exemestane and 26.6 months with placebo plus exemestane ( P = .1426).
• One reason for this p value in os was a lack of power to detect a realistic overall survival advantage because the chosen sample size was based on the primary end point of PFS.
• Additionally, clinicians may have been able to determine if patients were not receiving study treatment due to the absence of adverse events (AEs) and encouraged the initiation of more aggressive treatments (e.g., chemotherapy) after progression
Adverse events
• Everolimus was associated with serious side effects (grade 3/4), including stomatitis (8 percent), dyspnea (4percent), noninfectious pneumonitis (3 percent), and elevated liver enzymes (3 percent) [47,48].
• For patients who develop shortness of breath or increase in cough, everolimus should be held and patients assessed for pneumonitis.
• A brief course of steroids may be necessary.
Exemestane plus entinostat
• The Breakthrough Therapy designation for entinostat is based on data from the completed phase II ENCORE 301 study, in which entinostat was shown to extend both progression-free survival and overall survival when added to exemestane in postmenopausal women with ER-positive metastatic breast cancer whose cancer had progressed after treatment with a nonsteroidal aromatase inhibitor and with a very acceptable tolerability profile.
Fulvestrant
• An ER antagonist that has no agonist effects
• Effectively blocks ER dimerization and DNA binding, increases ER turnover, and inhibits nuclear uptake of the receptor
• Can theoretically overcome resistance that is driven by the agonist properties of tamoxifen
• Approved by the United States FDA for the treatment of HR
+ve MBC in postmenopausal women with disease progression following antiestrogen therapy
Fulvestrant…. Initially found equal to AI• fulvestrant (250 mg monthly, without the initial loading
dose) as effective as AIs and as well tolerated
• Individual and combined analysis of two trials, which compared fulvestrant (250 mg monthly, without the initial loading dose) and anastrozole (1 mg by mouth daily) in postmenopausal patients with advanced tamoxifen-resistant BC
• No significant difference in ORR (19 vs 17 months), TTP (the primary endpoint, 5.4 versus 4.1 months), and median OS(27.4 vs 27.7 months) between fulvestrant and anastrozole
• Both agents were well tolerated, but fulvestrant was associated with a significantly lower incidence of joint disorders.
EFECT trial• This trial studied the role of Fulvestrant vs AI
• In second line setting, after the failure of 1st line Non-steroidal AI treatment
• Fulvestrant used was 500 mg loading dose, followed by 250 mg Day 14, 28 and monthly thereafter
Fulvestrant• In the first-line setting, FIRST (Fulvestrant First-Line Study
Comparing Endocrine Treatments) was a phase II trial
• 205 postmenopausal women with HR +ve advanced breast cancer
• Fulvestrant 500 mg (500 mg intramuscular injection on day 0, then 500 mg on days 14 and 28 and every 28 days thereafter) vs anastrozole (1 mg orally daily)
• Fulvestrant 500 mg improved median TTP compared to
anastrozole (23.4 vs 13.1 months), corresponding to a 35 % reduction in risk of progression (HR 0.66; 95% CI 0.47-0.92).
• Significantly longer overall survival (median, 54 versus 48 months; HR 0.70, 95% CI 0.50-0.98)
Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009; 27:4530.
CONFIRM: OS when 50% pts died
CONFIRM: OS when 75% pts died
Visceral disease Vs No Visceral disease
Resistance to AI treatment
• In hormone receptor (HR)-positive metastatic breast cancer (MBC) without life-threating visceral metastases, aromatase inhibitors (AIs) or tamoxifen are the frst line treatments of choice.
• Initially hormone-dependent breast cancers acquire antioestrogen resistance after repeated endocrine therapies and,eventually, become hormone-independent.
• Recently, ESR1-activating mutations have been postulated as the keypotential mechanisms underlying the failure of endocrinetherapies.
• In particular, the representative four ESR1 ligand binding domain (LBD) “hot spot” mutations, ESR1 Y537S, Y537N, Y537C, and D538G, which cover more than 80% of ESR1 mutations associated with acquiredresistance to antioestrogen therapy
• CLINICAL RELAVENCE ::• The detection of these mutations may be useful as biomarker of
resistance to endocrine therapy and could help in choosing the most appropriate treatment for HR+ MBC .
• For ESR1 genotyping to be performed whenever a disease progresses, tissue smapling is an issue.
• 1. Firstly , tumor site is not easily accessible. 2.Secondly, the method of sample preservation and intratumoral or intertumoral heterogeneity, also hamper the use of tumor tissue. 3.Clinical complications of repeated biopsy.
• Circulating cell-free DNA (cfDNA) analysis by ddPCR has been developed as a way of
overcoming these limitations .
• ESR1 LBD mutations causing primary endocrine resistance are extremely rare.
• ESR 1 mutations are usually seen in a significant proportion of MBC patients that have been exposed to AIs.
• In patients from the SoFEA trial, the detection of ESR1 mutations in plasma DNA predicted relative resistance to exemestane and relative sensitivity to fulvestrant, which is ER degrading drug.
• In contrast, patients without ESR1 mutations detected may derive further benefit from exemestane, as well as fulvestrant.
• The combination of palbociclib and fulvestrant 500 mg appeared to be equally effective in patients
with or without ESR1 mutations .
• Patients with ESR1 mutant cancers have a poor prognosis.
OVARIAN ABLATION/SUPPRESSION FOR PREMENOPAUSAL WOMEN
Combined LHRH agonists and tamoxifen —
• Combined therapy with ovarian suppression (LHRH agonists) and tamoxifen compared to either therapy alone results in a superior
- ORR - PFS, and - OS
• Represents a preferred first-line treatment option in premenopausal patients
Combined LHRH agonists and Aromatase inhibitors
• Promising response rates and median TTP for combined therapy with an LHRH agonist and an AI in premenopausal women
• Preliminary results of a small randomized trial that compared goserelin and anastrozole with goserelin and tamoxifen
• Suggested a higher ORR (80 vs 53 %) and median time to death (18.9 vs 14.3 months) with goserelin and anastrozole
• Additional follow-up and validation of combined therapy with an LHRH agonist and an AI are needed
Milla-Santos, A, Milla, L, Portella, J, et al. A randomized trial of goserelin (Zoladex™) + tamoxifen versus goserelin + anastrozole (Arimidex™) ) in pre/perimenopausal patients with hormone dependent advanced breast cancer. Breast Cancer Res Treat 2002; 76 (suppl 1):S32.
Faslodex + AI vs AI
• In addition to single-agent therapy, two separate trials investigating the combination of fulvestrant plus anastrozole as first-line therapy have been published, but with discrepant results.
FACT trial
• Fulvestrant and Anastrozole Combination Trial (FACT) – FACT enrolled 514 women (one-third with endocrine-naïve disease) and randomly assigned treatment to anastrozole alone or in combination with fulvestrant (500 mg loading dose, 250 mg on days 14 and 28, then 250 mg every 28 days).
• Fulvestrant plus anastrozole resulted in an equivalent TTP (median, 11 versus 10 months with anastrozole; HR 0.99, 95% CI 0.81-1.20) and OS (median, 38 months in both arms; HR 1.0, 95% CI 0.76-1.32).
SWOG s0226
• In the Southwest Oncology Group (SWOG) S0226 trial, 707 women (60 percent endocrine-naïve) were randomly assigned to treatment with anastrozole plus fulvestrant or to single-agent anastrozole in Aug 2012.
• Compared with anastrozole alone, combined treatment resulted in an improvement in PFS (15 versus 14 months; HR 0.80, 95% CI 0.68-0.94) and OS (48 versus 41 months; HR 0.81, 95% CI 0.65-1.00).
• On subgroup analysis, the benefit of combination therapy appeared to be restricted to previously untreated patients.
• Of note, in both trials, fulvestrant was administered at a dose of 250 mg monthly, which is lower than the currently approved prescribed dose - But dose was later increased in SWOG trial
• There were significantly more cases of endocrine-naïve patients in the SWOG S0226 trial than the FACT trial, which explain the difference in trial outcomes.
• Further studies are needed to confirm the findings from the SWOG S0226 trial and to determine whether this combination is superior to anastrozole or fulvestrant alone.
• Taking into account its different mechanism of action, fulvestrant may be administered with a LHRH agonist to premenopausal women with breast cancer.
• Several studies have evaluated fulvestrant in premenopausal women with breast cancer and compared results with placebo or tamoxifen
[G. Steger, R. Bartsch, C. Wenzel, D. Hussian, U. Sevelda, U. Pluschnig, et al. Fulvestrant (FUL) and goserelin (GOS) in premenopausal women with advanced, hormone-sensitive breast cancer: a pilot study ASCO Meeting Abstracts, 23 (2005)]
• This study was designed to investigate the effects of fulvestrant at a dose of 750 mg on hormone receptor expression and proliferation in premenopausal women with ER-positive early breast cancer.
• 750 mg was chosen because a previous study investigating the effect of a single intramuscular injection of 250 mg fulvestrant had shown no significant effect on ER or PgR or Ki67 levels in premenopausal women.
• In contrast to the lack of effect of a 250 mg dose, fulvestrant 750 mg significantly downregulated ER and PgR and signifi- cantly reduced proliferation.
• It is clear therefore that fulvestrant is active in premenopausal women providing that it is delivered in a sufficient dose
• This randomised trial compared the effects on the tumours of a single dose of 750 mg fulvestrant to those of daily tamoxifen (20 mg) taken 14–16 days prior to surgery in 60 premenopausal women with ER-positive primary breast cancer.
• There were statistically significant falls in the expression of ER and Ki67 levels compared to the baseline with both drugs.
• Both drugs caused a decrease in PgR expression from baseline but this was only statistically significant with fulvestrant.
• The most common adverse events with fulvestrant were headaches, hot flushes, nausea and disturbance of menses.
• Contrary to previous studies with fulvestrant 250 mg, these findings suggest that at a dose of 750 mg fulvestrant is effective at reducing the effects of oestrogen on ER-positive breast cancer in premenopausal women.
Palbociclib
Palbociclib
• Palbociclib (formerly known as PD 0332991) is a highly selective, orally administered inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6).
• It was shown to selectively inhibit the proliferation of ER-positive breast cancer cell lines.
• Palbociclib plus letrozole received US FDA accelerated approval as 1st line therapy for ER-positive HER2-negative breast cancer in February 2015 .
PALOMA 1 Trial
• This approval was based on a phase II trial that enrolled 165 women with advanced ER-positive breast cancer who received no prior systemic therapy for the advanced disease, who were randomly assigned to treatment with letrozole (2.5 mg daily) with or without palbociclib (125 mg daily on days 1 to 21) on a 28-day cycle.
PALOMA 1 Trial
• A significant improvement in PFS compared with letrozole alone (median, 20 versus 10 months; HR 0.49, 95% CI 0.32-0.75)
• An improvement in OS, although it was not statistically significant (median, 37.5 versus 33 months, p = 0.81)
Study Design
• Study Design (PALOMA-1/TRIO-18)• Phase 2, randomized, open label trial
• 50 sites in 12 countries (North America, Latin American and Europe)
• Interventions• Palbociclib 125 mg daily (3 wks on/1 wk
off)+ Letrozole 2.5 mg daily• Letrozole 2.5 mg daily
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
PALOMA 1 Trial• Primary Endpoint:
• Progression free survival
• Secondary Endpoints:• Objective response, clinical benefit, duration of
response, overall survival
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
PALOMA 1 TrialInclusion criteria Exclusion criteria
Post-menopausalReceived treatment with
Letrozole within past 12 months
Locally recurrent disease not amenable to surgery or
metastatic diseaseAny previous treatment for advanced breast cancer
No previous treatment for advanced disease Brain metastasis
ER+/Her2-Any previous treatment with CDK
inhibitor
ECOG performance status of 0 or 1
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
PALOMA 1 Trial
• Significant Adverse Events: (>20%)Event Palbociclib+Letrozole
(n=83)Letrozole
(n=77)URI 31 18Neutropenia 75 5Leukopenia 43 3Anemia 35 7Stomatitis 25 7Nausea 25 13Diarrhea 21 10Alopecia 22 3Fatigue 41 23
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
PALOMA 1 Trial
• Efficacy Results: Investigator assessment PFS Intent to Treat PopulationProgression Free Survival
Palbociclib + Letrozole
(n=84)Letrozole
(n=81)
Number of PFS Events (%) 41 (48.8%) 59 (72.8%)
Hazard Ratio (95% CI) 0.488 (0.319, 0.748)Median PFS [months] (95%CI)
20.2 (13.8, 27.5) 10.2 (5.7, 12.6)
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
PALOMA 1 Trial
• PALOMA-1/TRIO-18• Conclusions
• Addition of palbociclib to letrozole significantly improved progression free survival in women with advanced ER+ and HER2- breast cancer
Finn, RS, et al., Lancet Oncol 2015;16: 25-35.
• 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole.
Results• The median progression-free survival was 24.8 months in the
palbociclib–letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo–letrozole (P<0.001).
• The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib–letrozole group vs. 1.4% in the placebo–letrozole group)
• leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%).
• Febrile neutropenia was reported in 1.8% of patients in the palbociclib–letrozole group and in none of the patients in the placebo–letrozole group.
• Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib–letrozole group and in 13 patients (5.9%) in the placebo–letrozole group.
Conclusion: Paloma 2 Phase III trial
• Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib–letrozole.
•
• Median progression-free survival was 9·5 months in the fulvestrant plus palbociclib group and 4·6 months in the fulvestrant plus placebo group .
• Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group.
• The most common grade 3 or 4 adverse events were neutropenia [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]).
• Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group.
• PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response.
Paloma 3: pts who received neo/adjuvant Rx only, but no Rx after
mets
Received at least one previous systemic therapy for MBC
Previous systemic therapy means chemotherapy or
endocrine therapy, or both
• In patients given fulvestrant plus palbociclib, a confi rmed objective response was noted in 66 (25%) of 268 patients with measurable disease, which compares favourably with historical data for cytotoxic chemotherapy.
• Responses to fulvestrant plus palbociclib were slow to manifest, with a median time to response of almost 4 months.
• The combination might also offer a more favourable safety profile than chemotherapy.
• chemotherapy is still advisable in patients at risk for visceral crisis, because in this setting in which the combination of fulvestrant plus palbociclib has not been assessed.
Paloma 3 : conclusion
• The combination of fulvestrant plus palbociclib is associated with signifi cant improvement in objective response, clinical benefi t, and progression-free survival.
• The effi cacy of fulvestrant plus palbociclib was noted irrespective of the number of previous endocrine therapies, reported sensitivity to previously received endocrine therapy, and biomarkers that aff ect sensitivity to endocrine therapy, such as the level of expression of oestrogen and progesterone receptors.
• The combination treatment was also effi cacious in patients in whom two lines of previous endocrine therapy were unsuccessful
• Ribociclib and abemaciclib
SEX STEROID HORMONES • Options for third- or fourth-line endocrine therapy,
especially for patients who have - low volume disease that is restricted to bone or soft
tissue, - few disease-related symptoms, and - a history of a response to tamoxifen or an AI
SEX STEROID HORMONES
Progestins — • Megestrol acetate & medroxyprogesterone acetate with RR of 25 %
and median duration of response of 15 months
• Activity appears to be maintained in patients who are refractory to tamoxifen, but the activity after an AI has not been systematically studied.
• Mechanism of action is unclear.
• May inhibit aromatase activity or increase estrogen turnover, since estrogen levels fall during therapy
Progestins
• Megestrol acetate is typically dosed at 160 mg daily (40 mg four times daily)
• Higher doses are no more effective
• Associated with more weight gain, fluid retention, and vaginal bleeding, and a lower quality of life
• Associated with an increased risk of thromboembolic events,
• Use should be avoided in patients with thromboembolic disorders or other risk factors for thromboembolic disease.
Estrogens
• Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, AIs) may respond to estrogen therapy
• Tumor cells chronically deprived of estrogen with AIs
may be sensitized to estrogen therapy
• Lower doses of estrogen may be just as effective as High dose estrogen with less toxicity
• Patients receiving estradiol therapy with an intact
uterus should be treated with medroxyprogesterone acetate 10 mg daily for the last 10 days of the month to avoid uncontrolled uterine bleeding.
Present guidelines
Second line treatment
• Premenopausal women — • For premenopausal women who progress following first line
treatment, ovarian ablation should be offered, which would allow the administration of endocrine agents only approvedfor postmenopausal women.
• However, for women with disease progression on ovarian suppression agents, serum estradiol levels should be checked to ensure menopausal status was achieved.
• If high estradiol levels are noted despite ovarian suppression, ovarian ablation should be pursued.
• For premenopausal women who refuse ovarian suppression or ablation, we recommend chemotherapy.
• Postmenopausal women — • There is a lack of clinical trials to address the optimal sequence
of therapy in second line and subsequent line settings.
• The available options include the administration of a non crossresistant AI, tamoxifen, fulvestrant, fulvestrant plus palbociclib, or endocrine therapy plus the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in the second line setting.
• • A choice between them should be individualized based on prior
treatment received.
Endocrine therapy combined with biologic agents
• Tamoxifen and anastrozole combined with TKI gefitinib showed no significant improvement in PFS
• Addition of VEGF inhibitor, bevacizumab, to letrozole, showed promising activity in a phase II trial, and further investigation is underway
Endocrine therapy combined with HER2-directed therapy
• Patients with HR +ve, HER2+ve BC recurrences that are not imminently life-threatening or symptomatic
- excellent candidates for first-line endocrine
therapy plus HER2-targeted therapy.
• For others, combination of chemotherapy with HER2-targeted therapy in the first line setting is preferred.
Endocrine therapy combined with HER2-directed therapy The TAnDEM study randomly assigned 207 postmenopausal pts with
HER2 +ve MBC to the combination of anastrozole and trastuzumab or anastrozole alone
Patients treated with anastrozole and trastuzumab experienced significantly longer median PFS (primary endpoint, 4.8 vs 2.4 months).
No significant improvement in median OS (28.5 vs 23.9 months)
70 % of patients treated with anastrozole alone received a trastuzumab-containing regimen upon progression.
Adverse events (including fatigue, diarrhea, vomiting) were more frequent with the combination of anastrozole and trastuzumab,
Incidence of asymptomatic LVEF declines were low and only one patient experienced symptomatic heart failure (NYHA class II).
Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27:5529.
Therapies in endocrine resistance
