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Hormonal Management of Metastatic Breast Cancer 1... · 2016-05-14 · HER2-positive breast cancer...
Transcript of Hormonal Management of Metastatic Breast Cancer 1... · 2016-05-14 · HER2-positive breast cancer...
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Hormonal Management of Metastatic
Breast Cancer
Dr. Khaled Abulkhair, PhD
Medical Oncology SCE, Royal College, UK
Ass. Professor of Clinical Oncology
Mansoura University, Egypt
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Case For Discussion • A 63 y.o postmenopausal female diagnosed by Lt. BC T2N1M0 post
BCS 6/2012, 2/12 L.N, ER++, PR+, Her-2 neg, Ki 67 10%. Given
FACx6 and RT. Was on Anastrozole since 1/2013. Feb, 2016 bone
pains. Bone scan showed 3 new lesions at Cx, dorsal and lumbar
vertebrae confirmed by MRI, CT is free apart from asymptomatic few
metastatic bilateral lung nodules largest 1.5 cm. Presented after
palliative RT:
1-What is your opinion about her adjuvant therapy? Agree / disagree
2- Would you recommend tissue biopsy if feasible? Yes / NO
2- What would you recommend for her right now?
A. Exemestane alone
B. Exemestane + Everolimus
C. Fulvestrant 500 mg monthly after loading
D. Tamoxifen
E. Single agent chemotherapy
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What is the plan?
• Facts to Learn
• Introduction and What to know about MBC?
• Available options
• Mechanism of actions
• What is the best? Analysis of data!
• Overcoming Resistance to ET
• How to Sequence?
• Conclusions
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FACT …Menopausal Status!
مسألة فقهية تغييرات فى
التعريفات
FACTS Do
Change
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Defining menopausal status in breast cancer Patients, Critical
Reviews in Oncology/Hematology 84 (2012) 252–260
Bio-markers including FSH, Estradiol, Inhibin and AMH are
not dependable 100%.
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FACTS..Changes in receptor profiles
• Changes in receptor profiles are an important issue, since the molecular
phenotype of the primary tumor is often used for treatment decisions in
the metastatic setting. Several retrospective studies have evaluated this
biological phenomenon.
• One prospective study, BRITS (Breast Recurrence In Tissue Study),
investigated 137 matched primary and recurrent breast cancer tissue
samples. A switch in receptor status, in either direction, was identified
for ER in (10.2%; p=0.983), PR (24.8%; p=0.003) and HER2 (2.9%;
p=0.074).
• In the judgment of the investigators the switch led to a change in the
subsequent treatment in (17.5%). This study demonstrated that the
management of locally recurrent or MBC should include tissue
sampling, since switches of ER, PR or HER2 status in the breast
cancer recurrence may change the planned treatment for one in six
patients (Thompson 2010).
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Introduction
• Breast cancer was shown to be a systemic disease where cancer cells can be found in the blood stream and lymphatic vessels resulting in micrometastases and perhaps lead to later recurrences.
• From 10% to 30% of lymph node-negative breast cancer patients and 35% to 90% of lymph node-positive patients will eventually relapse with local therapy alone.
• Controlling these micrometastases is the basic rationale behind the use of systemic therapy.
• Numerous studies suggest a strong link between the female hormones estrogen and progesterone and BC.
• OFS substantially decrease BC in both humans and animals.
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• A Cochrane Meta-Analysis was performed in 2003 whether
chemotherapy alone versus ET alone for MBC is more
favorable.
• A pooled estimate of reported response rates in eight trials
involving 817 women shows a significant advantage for
chemotherapy over endocrine therapy with RR=1.25 (1.01-
1.54, p=0.04). However the two largest trials showed trends
in opposite directions.
• Six of the seven fully published trials commented on
increased toxicity with chemotherapy.
• The Reviewers concluded that in women with MBC and
where hormone receptors are positive, a policy of treating
first with endocrine therapy rather than chemotherapy is
recommended except in the presence of rapidly progressive
disease.
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• Estrogen is linked to the pathogenesis of breast cancer.
• Endocrine therapy (ET) is medicines treat hormone-receptor-
positive breast cancers in two ways:
• by lowering the amount of the hormone estrogen in
the body
• by blocking the action of estrogen on breast cancer
cells.
• The ER status predicts equally well for all modalities of ET.
Patients with no detectable ER or PR in their tumors do not
benefit from endocrine therapy; however, breast cancers with
very low but detectable ER and/or PR respond, albeit
infrequently, to endocrine therapy.
• ET in postmenopausal HR+ BC is as effective as
chemotherapy in premenopausal patients (G. Hortobagei,
2003).
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Tamoxifen 1977 is the Oldest Targeted
therapy in BC
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• The benefit is not absolute.
• Response rate to ET (De Laurentiis M, et al. 2005):
ER PR Response
Negative negative < 10%
Positive negative 20 – 30%
Negative positive 30 – 50%
Positive positive 50 – 75%
• That’s why many authors consider PR to be more important.
• Until recently, arbitrary cutoff values were used to differentiate between ER-positive and ER-negative tumors. More recently, it has been recognized that virtually any ER expression indicates some probability of benefit from ET.
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MBC: What you need to know? • Patients with untreated MBC demonstrate a
considerable heterogeneous clinical course. Some have aggressive disease.
• Others have an indolent disease course, with slow progression alternating with long periods of stability in metastasis to soft tissues or bone.
• In this sense, patients are often classified into low- and high-risk groups on the basis of clinical information and imaging.
• Carcinomatous meningitis, extensive liver metastases, lymphangitic lung metastases, or brain metastases usually signify aggressive disease that is unresponsive to ET.
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Not all HR + are hormone sensitive How to Define?
• Older, postmenopausal patients with DFS that exceeds 12
months after completing adjuvant therapy, and/or small
volume metastatic disease located predominantly in soft
tissue and/or bone.
• Highly sensitive - ―Naive‖ patients No prior ET,
Progression >12 months of completing adjuvant.
• Moderate sensitivity: secondary resistance: Progression
during or within 12 months of completing adjuvant ET,
Progression after CB to prior ET for advanced disease.
• Low sensitivity: primary resistance: Very early
progression (<2 years) on adjuvant ET, No CB to prior
ET for advanced disease.
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• The time to obtain maximal response with ET can be quite prolonged, and treatment should not be abandoned prematurely.
• Patients should be continued on a therapeutic trial for 8 to 12 weeks in the absence of progressive disease.
• Prolonged SD is considered CB which is acceptable in patients with minimal or no disease-related symptoms.
• A "tumor flare" with increased bone pain, swelling, or erythema of superficial lesions or Hypercalcemia during the first few weeks of therapy should not be confused with disease progression.
• Maintaining a good QoL is the goal which is achievable for months or years. Eventually, most of them will lost their responsiveness to ET and will need chemotherapy.
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Options Of ET in Postmenopausal MBC
• Tamoxifen 20 mg po daily
• Anastrozole 1 mg po daily, Letrozole 2.5 mg or Exemestane 25 mg (post-menopausal)
• Fulvestrant 250 / 500 mg
• Megace 40 mg po 4 x daily
• Estradiol 6 mg daily
• Aminoglutethemide 250 mg po 4 x daily with hydrocortisone (post-menopausal)
• Overcoming Resistance… adding targeted agents
• What about Pre-menopausal Women?
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Timeline of Approval of Agents for HR+
ABC
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Tamoxifen in MBC, since 1977 Accidentally discovered during contraception trials.
Response Rates:
• All women: 16-52% (CR+PR)
• Postmenopausal women
– 50%: ER+ disease
– 60-70%: ER+/PR+ disease
• MoA:
– Bind competitively to the ER, but it has multiple additional
effects on the cancer cell. It can lower the production of IGF-1
and TGF-α; it blocks angiogenesis and induces the production
of TGF-β. reported to increase natural killer cell activity.
– Tamoxifen and its active metabolites have a prolonged serum
half-life (7 days) after reaching steady-state levels.
– It is antagonist on breast however…
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Aromatase Inhibitors
• Nonselective
– Amino-glutethimide (competitive)
• Selective
– Competitive – Noncompetitive
(non-steroidal) (steroidal)
• Anastrozole • Exemestane
• Letrozole • Formestane
• Vorozole
• Fadrozole
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• Anastrozole is At least as effective as Tamoxifen (time to progression and objective response)
• It has fewer thromboembolic events and is the first AIs to demonstrate at least equivalence to Tamoxifen—compared with previous studies using Fadrozole and Formestane— both had lower antitumor activity compared to Tamoxifen.
• Trials comparing AIs for their efficacy have not delivered conclusive results, although one study stated that response with Anastrozole was higher compared with Letrozole. However, this was not the primary end point of this trial.
• It seems likely that also the switch from non steroidal to steroidal AI is effective and is therefore a therapeutic option.
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Fulvestrant • Fulvestrant is a novel type of ER antagonist that.
• Fulvestrant binds to the ER, but due to its steroidal structure and long side-chain, induces a different conformational shape with the receptor to that achieved by the non-steroidal anti-estrogen Tamoxifen.
• Because of this, Fulvestrant prevents ER dimerization and leads to the rapid degradation of the Fulvestrant-ER complex, producing the loss of cellular ER.
• Thus, Fulvestrant, unlike Tamoxifen, inhibits ER binding with DNA and produces abrogation of estrogen-sensitive gene transcription.
• Treatment with Fulvestrant suppressed the growth for twice as long as treatment with Tamoxifen.
• First approved in 2002 with 250 mg monthly IM.
• Elimination is 90% through hepto-biliary to feces.
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Fulvestrant is equivalent to AI (or Tamoxifen) in the
first line ET of metastatic breast cancer
• Evidence suggests: switching therapy from non-steroidal
to a steroidal AI is as effective as Fulvestrant in its
approved dose of 250 mg/q4 weeks (study “EFFECT”).
• The “FIRST” trial using the HD of 500 mg/q4w stated
first-line Fulvestrant HD was at least as effective as
Anastrozole for CBR (the primary end point) and ORR,
but was associated with significantly longer TTP (a
secondary end point) in patients pre-treated with ET.
• A follow up analysis showed an even stronger superiority
with a median TTP of 23.4 months for Fulvestrant HD
and 13.1 months for Anastrozole (p=0.01).
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FIRST Trial confirms OS yet!
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CONFIRM Confirmed superiority of 500 mg dose, 2010
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CONFIRM.. Final Survival Analysis
2013
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Overcoming Resistance…new strategies
CDK
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mTOR • Everolimus may play an important role for second or further
lines of treatment.
• In the Bolero-2 study a phase III, randomized trial,
Everolimus (10mg/day) and Exemestane versus Exemestane
was compared in 724 patients after failure of other AIs/Tam.
• The median age was 62 years, 56% had visceral Mets.
• CBR (18 vs 33.4%, p< 0.0001) favors combination.
• Further at interim analysis median PFS was significantly
increased with the combination (4.1 vs. 10.6 months, HR
0.36, 95%CI, 0.27-0.47, p<0.001).
• Another smaller trial confirmed superiority of Everolimus
plus Tamoxifen versus Tamoxifen alone in 111 patients with
hormone receptor positive MBC and prior AIs.
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Analysis for patients on First line Therapy.
Clinical Benefit Rate?
Substantial benefit is shown, in the
first 2 years time shown in weeks,
What about later?
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The decision must take into account the increased toxicity. At
present, no predictive biomarker exists to identify those patients
who will benefit from this approach specially with absent benefits
of Temsirolimus plus Letrozole versus Letrozole.
Lost Benefit at 39 Months?
Moreover, Exemestane alone is
getting better, late deaths in Evero
Arm.
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CDK: Palbociclib.. A new Stallion
• Palbociclib (Ibrance), a first-
in-class CDK inhibitor.
• Significant increase PFS in patients with advanced ER+/HER2–.
• PFS: 20.2 vs 10.2 months; HR=0.488(0.28 -0.7) P=0.0004.
• Palbociclib plus Letrozole received US FDA accelerated approval as first-line therapy for ER(+)ve, HER2(-)ve MBC in February 2015.
• PALOMA 2 and 3 and introducing to neo-adjuvant are ongoing.
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New drugs….. Syndax..
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ONGOING IMPROVEMENT
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How to Sequence?
TAM AIs NS
AIs S
FULVEST EVERO
Others
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From ABC 1st & 2nd.. Important Messages
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How To Sequence?
CDK
CDK
CDK CDK
Everolimus may be added earlier if resistance is
suspected
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ET in Postmenopausal HER-2 Positive MBC
• Several lines of evidence support the hypothesis that HER2-positive breast cancer is associated with endocrine resistance.
• The addition of Trastuzumab or Lapatinib to aromatase inhibitor treatment is able to enhance the efficacy over endocrine treatment alone.
• However, given the relative short progression free interval in the phase III trials compared to those observed in trials with chemotherapy, we recommend to consider chemotherapy in HER2-positive patients.
• One phase III trial comparing Fulvestrant + placebo vs. Fulvestrant + lapatinib could not demonstrate an improved PFS or OS in 324 patients pretreated with an AI.
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HER-2 Positivity Equals Resistance to
Hormonal Therapy
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Combination or Sequential ET
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Concomitant or Sequential Endocrine-
Chemotherapy Treatment
• Concomitant endocrine cytostatic therapy can not be recommended because it induces an increase in toxicity and does not induce a prolongation of disease free interval or overall survival despite the increase of response rates.
• Thus, endocrine – cytostatic therapy should be performed as sequential treatment modality.
• Endocrine maintenance therapy after chemotherapy induced response might be considered, even if the evidence is quite small and not homogeneous, since only relatively little side effects are observed with this sequential treatment option.
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CASE For Discussion • A 63 y.o postmenopausal female diagnosed by Lt. BC T2N1M0
post BCS 6/2012, 2/12 L.N, ER++, PR+, Her-2 neg, Ki 67 10%.
Given FACx6 and RT. Was on Anastrozole since 1/2013. Feb, 2016
bone pains. Bone scan showed 3 new lesions at Cx, dorsal and
lumbar vertebrae confirmed by MRI, CT is free apart from
asymptomatic few metastatic bilateral lung nodules largest 1.5 cm.
Presented after palliative RT:
1-What is your opinion about her adjuvant therapy? Agree / disagree
2- Would you recommend tissue biopsy if feasible? Yes / NO
2- What would you recommend for her right now?
A. Exemestane alone
B. Exemestane + Everolimus
C. Fulvestrant 500 mg monthly after loading
D. Tamoxifen
E. Single agent chemotherapy
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Conclusion
Endocrine therapy is the therapeutic backbone in early
and advanced hormone receptor positive breast cancer.
Current guidelines support continuing endocrine-based
therapeutic approaches after HR+ ABC progresses.
Sequential use of those agents is considered the optimum
way to palliate those patients in the setting of MBC.
Maintaining a good QoL is the goal which is achievable
for months or years, eventually, most of them will lost
their responsiveness to ET and will need chemotherapy.
Combining CT plus ET in-spite increased RR in some
trials is not advised due to increased toxicities.
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Options for post-progression ET:
o Switching to a different ET.
o Combining ET agents does not appear to add benefit;
increasing dose intensity might provide benefit.
oAdding a targeted agent to ET is an emerging option
NCCN, Canadian Consensus, AGO, And ABC
Guidelines include this approach
Be cautious with the new trials … experience
showed that the shown early effects are not
always true rather longstanding!!
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