Editing Breast cancer (section)

== '''Chemotherapy''' ==

* '''Systemic chemotherapy''' is a risk-based proposition - must be individualised, using the specific pathological subtype (see above under histopathology) - can use calculators.
** Systemic therapy (not necessarily CHEMOtherapy, could be endocrine) is indicated in '''any woman deemed to have a significant risk of micrometastatic disease'''
** Indications for CHEMOtherapy
*** Any evidence of metastases on CT or other imaging
*** Node positive disease regardless of hormone receptor status and/or primary tumour size
*** Triple negative breast cancer with primary tumour >1cm
*** HER2 cancers at least 1cm in size regardless of nodal status, in addition to HER2 targeted therapy
*** CTX is STRONGLY CONSIDERED for medically fit patients with HER2 overexpressing or triple negative cancers measuring 6-10mm
** Start 4-6 weeks after surgery
* '''Neoadjuvant chemotherapy:'''
** Theoretical advantages:
*** Downstage locoregional disease, and perhaps reduce extent of surgery
*** Prognosticate based on response
*** Increase proportion of patients getting to systemic therapy
*** Treat micrometastases earlier
*** Time - genetics, reconstruction, fertility planning
** Disadvantage - 3% progression despite therapy
** Indications
*** Locally advanced cancer
*** Stage I or II cancers where BCS is not possible due to tumour size or location
*** T1c or T2 triple negative or HER2+ tumours
*** Limited clinically node positive disease
*** Temporary contraindications to surgery (awaiting genetic testing)
*** In some circumstances if immediate reconstruction is planned (can delay adjuvant therapy, can prevent radiotherapy)
*** Some ER+/PR+ cancers with high Ki67% - aromatase inhibitors
** Background
*** Usually 3-6 months, most commonly 6
*** Review the patient after three months to ensure they're not progressing
* '''Adjuvant chemotherapy'''
** Aim to start by 4-6 weeks post-op
** Duration 3-6 months
** Earlier not necessarily better
** Delays of >3 months are likely detrimental
* '''Specific situations:'''
** Triple negative ('basal-like'): adjuvant chemotherapy
*** Triple negative paradox means primary tumours are more sensitive to CTX than others, and can achieve pathological complete response at a rate of about 20-45%, and if they do achieve that, have similar overall survival with other breast cancers.
*** Size >0.5cm or pathologically involved lymph nodes regardless of size = adjuvant CTX
*** CTX becomes more appropriate as risk of recurrence increases, meaning size of tumour, histological factors, nodal disease, etc
*** Most commonly TAC
*** Targeted therapy (PARP inhibitors, immune checkpoint inhibitors, pembrolizumab) are available, and there will probably be an increasing role for these in the future
*** Pembrolizumab given to patients with PD-L1 combined positive score >10, in combination with traditional chemotherapy
** ER/PR positive, HER2 negative - luminal subtype - individualise based on risk
*** Benefit of CTX is less clear - can use the Recurrence Score (see '''histopathology''' section above)
*** But should have endocrine therapy - see below
*** Neoadjuvant endocrine therapy has shown some promise - potential for downstaging, allowing breast-conserving surgery
*** CDK 4/6 inhibitors are usually better than traditional CTX
** HER2 positive disease often has neoadjuvant CTX
*** Trastuzumab plus CTX (if >1cm yes, and if 6-10mm likely)
*** Also likely have adjuvant - trastuzumab for a year
*** Pertuzumab (Perjeta) can be given in addition to trastuzumab in high-risk disease, and may improve outcomes
** '''Locally advanced: neoadjuvant'''
*** Luminal
**** Usually chemotherapy rather than endocrine therapy
**** Endocrine would only be used based on strong patient preference or serious comorbidities
*** HER2+
**** Trastuzumab with or without pertuzumab
**** Chemotherapy (docetaxel and carboplatin - drop the anthracyclines due to cumulative cardiac risk)
*** Triple negative
**** Chemotherapy (AC-T +/- carboplatin) +/- immunotherapy
** '''Metastatic'''
*** Luminal subtype
**** Mostly endocrine therapy followed by chemotherapy (AC-T) if progression
**** CDK 4/6 inhibitors
*** HER2+
**** Trastuzumab, pertuzumab and a taxane
**** Add endocrine therapy if amenable
*** Triple negative
**** First-line chemotherapy
**** AC-T + carboplatin
**** Add pembrolizumab if PD-L1 is overexpressed
**** Add PARP if BRCA
** Pre-menopausal women with incomplete families:
*** Goserelin - reduces ovarian failure from 22% to 8%
*** Egg harvesting
* Regimes and specific additional medications:
** Anthracyclines
*** Most common
*** Doxorubicin (Adriamycin) and epirubicin
*** Can be given at 3-week intervals or in an accelerated 2-week interval with G-CSF
*** Concern for cardiotoxicity - CCF; also nausea/vomiting, bone marrow suppression, febrile neutropaenia
*** Usually 4-6 cycles
** Taxanes
*** Paclitaxel and docetaxel
*** Often combine with anthracyclines
*** Especially in patients with ER-negative and/or HER2-positive disease
*** Hair loss, bone marrow suppression, diarrhoea, hand and foot syndrome, peripheral neuropathy
** Platinum-based
*** Carboplatin
*** Electrolyte imbalances, BM suppression
*** Often given with triple-negative cancers in combination with taxanes
** Cyclophosphamide
*** Alkylating agent
*** Myelosuppression, haemorrhagic cystitis, alopecia, gonadal suppression 
** Trastuzumab (Herceptin/Kadcyla)
*** Recombinant humanised monoclonal antibody directed against the extracellular domain of the HER2 protein, blocking signalling. Approved in 1998 in USA.
*** Significantly improved disease-free and overall survival for HER2 subtype.
*** Generally given for a year as monthly infusions. Current thinking is that is should be given concurrently with adjuvant chemotherapy.
*** HER2 resistance

**** Approximately 15% relapse after treatment
**** Other drugs assist with overcoming this - Lapatinib, Pertuzumab

*** Can get/worsen CCF - need TTE prior to trastuzumab - 3.6% get reduced EF

**** Need to give out of sequence with anthracyclines

** Pertuzumab (Perjeta)
*** Another anti-HER2 monoclonal antibody, binding to a different epitope than trastuzumab
*** Also risk cardiotoxicity
** Bisphosphonates
*** Zoledronic acid is the most potent
*** Routinely given with bone metastases - thought to alter the bone micro-environment, making it less favourable for dormant tumour cells
** CDK 4/6 inhibitors
*** Abemaciclib, ribociclic and palbociclib
*** Approved for metastatic hormone receptor positive, HER2- cancer
** PARP inhibitors
*** Olaparib, rucaparib, niraparib, talazoparib
*** Inhibitors the PARP protein which repairs cellular DNA
*** Particularly effective for BRCA cancers since these already have reduced DNA repair capabilities