Hormonal Management of Metastatic

Breast Cancer

Dr. Khaled Abulkhair, PhD

Medical Oncology SCE, Royal College, UK

Ass. Professor of Clinical Oncology

Mansoura University, Egypt

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

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

FACT …Menopausal Status!

مسألة فقهية تغييرات فى

التعريفات

FACTS Do

Change

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%.

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).

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.

• 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.

• 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).

Tamoxifen 1977 is the Oldest Targeted

therapy in BC

• 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.

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.

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.

• 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.

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?

Timeline of Approval of Agents for HR+

ABC

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…

Aromatase Inhibitors

• Nonselective

– Amino-glutethimide (competitive)

• Selective

– Competitive – Noncompetitive

(non-steroidal) (steroidal)

• Anastrozole • Exemestane

• Letrozole • Formestane

• Vorozole

• Fadrozole

• 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.

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.

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).

FIRST Trial confirms OS yet!

CONFIRM Confirmed superiority of 500 mg dose, 2010

CONFIRM.. Final Survival Analysis

2013

Overcoming Resistance…new strategies

CDK

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.

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?

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.

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.

New drugs….. Syndax..

ONGOING IMPROVEMENT

How to Sequence?

TAM AIs NS

AIs S

FULVEST EVERO

Others

From ABC 1st & 2nd.. Important Messages

How To Sequence?

CDK

CDK

CDK CDK

Everolimus may be added earlier if resistance is

suspected

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.

HER-2 Positivity Equals Resistance to

Hormonal Therapy

Combination or Sequential ET

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.

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

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.

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!!