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Flashcards in Breast cancer Deck (70)
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1

Describe incidence and mortality of breast cancer

- mean age at first diagnosis

- stage at majority of new diagnosis

 

 

at first presentation; usually 60 year old post menopausal women; early stage, hormone receptor +ve, HER2 -ve, usually curable. 

 

•Breast cancer has the highest incidence rate of all cancers amongst women, and is estimated to be the most commonly diagnosed cancer in 2019.

•Mean age at first diagnosis is 60 years (post-menopausal)

•The vast majority of new diagnoses are early stage breast cancer (stages I-III)

•While the breast cancer mortality rates are improving, it remain the 2ndleading cause of cancer mortality after lung cancer

2

Describe breast cancer screening for general population 

 

•Women aged 50-74 years are invited for beast mammogram 2 yearly in Australia

•Women aged 40-49 years and > 74 years are not invited, but have access to free screening

•Breast cancer mortality rates have substantially improved since the implementation of breast cancer screening

•however there is controversy as to whether this is largely due to screening or improvements in treatments

3

Describe monogenetic breast cancer risk associations

almost polygenetic phenomenon, but monogenetic risk associations exist = BRCA1 & 2

 

•Germline mutations in several genes have been shown to be associated with increased lifetime risk of breast cancer but most are very uncommon

•The most common mutations are in the BRCA1 and BRCA2 genes

•In Australia, funding for BRCA mutation testing depends on the calculated pre-test probability of identifying a heritable mutation based on an algorithm used by genetic services (≥10%)

4

Clinical factors a/w germline BRCA1/2 mutations

 

•Invasive breast cancer ≤ 30 years 

•Triple negative breast cancer < 60 years

•Male invasive breast cancer of any age

•Ovarian or primary peritoneal cancer

•Ashkenazi Jewish heritage

5

Describe BRCA mutation carriers

- pathophysiology

 

 

BRCA1 and BRCA2 are breast cancer susceptibility genes which have functions in DNA damage response and in DNA repair 

•These genes are particularly important for repair of double-stranded DNA breaks using homologous recombination/HR (error-free repair)

•Deleterious mutations in BRCA1 or BRCA2 predisposes to homologous recombination deficiency, and over-reliance on non-homologous end-joining (error-prone repair)

•BRCA1/2 = Tumour suppressor genes

 

i.e. BRCA1/2 mutation -> reduced DNA repair -> accumulation of errors -> precancerous 

6

BRCA1 & 2 a/w with which types of breast cancers

 

BRCA1 mutations -> triple negative breast cancers

 

BRCA2 mutations -> hormone-receptor positive breast cancers

7

For those with BRCA mutation carreirs; what are some risk management strategies? 

 

•Risk reducing bilateral mastectomy

•Risk reducing salpingo-oophorectomy once childbearing is complete (before 40 years of age if possible)

•Increased surveillance –consider from 30 years of age including breast MRI

•Chemoprevention with tamoxifen, anastrazoleor exemestane

8

Describe PARP inhibitor in BRCA mutations

BRCA mutations can predict PARP inhibitor benefits (i.e. PARP inhibitors are good for BRCA mutations)

PARP inhibition leads to tumour selective cell death via synthetic pathway. 

Olaparib prolongs survival in patients with advanced breast cancer and a germline BRCA mutation

 

PARP inhibitors can inhibit PARP which inhibits DNA repair pathway

cancer genes collect mutations over time, when have incomplete DNA repair pathway, PARP repairs it, and often remains intact and viable; BRCA1/2 mutations + viable tumour that continues to grow.

PARP inhibitors; flood the cancer with mutations. genome becomes overloaded with mutations -> unstable -> unviable cells. 

tumour selective death. lose inability to repair cells. 

9

Describe chemoprevention in breast cancer

Chemoprevention with low dose tamoxifen in those with high risk of developing invasive breast cancers

  • 5mg instead of 20mg, 3years instead of 5 years. 
  • good adherence. no difference with VTE/endometrial cancer. 
  • decreased risk of invasive breast cancer. 

 

c.f. difficult compliance every day for 5 years. increased endometrial cancer, VTE as SE 

10

Describe general principles of Curative intent vs. non curative intent in breast cancer 

Generally: 

  • Stage I-II; no lymph nodes
  • Stage III: lymph nodes. no distant metastasis
  • Stage IV: distant metastasis 

 

•Stage I-III disease that is resectable (or potentially resectable) is typically treated with curative intent; consider more intensive treatment regimens despite higher rates of toxicity 

 

•Stage IV disease is generally still considered to be incurable and treatment is typically with palliative intent; intensive treatment with high rates of toxicity are considered only under limited conditions 

 

•Some potential exceptions:

•A number of HER2-positive breast cancer patients achieve long term disease control (and often with absence of imaging evidence of metastatic disease) on HER2-targeted agents and may be considered “cured”

•Aggressive curative-intent approaches for patients with “oligometastatic” disease may result in long term disease control in selected patients

•Unlike melanoma, long term disease control on immunotherapies is very uncommon

11

Describe breast cancer subtypes 

- estrogen/progresterone receptor expression

- HER2 amplification (need insitu hybridisation)

- proportion of new cases

- risk of disease recurrence after curative intent treatment

- effective treatments 

12

Which type of breast cancer subtype is the most common?

Hormone receptor positive, HER2 negative

13

Describe prognosis/risk of disease recurrence after curative intent treatment in different breast cancer subtypes

  • hormone receptor +ve, HER2 -ve: good prognosis, but late recurrence (>5 years) can occur
  • HER2 +ve: previousy poor, but now excellent prognosis due to effective therapies
  • triple negative breast cancer: poorest prognosis, but late recurrences (>5 years) are uncommon

14

In which breast cancer subtype is late recurrence common?

Hormone receptor positive breast cancers, particularly in bone 

15

Describe how nodal status in breast cancer affect mx guidance

If positive lymph node status, given higher risk of recurrence and death, (Neo)adjuvant chemotherapy is recommended.

If negative lymph onde status, given lower risk fo recurrence and death, Benefit of (neo)adjuvant chemotherapy is unclear and likely to depend on other prognostic factors

 

The absolute benefit of adjuvant chemotherapy depends on absolute risk. Anatomical staging factors (tumour size, nodal status) helps with prognostication, but more precise estimates will aid treatment decision making

 

chemotherapy benefits only those with higher risk of recurrence. proportional reduction of recurrence. hence higher benefit in those with higher absolute risk (e.g. 60% vs 5%)

16

Describe Predominant intrinsic subtype of clinical subtypes of breast cancer

1. HR positive, HER2 negative: Luminal A and Luminal B

2. HER2 positive: HER2-enriched

3. Triple negative cancer: Basal-like

 

Gene expression patterns can help refine prognostic estimates

17

Describe precision oncology approach to chemotherapy decision making in HR positive breast cancer 

21 Gene expression test; if high score, with bad progonsitc marker -> have chemotherapy

low score -> hormonal therapy, no chemotherapy

intermediate score was randomised to chemotherapy; no difference found. likely can be spared from chemotherapy 

 

OncotypeDX –a 21 gene expression assay can stratify HR-positive, node negative early breast cancer by likelihood of benefit to adjuvant chemotherapy

18

Benefits of increasing (neo)adjuvant chemotherapy dose intensity

  • most node positive early breast cancer will be mx with adjuvant chemo 3rd generation regimens; contain both anthracycline & taxane classes of chemotherapy. usually Q3week
  • now using G-CSF allow shortened interval between chemo agents; increased dose intensity (amount of drug delievered per unit time. dose dense without dose escalation) can enhance tumour cell kill & reduce recurrence, however can lead to higher rates of toxicity 
  • i.e. The use of dose dense regimens can moderately reduce the risk of recurrence and death from breast cancer and should be considered

 

Supportive care improvements

  • better antiemetics (5-HT3 antagonists, substance P antagonists)
  • growth factor support (e.g. G-CSF)
  • alopecia; scalp cooling
  • fertility preservation techniques e.g. egg harvest, ovarian tissue reservation, functional ovarian suppression (GnRH analogue) 
  • survivorship programs 

19

Selective of (neo)adjuvant HER2 directed therapies

•Adjuvant trastuzumab has significantly improved the outcomes for HER2-positive breast cancers

•The majority of patients are now cured -the 3 year invasive disease-free survival rate in the APHINITY trial control arm was 93.2%; however unclear optimal duration (2yrs vs. 1yr or less) 

•Increasing the intensity of HER2-blockade (e.g. pertuzumab, neratinib) only provides small absolute benefits

 

standard; adjuvant transtuzumab 52 weeks post chemotherapy 

The addition of other HER2-targeted agents could be considered in selected high risk patients. 

20

De-escscalation of adjuvant HER2 directed therapies in lower risk patients

 

•Tumour size ≤ 3 cm, node-negative, HER2-positive breast cancer

•The use of adjuvant paclitaxel (no anthracycline component of chemotherapy) for 12 weeks with trastuzumab (for 52 weeks) provides excellent DFS rates in these patients and is a reasonable regimen to use.

21

Rationale for neoadjuvant approach for breast cancer

- describe neoadjuvant treatment

- possible reasonings for neoadjuvant treatment

Neoadjuvant therapy: 

  • treatment given prior to surgery in breast cancer –typically a systemic treatment such as chemotherapy, HER2-targeted agents, or endocrine therapy
  • potential tool to accelerate drug development using complete pathological response (pCR) as a surrogate for survival
  • after neoadjuvant, some may have no viable cancer cells; complete patholgical response (pCR)

 

Possible reasons: 

•Refine prognostic estimates: compare patients that achieve pCR and patients that do not achieve pCR

•Convert a tumour that is unresectable/borderline resectable to resectable (uncommon)

•To better understand the disease biology in a patient who may be of borderline fitness for surgery

Neoadjuvant treatment can identify high risk populations that may benefit from escalation or change of treatment in the adjuvant setting

22

Benefit of adjuvant endocrine therapies

Endocrine therapy is still the mainstay of adjuvant therapy for HR-positive, HER2-negative early breast cancer

23

Describe benefit of ovarian function suppression in pre-menopausal women receiving hormonal therapy for breast cancer

 

•The addition of OFS to tamoxifen in pre-menopausal women demonstrated superior disease-free survival

•The use of exemestane plus OFS resulted in even greater disease-free survival

•The absolute benefit of OFS is greater in patients with higher risk disease (eg.patients who received adjuvant chemotherapy, and the very young [< 35 years])

24

Describe selection of adjuvant endocrine therapies in breast cancer

- mechanism of action

- common toxicities

- uncommon but important toxicities

- clinical utility

tamoxifen vs. aromatase inhibitor

aromatase inhibitor use in pre-menopausal women without ovarian function suppression (e.g. GnRH analogues) can cause paradoxical increase in estrogen levels

Tamoxifen: Selective (o)estrogen receptor modulator. SE; Hot flushes, Arthralgias and myalgias (AI > Tam). Vaginal atrophy (AI > Tam). rare but significant: VTE, endometrial cancer. can be used for both pre & post menopausal. 

Aromatase inhibitor: Reduces estrogen biosynthesis. SE; Hot flushes, Arthralgias and myalgias (AI > Tam). Vaginal atrophy (AI > Tam). rare but significant; Accelerated bone loss. Does not significantly cause VTE/endometrial cancer. Can be used post-menopausal, and pre-menopausal if ovarian function suppressed. 

 

AIs have demonstrated superiority to tamoxifen but the absolute increased benefit may be small

25

Benefit of extended adjuvant endocrine therapy

 

•For all trials assessing extended adjuvant endocrine therapy patients must have been disease-free at the time of initiation of extended endocrine therapy – i.e. hence selection bias

•Small but significant benefits for: 10 years tamoxifen vs 5 years tamoxifen, Switch strategy (5 yrs tam –5 yrs AI)

•Unclear benefits for: Extended AI for > 5 years vs 5 years

ongoing research required 

26

Describe antiresorptive therapy as part of adjuvant therapy in breast cancer

Bisphosphonates

•Safe and significantly reduces clinical fractures

•Significant but small absolute benefit to breast cancer outcomes, with definite benefit only in postmenopausal women

 

Denosumab

•Safe (atypical femoral fractures and osteonecrosis of the jaw are very rare) and significantly reduces clinical fractures

•Benefit to breast cancer outcomes (recurrence and death) is controversial

•Significant DFS benefit in one trial, no benefit in another –meta-analysis will be required

 

fertility preservation also needs to be considered 

27

Principles of metastsatic breast cancer treatment

can change over time when disease becomes metastatic

becomes genomically complex, and different to when they were primary. 

Phenotype changes are common and may be influenced by treatment exposure e.g. change of hormone receptor status 

new diagnosis of metastatic disease -> rebiopsy. 

 

•Combination chemotherapy ->  higher tumour response rates (tumour shrinkage) but increaed SE. no significant survival benefits c.f. sequential agent chemotherapy 

•sequential single agent treatment is preferred if no rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control.

Novel agents with specific targets and less toxicities are becoming developed, and have stronger rationale for synergism in combination (and radiotherapy)

28

General principles regarding targeted agents

 

•Novel agents targeting specific molecular features on tumours 

• an ideal target is either: more abundant on/in the tumour than normal tissue to avoid unwanted toxicities OR Abundant in the tumour and on normal tissue with minimal toxicities eg. rituximab

•Drugs that end in “ib” are small molecular inhibitors that target intracellular signaling, usually administered orally

•Drugs that end in “mab” are monoclonal antibodies that target cell surface receptors, usually administered intravenously

29

examples of novel agents recently approved for the treatment of metastatic disease

 

•Cyclin dependent kinase 4/6 inhibitors e.g. palbociclib, ribociclib, abemaciclib

•Alpha specific PI3-kinase inhibitors

•Antibody drug conjugates

•Checkpoint blockade (immunotherapy)

30

Describe cycline dependent kinase 4/6 inhibitors 

- mechanism of action

- beneficial in which breast cancer types

- drug names

- SE

 

• reduce phosphorylation of Rb and prevent cell cycle progression

• beneficial for Luminal breast cancer subtypes (HR-positive tumours) as most dependent on the cell cycle for cell division

•Beyond HR-positivity, no other clinically useful predictive biomarker have been found thus far (NB: complete RB1 loss is rare in HR-positive breast cancers)

Drug names -palbociclib, ribociclib, abemaciclib

•Significant PFS benefit in the 1st and 2nd line setting in combination with various endocrine agents, and in both postmenopausal and pre-menopausal women with HR-positive, HER2-negative advanced breast cancer

SE: 

•Palbociclib and ribociclib–neutropaenia is very common, however complications of infections are strikingly rare

•Ribociclib–severe LFT derangement, QTc prolongation

•Abemaciclib–broader spectrum of activity (CDK9 and CDK7 inhibition) –persistent diarrhea, but less neutropaenia