Question 1
Which phase of the cell cycle is Ki67 protein NOT expressed?

1. Go
2. G1
3. S
4. G2
5. Mitosis

A: Ki67 is strictly associated with cell proliferation. J Cell Physiol 182 (3): 311 – 322

Question  2
A 46 year old female is concerned about her risk of breast cancer. She is an Ashkanazi Jew. She has three immediate family members all under the age of 50 who have developed breast cancer. In addition, one of her sister’s has both breast and ovarian cancer. Prostate and pancreatic cancer also run in the family. She undergoes genetic testing which is positive for BRCA1 mutation. What would be the prophylactic measure that she could take that would improve her survival?

1. Unilateral mastectomy
2. Bilateral mastectomy
3. Bilateral salpingo-oophorectomy
4. Prophylactic radiotherapy
5. None of the above

C: After family completion, this surgical procedure leads to a 50% reduction in breast cancer and a 90% reduction in ovarian cancer, with improved survival demonstrated in trials. Domcheck, JAMA 2010

Question 3
What is the MOST significant prognostic risk factor regarding early breast cancer?

1. Number of involved regional nodes
2. Lack of expression of hormone receptors
3. High Ki67 proliferation markers
4. Larger initial size
5. Vascular invasion

A: According to ESMO guidelines 2015

Question 4
Which of the following subtypes is associated with the most aggressiveness with regards to breast cancer?

1. Her2 negative, low Ki67
2. Her2 positive, high Ki67
3. Her2 positive, non luminal
4. Hormone receptor negative
5. Triple negative – basal like

E: ESMO guidelines 2015


Question 5
What is the mechanism of tamoxifen induced venous thromboembolism?

1. Inhibition of antithrombin III
2. Inactivation of Protein C
3. Decreased synthesis of Protein S
4. Increased Tissue factor expression on endothelial cells
5. Upregulation of Factor XIII

A: Cancer. 1984 Jun 15;53(12):2607-9

Question 6
A 46 year old female who is perimenopausal has recently been diagnosed with stage 1 breast cancer. Sentinel node biopsy is negative. She receives a lumpectomy with wide local excision followed by local radiotherapy. Analysis of the surgical specimen reveals clear margins and a carcinoma which expresses ER/ PR but is HER2 negative. Which of the following is the most appropriate treatment for this patient?

1. Tamoxifen for 5 years
2. Tamoxifen for 10 years
3. Anastrozole for 5 years
4. Anastrozole for 10 years
5. Trastuzumab for 12 months

B: Given that she is ER+/PR+ (which up to 60% of breast cancers are), she should have 10 years of tamoxifen (this is more effective than 5 years according to Davies, Lancet 2013). She should not have Her2 directed agents such as trastuzuman, pertuzumab or lapatanib as her cancer does not express Her2. Aromatase inhibitors should not be given as she is perimenopausal meaning that she has some gonadal steroid synthesis reserve. Inhibition of peripheral oestrogen onversion would trigger an increase in concentration of gonadotrophic hormones leading to increased trophic effects.

Question 7
Tamoxifen and aromatase inhibitors can be used in the treatment of ER+/PR+ breast cancer. In post-menopausal women, which of the following side-effect profiles would favour the use of tamoxifen over aromatase inhibitors?

1. Venous thromboembolism
2. Hot flushes
3. Vaginal bleeding
4. Uterine cancer
5. Fracture risk

E: Fractures occur significantly more with aromatase inhibitors compared with tamoxifen. Arthralgias also occur significantly more in this group. The risk of endometrial cancer is 0.8% in the tamoxifen group compared to 0.2% for anastrozole. RPA  Course 2015

Breast Cancer notes

• Pathology
  • Mostly ductal > lobular + tubular + mucinous
  • Immunohistology important to appreciate: Her2/ ER/ PR, Dx now req FISH or CISH
• Risk factors
  • Strongest risk factor BRCA1/ BRCA2, but most relevant in terms of population = obesity
  • Chest radioRx age <30 gives RR10x
  • Risk factor of aggressiveness = lymph node involvement
• Genetic risk factors
  • BRCA --> different complexes of protein = TSG, increases risk of breast Ca + other Ca’s such as ovarian, prostate, pancreas, stomach
  • BRCA testing indicated if (1) 3+ Breast Ca or Ovarian Ca OR (2) 2 breast Ca <50yp OR (3) bilateral breast Ca OR (4) Male (5) Ashkanazi jew OR (6) Triple neg AND < 50
    • If testing have to offer counseling and always in adults
    • If BRCA + then surveillance --> yearly mammogram and MRI from age 30; Prophylactic bilateral salpingo-oophorectomy > mastectomy when done after family completion or by age 40 [improved survival, no improved survival for mastectomy but reduction in breast Ca by 90%]
  • Worst histological subtype = triple negative
• Risk reduction
  • Mammography programs have evidence, 2y from 50 – 70, offered free to >40, younger need U/S or breast MRI [better as breast denser, indicated if breast Ca screening with inherent germline mutation = higher sensitivity]
  • Chemoprevention: evidence for tamoxifen, raloxifene [NNT = 42], exemestane [ARR = 0.34%], anastrozole [high risk ARR = 2%]

• Her-2 + [over-expressed in 20-25% breast Ca’s]
  • Used to be poor prognosis, HER2 = EGFR2 receptor [note unknown ligand]. Mab target = trastuzumab AND Lapatinib [downstream TKI] AND trastuzumab emtansine [Trastuzumab + MCC conjugate] AND pertuzumab
  • To access Rx need FISH/ CISH
• Local Rx for early stage breast Ca
  • Option 1 if no nodal involvement and small tumour in big breast --> WLE + radiotherapy
  • Option 2 if big tumour, no nodal involvement and small breast --> mastectomy. Add XRT if tumour >5cm OR 4+ nodes
    • Breast XRT + node XRT cf breast XRT decreased breast Ca recurrence but no overall survival benefit [NEJM2015]
  • For option 1 and 2 --> sentinel node bx and if + (met >2mm) --> axillary node clearance
  • Adjuvant chemotherapy [taxane; SE = diarrhea, fluid retention/ tear duct stenosis/ anthracyclines] ALWAYS for node + or high risk [triple negative/ high Ki67/ HER2 +]
  • Add Hormone Rx if ER or PR+ [50-60% Breast Ca] --> Rx for 10y [advantage over 5y previous regime for tamoxifen only, 5y for AI]
    • Tamoxifen [SE = hot flushes, uterine Ca 1% postmenopausal, thromboembolism 1-2%] +/- AI [decreased bMD + osteoporosis, arthralgias/ myalgias but no thromboembolism or uterine Ca] only if perimenopausal
    • Aromatase Inhibitor [non-steroidal or steroidal] for postmenopausal [not pre-menopausal] --> upfront 5y, or 5y tamoxifen when pre-menopausal then 5y AI when post menopausal
  • Trastuzumab if HER2+ [irrerspective if node +/ -], SE = cardiac toxicity, reversible, HER-2 expression on cardiac muscles = T-tubule, 3/12ly ECHO, RF for cardiotoxicity = age, baseline poor LVEF, post anthracycline. DO NOT use trastuzumab with anthracyclines --> cardiac toxicity
  • Ovarian ablation --> only pre-menopausal pts and as alternative to chemotherapy
  • No evidence for zoledronic acid in adjuvant setting
• Metastatic Breast Ca
  • Bone only mets --> prognosis in years
  • Visceral mets --> prognosis in months
  • If ER/PR + --> hormonal therapy, at progression switch to other, eg AI to tamoxifen or non steroidal to steroidal AI, if further resistance add mTOR inhibitor [increased survival signaling if ER/PR + and resistance] everolimus + examestane > examestane
  • If HER2+ and treatment free interval >6/12 if trastuzumab previously usedà trastuzumab + pertuzumab + CTx > trastuzumab + CTx
  • If HER 2+ and treatment free interval <6/12 if trastuzumab previously used --> Lapatanib + capecitabine
  • If bone mets --> increased skeletal related events ameliorated by zoledronic acid, but denosumab > zoledronic acid