OPTIMIZING NEOADJUVANT/ADJUVANT TREATMENT OPTIONS IN PATIENTS WITH BREAST CANCER DR LASEBIKAN NWAMAKA RADIATION AND CLINICAL ONCOLOGIST UNTH

OUTLINE Breast cancer in Nigeria Treatment options Can we improve therapy Early Breast cancer Locally Advanced Recurrent/Metastatic Case presentations Panelist Discussions

Breast Cancer In Nigeria  Pattern of presentation  Diagnosis  Treatment outcome/ Survival Indices

Treatment options  Surgery  Systemic therapy- Chemotherapy  Hormonal Therapy  Targeted therapy  Radiotherapy  Best Supportive Care

CAN WE IMPROVE THERAPY General considerations  Treatment related factors -Type of tumour/stage -Available human resources and infrastructure -Requires multimodality approach/sequencing  Patient Related factors - Age - Co- morbidities - Patients choice - Finance

Crea Definition of risk categories for patients with operable breast cancer

EARLY BREAST CANCER

Recommended standard regimens (modified from (Carlson et al., 2009)Carlson et al., 2009  HER2-negative  Preferred Regimens:  AC × 4 (every 2 weeks with filgrastim support or every 3 weeks) followed by weekly paclitaxel × 12  TAC×6  Dose dense AC × 4 followed by dose dense paclitaxel × 4  TC×6 * *  Other Regimens: FAC/CAF × 6 FEC/CEF × 6 CMF × 6 AC × 4 followed by docetaxel × 4 every 3 weeks AC × 4 followed by paclitaxel × 4 every 3 weeks Doxorubicin × 3 followed by paclitaxel × 3 followed by cyclophosphamide × 3 every 2 weekly regimen with filgrastim support FEC followed by docetaxel * May be appropriate for women for whom antracyclines are not recommendeD Disease-free survival (DFS) and overall survival (OS) hazard ratios (HRs) and 95% CIs for weekly paclitaxel (P1) and docetaxel every 3 weeks (D3) compared with paclitaxel every 3 weeks (P3) in overall population (A, B) and in patients with TN

(A, B) Disease-free survival (DFS) and (C, D) overall survival (OS) in 1,025 patients with triple-negative breast cancer, based on (A, C) Kaplan-Meier estimates by treatment arm and (B, D) estimated hazard ratios (HRs) and 95% CIs from univariable Cox (A, B) Disease-free survival (DFS) and (C, D) overall survival (OS) in 2,879 patients with hormone receptor–positive, human epidermal growth factor receptor 2–nonoverexpressing breast cancer, based on (A, C) Kaplan-Meier estimates by treatment

Her 2 positive disease  HER2-positive  Preferred Regimens: AC, followed by paciltaxel (various schedules) and concurrent trastuzumab +/- pertuzumab  Dose- dense AC followed by Trastuzumab  TCH  TCH +Peruzumab  Other Adjuvant Regimens:  AC followed by docetaxel and trastuzumab  Docetaxel and trastuzumab followed by FEC  Paclitaxel and trastuzumab followed by CEF and trastuzumab

Her 2 positive disease

Hormonal Therapy Premenopausal- Tamoxifene Menopausal - AI

TNBC  AC-T; T AC: Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 IV on day 1 every 3 wk for four cycles followed by paclitaxel 80 mg/m 2 IV weekly X12  NOTE: IF NO CLINICAL RESPONSE AFTER 2-3 CYCLES OF AC, SWITCH TO PLATINUM  Carboplatin AUC 6 IV on day 1 every 3 weeks plus Paclitaxeal 80 mg/m 2 IV weekly X12

OUTCOME OF NAT PREOPERATIVE CHEMOTHERAPY CONFIRMED PROGRESSIVE DISEASE MASTECTOMY PARTIAL RESPONSE MASTECTOMY PARTIAL RESPONSE, BCS POSSIBLE BCS COMPLETE RESPONSE BCS

Summary

LOCOREGIONAL TREATMENT  Radiotherapy (RT): whole breast radiotherapy following BCS or chest wall radiotherapy after mastectomy. Treatment fields are determined by axillary nodal status.  Although clinically apparent lymph node relapses (especially axillary and internal mammary) are rare, nodal irradiation remains indicated for patients with involved lymph nodes.  Shorter fractionation schemes are recommended.  RT should follow chemotherapy if adjuvant chemotherapy is indicated and can be safely combined with trastuzumab  Adjuvant chemotherapy commences as soon as the wound has healed, within 2-6weeks following surgery but not later than 12weeks.  Option of breast reconstruction discussed with patient and plastic surgeon.

ADJUVANT THERAPY-INDICATIONS  Weigh risk/benefit  Multiple components determine the necessity for patients requiring adjuvant chemotherapy. These include but are not limited to:  tumor size, molecular subtype, histology and its grade.  The axillary and regional lymph node status.  Tumor hormone receptor expression are also important considerations.  Patient’s age, concomitant co-morbidities and their performance status play a significant role in determining the benefit of adjuvant chemotherapy

ADJUVANT SYSTEMIC THERAPY FOR HORMONE RECEPTOR +VE AND/OR Her 2 OVEREXPRESSION HR+/HER 2 +VE NODE NEGATIVE CONSIDER ADJUVANT CTH +/- ADJUVANT CTH WITH TRASTUZUMAB ADJUVANT ET OR ADJUVANT CTH + TRASTUZUMAB FOLLOWED BY ET NODE POSITVE ADJUVANT CTH + TRASTUZUMAB THEN ET Hormone Receptor positive HR+VE/Her 2 -VENODE NEGATIVECONSIDER ADJUVANT ET ADJUVANT ET+/- CTH THEREAFTER ET NODE POSITIVEADJUVANT ET + CTH

ADJUVANT ENDOCRINE THERAPY

ADJUVANT TREATMENT FOR HORMONE RECEPTOR NEGATIVE +/- HER 2 OVEREXPRESSION HORMONE RECEPTOR NEGATIVE HER2 POSITIVE NODE NEGATIVE CONSIDER ADJUVANT CTH WITH TRASTUZUMAB T>1CM ADJUVANT CTH WITH TRASTUZUMAB NODE POSITIVE ADJUVANT CTH WITH TRASTUZUMAB HER2 NEGATIVE NODE NEGATIVE NO ADJUVANT CTH/CONSIDER ADJUVANT CTH T>1CM- ADJUVANT CTH NODE POSITIVE ADJUVANT CTH

LABC  Neoadjuvant CTH  Anthracyclin based chemotherapy is standard of care and should be sequenced with Taxane.  Mastectomy  Adjuvant systemic therapy depending on intrinsic tumour subtype- ET is a reasonable option in elderly women with slow growing ER +VE tumours

LABC  For triple negative tumours, the addition of the platinum compounds has been shown to improve pCR.  Patients who do not respond after 4 cycles of optimally dosed anthracyclines generally should receive local treatment.  Postmastectomy radiotherapy immediately after surgery or on completion of adjuvant chemotherapy.  Adjuvant Endocrine therapy should be given for hormone-responsive tumors for 10 years.  For Her2neu positive tumours, trastuzumab therapy should continue post surgery at 3-week intervals for 1 year or until disease recurrence (whichever is the shorter period)  Commence biphosphonate therapy should continue for 1 year

RECURRENT DISEASE

 Depends on prior treatment.  Lumpectomy Mastectomy  Mastectomy + Radiotherapy consider surgery  Mastectomy – Radio consider surgery+radiotherapy  Consider surgery if possible and radiotherapy LOCAL ONLY Locoregional RE-BIOPSY ALL LUMPS

METASTATIC DISEASE- DE NOVO  Systemic therapy depending on intrinsic tumour type- as previously discussed  ER+/PR+ with visceral crisis commence chemotherapy first.  Systemic therapy + Biphosphonate NO BONE DISEASEBONE DISEASE

ER/PR POSITIVE MBC  Continue hormonal therapy until disease progression or unacceptable toxicity and consider chemotherapy.  Postmenopausal patients on AI with refractive disease should switch to fulvestrant.

Chemotherapy for MBC  Is based on the concept of following a treatment continuum in responders (1st, 2nd, 3rd line therapies) ensuring non-overlapping toxicities.  Reserved for patients with hormone-insensitive disease or for patients with symptomatic hormone-sensitive disease who have failed all hormone therapy options or who are moderately to severely symptomatic and in urgent need of symptom palliation  The options for cytotoxic-containing chemotherapy include single- agent therapy and combination cytotoxic therapy

OPTIONS FOR CHEMOTHERAPY  Doxorubicin  Epirubicin  Paclitaxel  Docetaxel  Capecitabine  Gemcitabine  Vinorelbine PREFERRED SINGLE AGENTS

1 ST LINE COMBINATIONS  CAF: Cyclophosphamide 100 mg/m 2 IV on day 1 plus doxorubicin (Adriamycin) 30 mg/m 2 IV on days 1 and 8 plus 5-fluorouracil (5-FU) 500 mg/m 2 IV on days 1 and 8 every 4 wk for six cycles  FAC: 5-FU 500 mg/m 2 IV on days 1 and 8 or days 1 and 4 plus doxorubicin 50 mg/m 2 IV on day 1 plus cyclophosphamide 500 mg/m 2 IV on day 1 every 3 wk for six cycles  FEC: 5-FU 500 mg/m 2 IV plus epirubicin 100 mg/m 2 IV plus cyclophosphamide 500 mg/m 2 IV on day 1 every 3 wk for three cycles  AC: Doxorubicin 60 mg/m 2 IV plus cyclophosphamide 600 mg/m 2 IV on day 1 every 3 wk for four cycles  EC: Epirubicin 100 mg/m 2 IV on day 1 plus cyclophosphamide 830 mg/m 2 IV on day 1 every 3 wk for eight cycles  AT: Doxorubicin 50 mg/m 2 IV plus paclitaxel mg/m 2 every 3 wk  AT: Doxorubicin 50 mg/m 2 IV plus docetaxel 75 mg/m 2 IV every 3 wk  CMF

CHEMOTHERAPY OPTIONS  Docetaxel/capecitabine: Docetaxel 75 mg/m 2 IV on day 1 plus capecitabine 950 mg/m 2 PO BID on days 1-14 every 3 wk  GT: Paclitaxel or Docetaxeal: Paclitaxel 175 mg/m 2 on day 1 plus gemcitabine 1250 mg/m 2 IV on days 1 and 8 (following paclitaxel on day 1) every 3 wk OR Docetaxell 75mg/ m 2 on day 1 plus Gemcitabine 1000mg/ m 2 on day 1 and 8 every 3 weeks.  Gemcitabine/ Carboplatin: Gemcitabine 1000mg/ m 2 on day 1 and 8 every 3 weeks and Carboplatin AUC 2 1V on days 1 and 8, every 3 weeks.  Vinoelbine 25 mg/m 2 IV weekly  Eribulin 1.4 mg/m 2 IV on days 1 and 8 every 3 wk( not readily available) 2 nd Line Chemotherapy Considerations 3 rd Line Chemotherapy Considerations

HER2 NEU POSITIVE

SUMMARY Treatment outcomes will improve when  patients present early  There is prompt and accurate diagnosis  Optimal treatment involving multidisciplinary management  Early palliative care intervention  Physicians balance risk/benefit ratio

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CASE PRESENTATION