Overview of Rx Secondary Breast Cancer

Transcription

1 Overview of Rx Secondary Breast Cancer 2016 Prof Fran Boyle AM Sydney Medical School

2 The big picture

3 Different disease risks may require different responses Slowly progressing bone mets Rapidly progressing visceral mets

4 De novo Stage 4 BC Around 10-15% of all newly diagnosed women May be picked up on scans without any symptoms in Early BC More common in older and younger women More common in Her2+ and Triple negative BC Does not necessarily have a worse outlook Two Journeys to Secondaries All treatment options are open as no prior therapy Recurrence after Early BC Less common than in the past due to better treatment Often later than in the past due to longer adjuvant hormone blocking therapy eg Tamoxifen Consider re-biopsy before deciding on treatment to check ER/Her2 are the same as primary Need to consider prior therapy in choosing treatment - Resistance of cancer cells - Side effects that accumulate

5 How long have I got? It depends on.. Disease subtype Disease free interval Extent of prior therapy Location and extent Response to first line therapy How many therapies one would consider using Whether affordable new therapies appear Avoiding infection and clotting General health and motivation and support Avoiding cumulative toxicity and organ failure

6 Improving Survival Over time Her 2 positive population Pooled data MD Anderson Cancer Centre Dawood JCO 2010

7 Capecitabine (ANZ 0001) Improved Overall Survival Capecitabine group stayed on therapy longer Stockler et al, JCO 20111

8 Median poorly understood Communicating survival data Relative survival advantage with particular treatments not likely to be understood well eg HR Consider using a survival curve from a relevant trial Useful lay concepts Correlates to - Average or Typical ½- 2 x Median - Shortest, if treatment does not go well ¼ Median - Longest, if treatment goes well Triple Median Kiely et al, JCO 2011

9 Avoid Cumulative Side effects Neuropathy - Paclitaxel - Docetaxel - Nab-paclitaxel - Vinorelbine - Eribulin - Platinum agents Hand-Foot Syndrome - Capecitabine - Caelyx Cardiac Toxicity - Doxorubicin - Epirubicin - Liposomal doxorubicin - Mitoxantrone - Her 2 Blocking drugs - Trastuzumab - Lapatinib - T-DM1 - Pertuzumab Avoid using drugs from the same group back to back

10 Don t use a combination when a single agent will do* Dear RF et al, Cochrane Database Syst Rev 2013, Combination vs Sequential single agent Chemo for metastatic breast cancer. *Unless it s a Her 2 targeted therapy

11 Aim for continuous therapy N Engl J Med Dec 10;317(24): Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. Coates A 1, Gebski V, Bishop JF, Jeal PN, Woods RL, Snyder R, Tattersall MH, Byrne M, Harvey V, Gill G. for the ANZ Breast Cancer Trials Group Ludwig Institute for Cancer Research (Sydney Branch), University of Sydney, N.S.W., Australia. 11

12 Counter-intuitive result Intermittent Chemotherapy - MFP x 3 - AC x 3 Only gave further chemo when disease progressed Continuous Chemotherapy - Only ceased when disease progressed or unacceptable toxicity Results favouring continuous therapy - Response Rate - Time to Progression - Overall Survival - Quality of Life 12

13 Its good to have more drugs Survival from first metastasis (days) * * Survival Taxol Vin AI, Tax Cap/Herc Chia et al The impact of new chemotherapeutic and hormonal agents on the survival in a population based cohort of women with metastatic breast cancer. Cancer 2007

14 Her 2 positive disease PBAC May 2016

15 Progression-free survival (%) Cleopatra trial Primary endpoint: Independent PFS n at risk Ptz + T + D Pla + T + D Time (months) D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months = 6.1 months HR = % CI p< Stratified by prior treatment status and region Baselga, SABCS 2011

16 OS (%) Cleopatra Trial Final OS Analysis n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) months Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab. Swain, ESMO

17 ER/PR positive breast cancer Most patients will have received adjuvant endocrine therapy - Variable adherance is common (40% discontinuation in 45 and up study) (1) - 5 vs 10 years to prevent late relapse - Ovarian suppression improves efficacy in youngest women Mechanisms of endocrine resistance (2) - Signalling bypass / cross talk pathway activation - Post-translational modification of ER - Alterations in ER interacting proteins - ER mutations with constitutive activation or alteration in SERM binding - Loss of ER or aromatase expression by histone methylation or deacetylation (1) Kemp 2015, (2) Redfern 2016

18 Overcoming resistance to endocrine therapies Afinitor (mtor inhibitor) Taken as daily tablet with Exemestane Increases PFS (Bolero 2) More side effects - Mouth ulcers - Fatigue - Skin rash - Abn LFT s, anaemia - pneumonitis PBS June Palbociclib (CDK 4/6 inhibitor) Taken as daily tablet with other hormone blockers Increases PFS in first line - Paloma 1, Paloma 2 (ASCO 2016) In Australia 2016 late line trials - TGA 2017? PBS Buparlisib (PI3kinase inhibitor) Belle 2 Trial showed benefit in patients with mutations of Pi3KCA in ctdna (with Faslodex) Novel SERM s In trial at present Beith J, APJCO, 12 suppl 1, 2016

19 New chemotherapy agents Marine sponge Halichondra okadai Inhibits microtubule growth (not shortening) - Sequesters tubulin into non-functional aggregates - G2/M arrest and apoptosis Eribulin has activity in taxane-resistant cell lines Expected to have neurotoxicity - Care prior neuropathy from chemo, diabetes, compression, brachial plexopathy etc

20 Study 305: EMBRACE Schema Patients (n=762) Locally recurrent or metastatic breast cancer 2 5 prior chemotherapies ( 2 for advanced disease) Prior anthracycline and taxane Progression on or within 6 months of last chemotherapy RANDOMISED Recruitment completed 2:1 Eribulin mesilate 1.4 mg/m 2* IV over 2-5 minutes on Day 1,8 q21 days Stratified by HER2 status, prior capecitabine therapy, and geographical region Physician s choice: Any monotherapy (cytotoxic, hormonal, biological); or Palliative treatment; or Radiotherapy * equivalent to 1.4 mg/m 2 eribulin mesilate HER2, human epidermal growth factor receptor type 2 Cortes J et al. Lancet 2011;377:

21 Probability of survival Study 305: EMBRACE Overall Survival p value from stratified log-rank test (pre-defined primary analysis) *HR Cox model including geographic region, HER2/neu status, and prior capecitabine therapy as strata CI, confidence intervals; HER2, human epidermal growth factor receptor type 2; HR, hazard ratio Intent-to-treat population Cortes J et al. Lancet 2011;377:

22 Parp inhibitors About 5% of women with breast cancer will have mutations of BRCA1 or 2, which are inherited Defect in DNA damage repair PARP inhibitors further reduce repair capacity so cancer cells are vulnerable - Tablet based treatments Olaparib, Veliparib - Can be combined with other chemotherapy drugs eg cyclophosphamide (carefully) Trials underway in Australia

23 Immunotherapy Variable immune response associated with secondary breast cancer - Tumour infiltrating lymphocytes carry a better prognosis in neoadjuvant setting - PD L1 expression variable Current anti PD1 trials in - Her 2 positive - Panacea: Westmead and Peter Mac: late line herceptin plus Pembrolizumab - Triple negative - Keynote: Mater Sydney, Westmead, Peter Mac: first line single agent 23

24 Brain metastases Local Therapy Consider surgery or radiosurgery in selected patients with a single or limited brain metastases Size of lesions (s) accessibility of lesion(s), status of extra-cranial disease, co-morbidities, intracranial pressure, other symptom control Following local treatment, consider observation and salvage therapy on progression if required no survival advantage to immediate WBRT although reduced brain progression 3 monthly MRI if otherwise systemically stable LOE B B Cancer Australia Brain Metastasis Guidelines 2014

25 Brain metastases Whole Brain RT Consider initial Whole Brain Radiotherapy (WBRT) for patients with multiple lesions or poorer prognosis Symptomatic and cognitive improvement is usual Reduced need for salvage therapy No survival advantage with higher doses (more than 30Gy in 10 fractions) No survival advantage for radiosensitisers or concurrent chemotherapy SRS / Gamma Knife after WBRT is possible on progression if systemically stable Late cognitive effects a consideration if prognosis is otherwise good LOE C Cancer Australia Brain Metastasis Guidelines 2014

26 Brain metastases systemic therapy HER2-targeted therapies should be started or continued in HER2-positive patients Improved survival in retrospective series with trastuzumab Uncertain whether pertuzumab has same effect, but if isolated progression in CNS, continue it If intracranial progression consider lapatinib and capecitabine Lapatinib has some brain penetration and satisfactory response rate in a small phase II neoadjuvant trial with capecitabine (LANDSCAPE) with potential to delay WBRT in selected cases Some emerging case reports of responses after Radiotherapy with newer agents eg T-DM1 LOE C Cancer Australia Brain Metastasis Guidelines 2014

27 Supportive Care in brain metastases Practice Points Limit steroid dose and duration to avoid side effects - Morning dosing is sufficient for most patients, wean ASAP Use anticonvulsants only if seizures occur Rehabilitation may assist in improving function Specialist palliative care services should be engaged for patients considered unlikely to benefit from local therapies or WBRT, or who have ongoing symptoms Driving is not recommended for patients with newly diagnosed CNS metastases Reassess after treatment May require ophthalmologist to assess visual fields May require on road testing (Rehab centres) Seizures and craniotomies have longer lock out times Refer Fitness to drive guidelines on RTA website Cancer Australia Brain Metastasis Guidelines 2014

28 Guess who has cancer? Chemo Babs Qantas Cabin Crew Cancer Support Group 28

29 Can I avoid losing my hair? Choose drugs that spare Hormone blocking drugs - Tamoxifen - Aromatase inhibitors - Faslodex Oral chemotherapy Choose more localised radiotherapy Stereotactic radiotherapy and gamma knife treat only the metastases - Capecitabine (Xeloda) - Cyclophosphamide and methotrexate (low dose) IV chemotherapy - Gemcitabine - Carboplatin - Vinorelbine Herceptin or Kadcyla

30 Managing CIA in SBC Many women have lost their hair before - I am not going to die bald - May restrict choices of therapy 3 weekly Docetaxel 75 g/m2 suitable Weekly paclitaxel or nab-paclitaxel may be suitable - More chair time Consider previous radiotherapy and hepatic function Eribulin under investigation - Short infusion time ( 5 mins ) - Evaluating half hour pre and 1 hour post cooling After 3 months of Abraxane 30

31 New Generation Cooling Devices Paxman Orbis Dignitana Dignicap 31

32 Help with finances? Superannuation - People with a terminal illness can access their super tax free - They have know idea how long you are going to live and won t take the money back if you live longer than 24 months - Disability insurance is included in some policies, consider if you are working reduced hours Social Security - Support if not working for patients and carers Safety nets - Medication and out of pocket expenses can be tracked

33 The bucket list Choose countries with reciprocal medicare agreements if you can t get pre-existing condition insurance Get a letter about your medications and carry them in your hand luggage Take a copy of blood results and your latest scan CD Don t bungy jump with bony mets Prevent clots Take antibiotics with you wot if don t book too far ahead

34 Getting help with symptoms Accurate diagnosis - Cancer or treatment? - Something else? Palliative Care referral - Symptom control - Assistance with adjustments to support care at home - Support for families - Earlier referral may improve survival (Lung Ca)

35 Better pain control = better survival Tools for tracking pain - Specifics and severity - App / diary - Goals BD dosing or patches improve adherance Constipation alert - Consider Targin Bone Pain - Radiotherapy helpful - Prevent with Bisphosphonates or denosumab (Xgeva)

36 Support Groups

37 Knowing when to stop There comes a time when continuing chemotherapy will shorten the patients life - Falling PS, no longer independent - Increasing toxicity - Oedema - Running out of Rx options - Running out of Puff - Ticked off the bucket list

38 Boyle s Law When the bilirubin is higher than the platelet count, Its time to stop the chemotherapy.

39 Minimal metastatic disease - Detected on screening? - Scans or ctdna or CTC s Secondary Breast Cancer Cures? Combination treatments to overcome resistance Reduced toxicity of therapy to allow prolonged use Monitoring of minimal residual disease Enhanced immune responsiveness

40 In your working lifetime