Hormonal Management of Metastatic Breast Cancer

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1 Hormonal Management of Metastatic Breast Cancer Dr. Khaled Abulkhair, PhD Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt

2 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

3 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

4 FACT Menopausal Status! مسألة فقهية تغييرات فى التعريفات FACTS Do Change

5 Defining menopausal status in breast cancer Patients, Critical Reviews in Oncology/Hematology 84 (2012) Bio-markers including FSH, Estradiol, Inhibin and AMH are not dependable 100%.

6 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).

7 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.

8 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 ( , 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.

9 Estrogen is linked to the pathogenesis of breast cancer. Endocrine therapy (ET) is medicines treat hormone-receptorpositive 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).

10 Tamoxifen 1977 is the Oldest Targeted therapy in BC

11 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.

12 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 lowand 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.

13 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.

14 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.

15 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?

16 Timeline of Approval of Agents for HR+ ABC

17 Tamoxifen in MBC, since 1977 Accidentally discovered during contraception trials. Response Rates: All women: 16-52% (CR+PR) Postmenopausal women MoA: 50%: ER+ disease 60-70%: ER+/PR+ disease 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

18 Aromatase Inhibitors Nonselective Amino-glutethimide (competitive) Selective Competitive Noncompetitive (non-steroidal) (steroidal) Anastrozole Exemestane Letrozole Formestane Vorozole Fadrozole

19 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.

20 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.

21 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).

22 FIRST Trial confirms OS yet!

23 CONFIRM Confirmed superiority of 500 mg dose, 2010

24 CONFIRM.. Final Survival Analysis 2013

25 Overcoming Resistance new strategies CDK

26 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< ) favors combination. Further at interim analysis median PFS was significantly increased with the combination (4.1 vs months, HR 0.36, 95%CI, , 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.

27 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?

Lost Benefit at 39 Months? Moreover, Exemestane alone is getting better, late deaths in Evero Arm. The decision must take into account the increased toxicity.

28 Lost Benefit at 39 Months? Moreover, Exemestane alone is getting better, late deaths in Evero Arm. 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.

CDK: Palbociclib.. A new Stallion Palbociclib (Ibrance), a firstin-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.

29 CDK: Palbociclib.. A new Stallion Palbociclib (Ibrance), a firstin-class CDK inhibitor. Significant increase PFS in patients with advanced ER+/HER2. PFS: 20.2 vs 10.2 months; HR=0.488( ) P= Palbociclib plus Letrozole received US FDA accelerated approval as first-line therapy for ER(+)ve, HER2(-)ve MBC in February PALOMA 2 and 3 and introducing to neo-adjuvant are ongoing.

30 New drugs.. Syndax..

31 ONGOING IMPROVEMENT

32 How to Sequence? AIs NS TAM AIs S FULVEST EVERO Others

33 From ABC 1 st & 2 nd.. Important Messages

34 Everolimus may be added earlier if resistance is suspected How To Sequence? CDK CDK CDK CDK

35 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.

36 HER-2 Positivity Equals Resistance to Hormonal Therapy

37 Combination or Sequential ET

38 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.

39 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

40 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.

41 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. o Adding 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!!

Endocrine Therapy of Metastatic Breast Cancer

Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Endocrine Therapy of Metastatic Breast Cancer Endocrine Therapy of Metastatic Breast Cancer Version 2002: Gerber / Friedrichs