Paste Triple Negative Breast Cancer (TNBC) Name : R M Lasika Mauri Age : 30 years Sex : Female Clinic File No : 8602/15 Case History 30year old female referred to Cancer Institute, Maharagama for further management of carcinoma of left breast following left sided breast conservative surgery at National Hospital of Sri Lanka. She was apparently well 5 months back when she first noted a lump in her left breast. It gradually increased in size with nipple discharge and pain in the breast. She didn’t have palpable lumps in right breast, bilateral axillae or neck. There was no history of left arm swelling or weakness. She had no53symptoms of metastatic disease such as bon pain,headache, difficulty in breathing, cough, loss of appetite or loss of weight at presentation. Her past medical, surgical and allergy histories were not significant. There was no breast, ovarian, colonic or any other cancers among her siblings or other first and second degree relatives. She attained menarche at the age of 13 years and her menstrual cycles were generally regular. She had never received exogenous hormone replacement therapy. There was no history of exposure to radiation in the past. She is an unmarried teacher with good family support. Triple assessment: Clinical Examination – Bimanual palpation of breast had revealed a 2 x 2cm firm, mobile lump in the lower outer quadrant of left breast without skin changes or nipple discharge. Neither loco-regional lymph nodes nor signs of distant metastasis detected clinically. Radiological assessment – ? Mammogram: Right breast was normal. An area of pleomorphic calcifications seen in the lower outer quadrant of left breast, no definite masses seen, BIRADS V ? USS Breast: 15 x 22mm ill-defined irregular mass at 4 o’clock position of left breast, 15mm deep to skin surface, almost reaching chest wall, sub areolar attachment could not be seen. Left axilla – 2 nodes – 10mm and 06mm in size Pathological assessment – ?112US guided Fine Needle Aspiration Cytology ofbreast lump: Malignant smear (C5) ? US19guided Fine Needle Aspiration Cytology of lymph node:Malignant smear, probably metastatic deposit of a breast carcinoma ? True cut biopsy of left breast lump: High126grade ductal carcinoma in situ with comedo necrosis andcalcifications Since there was a discrepancy between cytology and true cut biopsy, an urgent MRI scan of the breast had been arranged as decided at multi-disciplinary meeting: MRI appearance confirmed the histologically proven malignancy in L/ breast which is attached to sub-areolar tissue and L/ axillary lymphadenopathy. Other pre-operative investigations including full blood count, renal and liver functions, alkaline phosphatase and calcium levels were within normal range. Surgical management: Wide local excision of the left breast lump and level II axillary clearance had been performed and patient was referred to us with the histology report. Clinical Examination at first visit to NCIM General examination: She was not pale and not icteric. ECOG performance status – 0 Height – 160 cm Weight – 50 kg BSA – 1.5 m2 No supraclavicular lymphadenopathy. Examination of breasts: Healed surgical scar which is about 3cm in size was seen over the outer lower quadrant of the left breast. No other abnormality was seen in the left breast. Another surgical scar was seen in the left axillary region. Right breast and axilla were normal. Other system examination: Examination of lungs did not show features of pleural effusion; no abnormal sounds were heard. Cardiovascular and neurological systems were clinically normal. Abdominal examination did not reveal hepatomegaly, ascites or any mases. Investigations ? Histology of wide local excision and axillary clearance specimen: Invasive Duct carcinoma (NST) Tumor size – 2.8 X 2.5 X 2cm, Nottingham grade II Lympho-vascular invasion seen Perineural invasion not seen High grade DCIS present Resection margins not involved by the tumour 12 out of 23 lymph nodes show tumour deposits Pathological stage: T2N3Mx Nottingham prognostic index (NPI): 5.56 Immunohistochemistry :158ER : negative, PR : negative, HER2 neu : Negative 1+ CK 5/6 : tumour cellspositive EGFR &Ki 67: not done ? Cytogenetic studies for BRCA 1 and 2 – not done ? Staging investigations: Chest X-ray – Normal Ultrasound scan of the abdomen – Normal study No liver metastasis Tc99 Bone Scan – date taken ? Baseline blood investigations: Full102blood count, Liver function tests, Renal function tests, Serum Alkaline phosphatase, and Serum Calcium levels were within normal range.? Cardiac assessment: 2D Echocardiogram- Normal, ejection fraction > 60% Summary 30year old, unmarried lady with good performance status, without any comorbid factors or family history presented with a left sided breast lump for 5months duration. She underwent breast conservative surgery with level II axillary clearance. Diagnosis – Invasive duct carcinoma (NST) of left breast T2 N3 M x GII Stage III C Triple negative, CK 5/6 positive Management General management: Patient and the family were counselled regarding the condition and treatment options were discussed. Patient was informed about the side effects of treatment eg: neutropaenia, hair loss, nausea, vomiting, etc. Limb physiotherapy was arranged. Extensive counselling was arranged as patient had been preparing for wedding in a few months’ time. Possible fertility issues were discussed. Informed written consent was obtained before commencement of specific management. Specific management: According to the surrogate molecular classification of158intrinsic subtypes of breast cancer – 2015 St Gallen consensus,our patient belongs to ‘Basal-like’, Triple negative subtype. Because of the high risk nature, it is decided to treat her with anthracycline and taxane based adjuvant chemotherapy followed by adjuvant radiotherapy to whole breast (indicated due to breast conservation) along with regional lymph node irradiation (> 4 positive lymph nodes) and tumour bed boost (age<40years). Adjuvant Chemotherapy schedule – AC followed by Taxanes Doxorubicin 60mg/m2 (90) in 250ml normal saline over 1hour IV D1 Cyclophosphamide 600mg/m2 (900) in 500ml normal saline over 1hour IV D1 Repeat D21 x 4 cycles Pre-medicated with Ondansetron 8mg IV and Dexamethasone 8mg IV half an hour before commencement and post chemotherapy anti-emetics/ antacids given for 5 days. Paclitaxel 175mg/m2 (260) in 500ml normal saline over 3hours IV D1 Repeat D21 x 4 cycles Pre-medicated with oral dexamethasone 20mg 12hours and 6 hours before commencement along with ranitidine 50 IV and carefully monitored for reactions. After completing first four cycles of chemotherapy, CT simulation was arranged to plan 3D conformal radiotherapy to be commenced after completing the balance four cycles of chemotherapy. Chemotherapy was well tolerated. There was no treatment delay due to side effect. She started losing her hair with second cycle of chemotherapy and experienced total alopecia with completion of chemotherapy. Adjuvant Radiotherapy: Patient Simulation – Patient was immobilized73on a breast board with a knee rest. Arms were kept above the head.Set up marks were placed using the lasers. A lead wire was placed around the conserved left breast and over the surgical scar. CT data were acquired superiorly179to include the full neck and inferiorly to include the whole ipsilateral lung and 5cm below breast tissue.Target Volume Definition – CTV breast was defined to include the whole breast excluding skin and chest wall and muscles down to the deep fascia. 1cm margin was added to create PTV. Ipsilateral lung and heart was marked as organs at risk. CTV tumor bed was delineated by adding 1.5cm margin to tumour bed and 0.5 cm was added to create PTV. CTV supraclavicular fossa was then delineated from caudal edge of cricoid cartilage to caudal edge of left clavicular head to approximate the cranial border of the breast field. Treatment planning was done using 6MV energy with 2 tangential wedged (150) beams for the conserved breast and single direct anterior beam for supraclavicular fossa and the common iso-centre technique was used to match the beams. The central lung distance was kept less than 2cm. Dose prescription – 40.05Gy in 15 fractions, 2.67Gy per fraction, one fraction per day, Monday to Friday treated over period of 3 weeks. Unfortunately, patient could not receive breast radiotherapy as planned. 2 weeks after completing last chemotherapy cycle, she presented with severe headache and one episode of generalized tonic-clonic seizure. There were no focal neurological signs. Full blood count, serum electrolytes, serum calcium and other parameters were normal. There were no signs of sepsis. She was started on Dexamethasone 8mg IV bd with antiemetics, antacids and kept under observation for further episodes of seizures. Urgent CT brain showed multiple, peripherally enhancing lesions in left posterior parietal, both frontal lobes, left basal ganglia and R/cerebellum with perilesional edema suggestive of multiple cerebral and cerebellar metastasis. Patient and the family members were counselled and informed consent was obtained for radiotherapy. Whole brain radiotherapy was planned in supine neutral neck position and a thermoplastic shell was used for immobilization. Beams were defined to cover whole skull from vertex to 2cm below the Reid’s baseline. Opposing lateral beam arrangement was used and she was treated in Co60 with palliative intent to19a total dose of 30Gy in 10 daily fractions,3Gy per fraction from Monday to Friday, over 2 weeks. Dexamethasone dose was slowly tailed off.104Acute side effects were limited tomild skin toxicity and fatigue. Discussion Breast cancer is the most common cancer in women worldwide. In Sri Lanka, it is the commonest female cancer comprising 26%30of all Sri Lankan female cancers,3014.3% of all cancers and is the commonest site specific cancer.19Increasing age is the most important risk factor.Family history, and both endogenous (i.e.97early menarche, late menopause, nulliparity, older age at first birth) and exogenous ovarian hormoneexposure have an important effect on risk while126diet, alcohol use, and other factors play a smallerrole. Low-dose radiation exposure to the breast is carcinogenic, and risk increases with increasing dose. The2risk is particularly high before the age of 20 yearsand is minimal after menopause. Extended field radiation for Hodgkin lymphoma,79has been associated with an increased risk of breast cancer.21 5 – 10% of the breast cancers are inherited.152BRCA1 and BRCA2 are tumor suppressor genes that play a critical role inthe cellular response to DNA damage and germline mutations in these genes are associated with an increased risk of59breast cancer. About 12 percent of women in the general population will develop breast cancer sometime during their lives. By contrast, according to the most recent estimates, 55 – 65% of women who inherit BRCA1 mutation and around 45% of women who inherit BRCA2 mutation will develop breast cancer by age 70 years.Of them, around 50% and 29% of BRCA 1 and BRCA 2 mutation carriers respectively are at risk of developing breast cancer before age of 50years. PTEN, and TP53 mutations also29play a role in inherited breast cancers. 4 Thediagnosis of breast cancer164is based on clinical, radiological and pathological assessment.11 Clinicalassessment includes bimanual palpation of the breasts, loco -regional lymph nodesand examination for distant metastases. Radiological assessment includes bilateral mammography and ultrasound scan of bilateral beast and axilla. Bilateral mammography is indicated for all patients. It characterizes the suspicious area, evaluates the remainder of the breast for occult lesions, and assesses the contralateral breast. Malignant calcifications typically are linear, or small (<1 mm) in diameter, non-uniform in size, and clustered. Benign calcifications usually are larger and coarser, and are often round with smooth margins.6 Ultrasound is of greatest use when the mammographic findings are equivocal. Ultrasonic image texture analysis effectively distinguishes benign from malignant breast lesions. Doppler flow analysis may provide additional information about solid lesions. Malignant tumors show increased blood flow compared with benign tumors, resulting in a characteristic blood flow signal. MRI breast is not usually recommended and14considered in cases of familial breast cancer associated with BRCA mutations, breast implants, lobular cancers, suspicion of multifocality/ multicentricityor when there is a discrepancy between conventional imaging and clinical examination.11 This discrepancy was the reason in my patient to decide on MRI at MDM. Methods used in pathological assessment includes fine-needle aspiration cytology, needle- core biopsy with ultrasound or stereotactic guidance, and excisional biopsy. Studies indicate that a biopsy needle larger than 14 gauge is preferred, because it significantly increases the rate of concordance with surgical biopsy.53Approximately one-half to two-thirds of patientsdiagnosed by stereotactic cores as having23ductal carcinoma in situ (DCIS) ultimately may befound to have invasive cancer16 and my patient also belongs to this category. If preoperative chemotherapy14is planned, core needle biopsy is mandatory for diagnosis and for assessment ofreceptor status.14Other assessments include past medical history, family history relating to breast/ ovarian and other cancers, other system examinationand laboratory investigations (i.e.14full blood count/ liver and renal function tests/ serum alkaline phosphatase/serum calciumand serum oestradiol/ follicular stimulating hormone level if in doubt of the menopausal status). Final pathological diagnosis of the surgical specimen is made according to the WHO classification and TNM staging system and include number, location and size of the tumors,136number of removed and positive lymph nodes with extent of metastases in the lymph nodes [isolated tumor cells, micro metastases (0.2–2 mm),macro metastases], histological type and grade, resection margins, vascular invasion, and immune-histochemical evaluation of oestrogen receptor (ER) status (using Allred or H score),14progesterone receptor (PR) and human epidermal growth factor 2 receptor (HER2) gene expression.11 Most invasive breast cancers are epithelial neoplasms. Sarcomas, lymphomas, and non- epithelial tumors are rare. Infiltrating breast cancers are histologically heterogeneous. Most of them are adenocarcinomas arising from the terminal ducts.111Invasive ductal carcinoma, which accounts for approximately 85% of breast cancers,has no specific histologic features. Inva- sive175lobular carcinoma is characterized by single- filing (“Indian file”) of small, regular epithelial cells that tend to grow around ducts and lobulesand85accounts for 5 – 15% of breast cancers. The expression of nuclear estrogenandprogesterone receptors85plays an important role in the differentiation and growth of normal breastepithelium andare29predictive markers for response to endocrine therapy.14High ER expression is usually associated with lesser absolute benefit of chemotherapy.HER2133is a growth- signaling molecule on the surface of normal breast cells that is overexpressed in approximately 20% of breast cancer tumors, contributing togrowth autonomy and genomic instability.It is considered positive by IHC (3+) when >10% of tumor cells harbor complete membrane staining or by FISH14if the number of HER2 gene copies is ≥ 6 or ratio HER2/chromosome 17 is ≥ 2. 11 Accurate determination ofHER2 status identifies patients who should be considered for adjuvant therapy113with a trastuzumab- based regimen. Ki67 labelling index, aproliferation marker may supply113additional information with regard to behavior of thetumor. Prognostic factors include pathological tumor size,113expression of ER, PR, HER2 and proliferationmarkers, axillary nodal status, histologic subtype, tumor grade, vascular invasion and perhaps age.9 These parameters are integrated in to scoring systems for relatively accurate estimation of survival. Eg: NPI. It was 5.56 in my patient and corresponds to the poor prognostic group (>5.4). The overall prognosis of classic invasive lobular cancer is thought to be similar to that of the invasive ductal subtype.8 Multiple gene expression profiling assays have been developed as prognostic tests. Oncotype DX, which30uses real-time RT-PCR to check for a panel of 21 geneshas been incorporated in to NCCN guidelines for ER positive, node negative patients, to predict response to adjuvant chemotherapy and to predict loco-regional and9distant recurrence for postmenopausal patients treated with tamoxifen/aromatase inhibitors .7 Mammaprint is a70-gene predictor set approved by FDA to help identify44patients with ER positive or negative, node negative breast cancer who are likely todevelop distant metastasis. These assays are14being prospectively evaluated in randomized clinical trials as predictive markers fortherapy selection. Eg: MINDACT, TAILORx, RxPONDER.10 These molecular assays do not have a role in patients with TNBC and therefore do not apply to my patient. According to142015 St Gallen Consensus Conference and also recommended by ESMO clinical practice guidelines,tumors are grouped in to14surrogate intrinsic subtypes defined by routine histology and IHC data143for the purpose of prognostication and treatment decision making. Theyare as follows; Intrinsicsubtype Luminal A Clinico-pathologic surrogate definition52‘Luminal A-like’ ER-positive, HER2-negative Ki67 low, PgR high low-risk molecular signature (if available) Luminal B ‘Luminal B -like (HER2-negative)’ ER-positive, HER2-negative and either Ki67 high or PgR low high-risk molecular signature (if available) ‘Luminal B-like (HER2-positive)’ ER-positive, HER2-positive any Ki67, any PgR HER2 overexpression ‘HER2 -positive (non-luminal)’ HER2-positive, ER and PgR absent ‘Basal-like’ ‘Triple-negative (ductal)’ ER and PgR absent, HER2-negativeCK 5/6, EGFR positive30Human mammary glands contain two distinct subtypes of epithelial cells, basal (myoepithelial) and luminal, which can be recognized by cytokeratin expression. Most breast cancers are of the luminal type but less commonly basal types which represent more aggressive tumours occur.7 According to this molecular classification, my patient belongs to ‘Basal like’ – Triple negative sub type.9TNBC TNBC is defined by absence of ER, PR and HER2expression and account176for approximately 20% of breast cancers diagnosed worldwide. It is more commonly diagnosed in women less than 40 yearscompared to hormone-positive breast cancer. 20 They72behave more aggressively than other types of breast cancer.Approximately18175% of metastases occur within the first 5 years after the diagnosis of early stage disease.There are no targeted treatments available, other than the administration of chemotherapy.12Basic principles of the diagnosis and management of triple-negative breast cancer are similar to those of breast cancer in general. But risk factors, molecular and pathologic characteristics, natural history, and chemotherapy sensitivity, are unique to triple-negative breast cancer.72Up to 20% of patients with triple-negative breast cancer harbor a BRCA mutation, particularly in BRCA 1. In contrast, less than six percent of all breast cancers are associated with a BRCA mutation.18 Triple negative12breast cancer is usually a high-grade, infiltrating ductal carcinoma. These cancers exhibit necrosis, a pushing border of invasion, and a stromal lymphocytic response.By definition they lack IHC expression of the ER, PR, and HER2.15 Molecular classification of triple-negative breast cancer —30Most triple negative tumours are basal-like and most basal-like tumours are triple negative, but the overlap of these two categories (which account for 14-20% of all breast cancers) is not 100%.The40triple-negative clinical phenotype is mostly comprised of the basal-like molecular subtype, which is characterized by expression of the “basal cluster”,a unique cluster of genes that includes the epidermal growth factor receptor (EGFR, also called HER1), basal cytokeratins 5/6, and c-Kit; the proliferation cluster; and low expression of the hormone-receptor and HER2-related genes. Separate subtypes oftriple-negative breast cancer have been characterized by gene expression, including1882 basal-like subtypes (BL1 and BL2), an immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgensubtypes. Additional subtypes that have been characterized include claudin-low and interferon-rich subtypes.2027Gene expression analysis has revealed that the tumor suppressor gene p53 and several DNA repair genes, particularly the BRCA genes, are either mutated or aberrantly expressed in TNBC.12These molecular features may have implications for chemotherapy sensitivityto platinum agents. The diagnosis and clinical staging of TNBC is44similar to that of other breast cancer subtypes.Treatment approach to TNBC —44Management of breast cancer involves multidisciplinary approachand requires multimodality treatment. The27principles for the surgical management, radiation therapy,27neoadjuvant or adjuvant chemotherapy options for patients with TNBC are similar to the approach used in other breast cancer phenotypes.9Options for surgical management of primary tumor include;1.9Breast conserving surgery (BCS) and sentinel lymph node (SLN) biopsy with or without axillary lymph node dissection for positive SLNsfollowed by whole breast radiotherapy (WBRT). 2. Modified radical mastectomy9with or without breast reconstruction and SLN biopsy with or without axillary lymph node dissection for positive SLNs.9Survival is equivalent with any of these options as shown inEORTC 10801, NSABP B-06, Milan cancer institute trial and other prospective randomized trials.209Presence of inflammatory cancer regardless of histologic subtype is a contraindication to breast conserving therapy.Other relative contraindications are: 1. Scleroderma, cutaneous lupus erythematosus, and other active collagen disease of these tissues. 2. Diffuse calcifications indicating an extensive intraductal component 3. Multicentric invasive cancers or DCIS 4. Large residual disease after preoperative chemotherapy Since my patient did not have these contraindications, she was offered BCS. Based on primary evidence from a meta-analysis of 33 trials, it is recommended that9no ink on tumour be the standard for an adequate margin in invasive cancer. There was no evidence to say that more widely clear margins reduced tumourrecurrence for young patients,9unfavorable biology, lobular cancers, or cancers with an extensive intra-ductal component.Positive margins9were associated with a 2-fold increase in the risk of ipsilateral breast tumourrecurrence.11 Surgical management of axilla – Axillary45lymph node status is the most important predictor ofoutcome. SLN mapping is now the standard of care as it is more accurate and less morbid than axillary dissection. SLN biopsy has replaced axillary dissection (ALND) for patients with clinically negative axillae. When suspicious axillary lymph nodes are present, ALND should be done. Levels I and II dissection is now the standard for axillary clearance with removal of9a satisfactory number of nodes for evaluation (at least 6 – 10).When bulky lymph nodes at levels I and II are present, or suspicious level III nodes are detected, the removal of the level III nodes should be performed to avoid possible axillary recurrences, which are difficult to treat with chemotherapy and radiation, and sometimes are associated with axillary vein thrombosis and invasion of the axillary plexus, as well as lymphedema and poor quality of life. NSABP131-B- 32, a randomized phase iii trialhas shown that131SLN biopsy is equivalent to ALND9in overall survival, disease free survival and regional control.SLN biopsy131is “falsely negative” in 5% of node-positive patients, or 2% to 3% of allcases.14Based on results of IBCSG 23-01 trial, further axillary dissection is not required whenSLN contain micrometastsis (0.2 – 2mm).21 Can the SLN biopsy be used after primary systemic therapy? Data from the NSABP B-27 study shows that SLN biopsy appears to be a reliable procedure following preoperative chemotherapy. The other important question is, whether an ALND must always be performed when the SLN is positive?77Data from the American College of Surgeons Oncology Group Z0011 (Z11)trialfor patients with clinical T1-T2c and one to two SLN containing macrometastasis has observed no statistically significant difference in local recurrence in patients randomly assigned to SLN biopsy and ALND or just SLN biopsy alone in patients receiving breast- conserving surgery and53radiation therapy with a follow-up of 6.3 years.6 As demonstrated by AMAROS study where the9trial studied ALND and Axillary RT after identification ofa positive sentinel node, axillary RT provided comparable axillary control for patients with T1/2 tumors and was associated with significantly less morbidity. In Lasika’s case, there were suspicious nodes on imaging and guided FNAC confirmed metastatic deposits. Therefore, SLN biopsy was not done and she underwent level II axillary clearance which yielded 23 lymph nodes with 12 nodes having metastatic deposits. Adjuvant radiotherapy – Postoperative RT is strongly recommended after BCS. The main goal9is to eradicate residual disease thereby reducing the local recurrence.9Risk of recurrence in the conserved breast is>20% with breast conserving surgery alone,9even in confirmed axillary lymph node negative women.170A meta-analysis of 17 clinical trials performed by the Early Breast Cancer Trialists’ s Collaborative Group (EBCTCG) has shown that asignificant reduction (15%) in 10year risk of recurrence with WBRT compared to BCS alone9and a significant reduction in 15year risk of breast cancer death(4%).5 EORTC trial has evaluated the need for a boost irradiation and demonstrated that the boost reduced the1local failure rate by a factor of 2. Radiation boost14is indicated for patients who have unfavorable risk factors for local control such as young age(? < 50yrs/ 40years, there is a controversy),14grade 3 tumors, extensive DCIS, vascular invasion or non-radical tumorexcision.11 In my patient, radiation boost was indicated, since she was young, and had high grade DCIS and vascular invasion. The standard radiation therapy schedule treatment delivers 1.8 – 2.0Gy per day for 25 – 28 days for a total dose of 45 – 50.4Gy followed by a 5 – 8 fraction boost (10 – 16Gy) for a total dose of 60 – 66Gy delivered over 6 – 7.5 weeks. Hypofractionated schedules of18440Gy in 15 fractions of 2.67Gy over3 weeks (UK) or18442.5Gy in 16 fractions of 2.65Gy over 3weeks+1day (Canada) have45been shown to be safe and effective as a standard treatmentschedule in multiple randomized trials. Eg: UK START A & START B Trials.21 Tumor bed boost is usually delivered by electrons, but mini tangential fields are sometimes needed in patients with large breasts. Ideally surgical clips are the most suitable way of localizing the tumour bed. Accuracy of using surgical scar to distinguish lumpectomy cavity is controversial. However, there were no surgical clips inserted in my patient.9Optimal sequence of adjuvant chemotherapy and radiation therapy afterBCS has also been studied. Based onseveral randomized trials eg: NSABP-B-15 trial and9International Breast Cancer Study Group trials VI and VII,and as confirmed in a meta-analysis, delaying radiotherapy for 2-7 months after surgery, until completion of adjuvant chemotherapy9had no effect on the rate of local recurrence.21 Late toxic effects of radiation with current treatment delivery techniques are rare and may include radiation pneumonitis, rib fractures, cardiac events, brachial plexopathy, contralateral breast cancer and risk of second malignancy like sarcoma. Arm lymphedema is a major concern for patients with9breast cancer. Single modality treatment eg: surgery or RT is associated with low incidence, but in patients who have undergone axillary dissection, adjuvant RT increases the riskand occurs in about 20% of patients. Adjuvant chemotherapy — Treatment decisions for TNBC79are exclusively based on clinico-pathological factors like TNM and grade.Ongoing studies are testing79new molecular assays based on DNA methylation, immune markers, andother gene expression signatures.Currently Adjuvant chemotherapy is recommended for all patients with TNBC27≥0.5 cm or with node-positive TNBC, regardless of the tumor size.209There is a larger benefit to adjuvant chemotherapy among patients withTNBC compared to those with hormone-positive disease. Three randomized trials have shown29that patients with ER-negative breast cancer had higherabsolute improvement in disease-free survival and overall survival emphasizing the importance of adjuvant chemotherapy for women with TNBC. They are9insensitive to some of the most effective therapies9including HER2 directed therapies such as trastuzumab and endocrine therapies such as tamoxifen or aromatase inhibitorsand therefore not eligible for these targeted therapies.12Although there is no standard chemotherapy regimen that specificallyapplies to women withTNBC, anthracycline and taxane-based chemotherapy remains the most commonly used regimen, especially since taxanes have significant activity in the treatment of TNBC. In the GEICAM 9906 trial of 5-9fluorouracil, epirubicin, and cyclophosphamide (FEC) versus FEC followed by paclitaxel , the addition of paclitaxelwas associated with a significant improvement in disease-free survival at seven years.21 The14addition of taxanes improves efficacy of chemotherapy independently of age, nodal status, tumor size, grade or receptor expression but at the cost of non-cardiac toxicity.14Sequential use of anthracyclines and taxanes has shown to be superior toconcomitant use.119Platinum agents have emerged as drugs of interest for treatment of TNBC.9A randomized clinical trial CALGB-40603 evaluated the benefit of addingcarboplatin to paclitaxel and doxorubicin/ cyclophosphamide in neoadjuvant setting. The Triple Negative Trial is evaluating carboplatin versus docetaxel in metastatic setting.But currently, no prospective randomized14data exist on the use of platinum compounds in the adjuvant setting.21 There are also inadequate data to make recommendations regarding adjuvant chemotherapy in patients with very small triple negative27tumors (<0.5 cm). Therefore, the decision to administer adjuvant chemotherapy in those patients must be individualized based onpatient and clinician preferences.9Optimal time to initiate adjuvant chemotherapy is uncertain. A retrospective observational study hasrevealed that delay in initiating adjuvant chemotherapy adversely affect survival outcomes.21 Common short-term effects of adjuvant chemotherapy include alopecia, myelosuppression, gastrointestinal symptoms, febrile neutropenia or neutropenic infection and mucositis. Peripheral neuropathy, arthralgia, and myalgia also are seen with taxanes. With regard to anthracycline-related cardiac toxicity – approximately 8% of women may have asymptomatic systolic dysfunction 10 years after receiving doses of doxorubicin around 300 mg/m2. Risk of congestive heart failure associated with conventional doses of anthracyclines is small (≤1%), but this risk is increased with the subsequent use of adjuvant trastuzumab. Older age and lower left ventricular ejection fraction at baseline increase this risk. Secondary23acute myeloid leukemia and myelodysplastic syndrome are rarely seen withexposure to alkylating agents, topoisomerase II inhibitors, and antimetabolites. Risk of29acute myeloid leukemia or myelodysplastic syndrome after four cycles withconventional doses of AC (60 and 600 mg/m2) at 5 years is about 0.21%. Young women are at risk for premature menopause after adjuvant chemotherapy, and the risk correlates with both age and choice of adjuvant chemotherapy (classic CMF for 6 cycles > AC followed by paclitaxel = TAC with docetaxel > AC for 4 cycles). Temporary cessation of menses during adjuvant therapy also correlates with earlier occurrence of menopause. Premature menopause leads to significant23effect on quality of life because ofsevere23hot flashes and vaginal dryness andthese issues need to be carefully addressed. For women who retain fertility, pregnancy152does not appear to increase the risk of another breast cancerevent. Women who have chemotherapy-induced ovarian failure after adjuvant chemotherapy113are at risk for rapid bone lossand complications from osteoporosis. Symptoms of fatigue, weight gain, and cognitive dysfunction are also encountered with some frequency after the completion of therapy. Neoadjuvant chemotherapy — For women with TNBC, neoadjuvant chemotherapy is an alternative143to adjuvant chemotherapy, particularly in patients with locally advancedbreast cancer,who are not considered operable at presentation or who are not candidates for breast conservation at diagnosis. For these patients, pathologic complete response (pCR)171is associated with improvement in disease-free survival.Response of TNBC to12neoadjuvant chemotherapy has commonly been referred to as “paradoxical”due to the relatively high likelihood of excellent response but a poorer overall outcomecompared to85patients with hormone receptor-positive and/or HER2- positive breast cancer.43In one of the largest studies involving 1118 patients identified in a prospectively collected clinical database, women with TNBC had a higher pCR rate compared to those with othertypes of breast cancer.43However, there was a higher risk of recurrence or deathamong women with residual disease after neoadjuvant chemotherapy.20 Experimental options – ?12Epithelial growth factor receptor inhibitors – EGFR/HER1 isknown to overexpressed in TNBC.12Three phase II clinical trials have evaluated the efficacy of cetuximab, an anti-EGFR monoclonal antibody, in combination with chemotherapyand shown it has only modest activity. ? Angiogenesis inhibitors -12Clinical trials of bevacizumab with chemotherapy have demonstrated significantly improved progression-free survival. But no overall survival benefit was seen in any of the phase III trials.12Given the excess toxicity and expense of adding12bevacizumab, approval by the United States Food and Drug Administration for bevacizumab in metastatic breast cancer was withdrawn in December 2010. Efficacy of anti-angiogenic agents in the neoadjuvant and adjuvant settings, including triple- negative disease, remains under investigation.Neoadjuvant GeparQuinto study, randomly assigned patients to treatment with anthracycline and taxane-based chemotherapy plus or minus bevacizumab and found an increase in the pCR particularly in women with TNBC. CALGB 40603 evaluating the addition of bevacizumab (and/or carboplatin) to standard anthracycline/taxane-based neoadjuvant chemotherapy19in the setting of locally-advancedTNBC is ongoing.14 ? PARP inhibitors – Poly (adenosine diphosphate177-ribose) polymerase (PARP) are a family of enzymes involved in DNA repair. PARP inhibitors are being evaluated in clinical trials ofpatients with BRCA mutations and in TNBC. However, it is not commercially available for use.12There are several PARP inhibitors in clinical development– Olaparib, Veliparib, Iniparib ? Src inhibitors -12Gene expression profiling has suggested that triple-negative breast cancer might be preferentially sensitive to inhibition of the proto-oncogene Src. Dasatinib, a potent orally- available inhibitor of Src-family kinase, is being studied in the setting of advancedTNBC. Prognosis83Patients with TNBC have a poorer prognosis compared to patients with otherbreast cancer subtypes. In a study of 12,902 women who presented to National Comprehensive Cancer Network centers, compared to women with hormone receptor -positive, HER2-negative breast cancer, women with TNBC have experienced a worse breast cancer specific survival/overall survival and an increase in death within two years of diagnosis.10 The poorer prognosis may be attributed to biologic characteristics, proliferative rate and129may be explained in part by different routes of metastatic spread.According to the current theory, TNBCs metastasize toaxillary nodes and bones less frequently, favoring a haematogenous spread129to develop metastatic deposits in brain andlung.12 Follow-up27There are no specific posttreatment follow-up guidelines for patients with TNBC.Patients should undergo a similar surveillance routine regardless of breast cancer subtype.130Aims of follow up are to detect early local recurrences or contralateral breast cancer and to evaluate and treat therapy related complications.This should include history and complete physical examination every three months for the first 2years, every 6 months up to 5 years and annually thereafter. Annual mammography with ultrasound scan is recommended. Current evidence indicate that routine laboratory investigations and imaging do not provide a survival benefit.11 Metastatic disease The12risk of distant recurrence and death peaks approximately three years after diagnosis and declines rapidly thereafter.1643TNBC is characterized by higher relapse rates including an increased risk ofloco-regional recurrence,lung, and brain involvement, but less likely to recur in bone.79In patients with metastatic breast cancer, a confirmatory biopsy ofa suspected lesion should be obtained when possible with reassessment of44ER, PR, and HER2, because these could be different inprimary and111metastatic disease. The primary goal of therapy in patients with metastaticbreast cancer139is palliation of symptoms and prolongation of high-quality life, becausemost patients with metastatic breast cancer ultimately die of their disease.19 Therefore, treatments associated with minimal toxicity are preferred. There is no standard approach for patients requiring second or further line chemotherapy treatment in TNBC and it173should be tailored according to the individual patient depending in theirsymptoms andperformance status.43In one study involving 116 patients with metastatic TNBC, brain metastases were the initial site of metastatic disease.Patients with TNBC and brain metastases have the poorest prognosis out of all breast cancer subtypes with CNS involvement.12The median survival following a diagnosis of CNS metastases is less than six months.According to a study done in Memorial Cancer Centre, Poland, factors influencing survival from brain metastases are the performance status and the extent of extracranial disease.147Treatment options include steroids, surgical excision of solitary metastases, stereotactic radiosurgery for small lesions (<3cm) not amenable to surgery and WBRT.In case my patient, she needs to be on regular follow up after completion of WBRT and a next line treatment will have to be decided if develops another symptomatic recurrence. BRCA mutation positive breast cancer — Most breast cancers that arise in the setting of a germline mutation in BRCA1 are triple negative. In light of the association of particularly BRCA1 mutations with TNBC it is recommended that27women diagnosed before 60 years with a TNBC undergo BRCA mutation testing regardless of family history.