Dr kundan Junior Resident , Department of surgery

Patna medical college & Hospital

Risk assessment tools Imagings Non Palpable Lesions and Localization

Techniques Biomarkes Genomic analysis Surgery Chemoprevention Chemotherapy

Gail model-focuses primarily on nongenetic risk factors, with limited information on family history

Claus model- based on empiric data from the Cancer and Steroid Hormone Study

Estimates a woman’s risk of breast cancer based on her age, the number of first- and second-degree relatives with breast cancer (up to two); and their age at onset.

BRCAPRO incorporates BRCA1 and BRCA2 mutation

frequencies, cancer penetrance in mutation carriers, cancer status (affected, unaffected, or unknown), and age of the patient's first-degree and second-degree relatives.

The Breast Cancer Risk Assessment Tool Cuzick–Tyrer model - includes history of benign breast disease estrogen exposure

Does the woman have a medical history of any breast cancer or of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) or has she received previous radiation therapy to the chest for treatment of Hodgkin lymphoma?  

2. Does the woman have a mutation in either the BRCA1 or BRCA2 gene, or a diagnosis of a genetic syndrome that may be associated with elevated risk of breast cancer?  

3. What is the woman's age?This tool only calculates risk for women 35 years of age or older.  

4. What was the woman's age at the time of her first menstrual period?   5. What was the woman's age at the time of her first live birth of a child?   6. How many of the woman's first-degree relatives - mother, sisters,

daughters - have had breast cancer?   7. Has the woman ever had a breast biopsy?     7a. How many breast biopsies (positive or negative) has the woman had?  

  7b. Has the woman had at least one breast biopsy with atypical

hyperplasia?   8. What is the woman's race/ethnicity?     8a. What is the sub race/ethnicity?  

luminal B ER/PR + Her-2/neu +Basal-like ER/PR - Her-2/neu -luminal A ER/PR + Her-2/neu - Her-2 overexpressing

ER/PR - Her-2/neu +

HER-2 positive and triple negative subtypes have been shown to preferentially metastasize to the brain over the other subtypes

Full-field digital mammography -superior to standard mammography in women under 50 years of age and in those with dense breasts.

Computer-Aided Detection CAD programs are commercially available systems that use

computer software to assist the mammographer in detecting or identifying potentially suspicious abnormalities on a mammogram. The CAD program identifies potential abnormalities on the images and marks areas on the study that the computer considers to be suspicious.

DYNAMIC MRI – Contrast enhancement with Gd-DTPA The cancers are found to have rapid wash-in of contrast and

either a rapid wash-out of contrast or a leveling off of contrast. These two patterns of dynamic contrast enhancement yields 91% sensitivity and 83% specificity for malignancy detection.

Positron-Emission Mammography- Most breast malignancies have greater metabolism than normal

tissues and concentrate 18F- fluorodeoxyglucose(FDG)

Molecular breast imaging

utilizes small semiconductor-based γ-cameras in a mammographic configuration to provide high-resolution functional images of the breast.

have used Tc-99m sestamibi, Imaging can be performed within 5 min postinjection, with the

breast lightly compressed between the two detectors. Images of each breast are acquired in the craniocaudal and mediolateral oblique projections facilitating comparison with mammography.

overall sensitivity of 90%, with a sensitivity of 82% for lesions less than 10 mm in size

Digital Infrared Imaging based on the principle that metabolic activity and vascular

circulation in both pre-cancerous tissue and the area surrounding a developing breast cancer is almost always higher than in normal breast tissue

3-dimensional (3-D) imaging technology reduces or eliminates the tissue overlap

effect

non-palpable lesions are associated with both a lower stage of disease and a substantially decreased incidence of lymph node involvement

Wire localization (WL)- pain and discomfort dislodgement of the wire, intraoperative wire transection, retention of wire fragments, thermal injury with the use of cautery, hematoma syncope

Radioguided occult lesion localization (ROLL)

injection of a nuclear tracer (99 m TC-labelled colloidal albumin) directly around the tumor under ultrasound or stereotaxic guidance

the excision of the primary tumor is guided by a gamma probe, and a sentinel node biopsy can be performed at the same time if needed

intraoperative ultrasound (IOUS).

used to collect cellular material for cytomorphology and biomarker studies

cellular material is retrieved by inserting a 1.5-cm flexible microcatheter through through the nipple surface orifices

under local anesthesia and infusing the same with saline uses of ductal lavage include selection of women for risk-reduction therapy, diagnostic workup of a nipple discharge, early diagnosis of an occult cancer monitoring response, study genetic alterations

In conjunction with the newly identified genetic markers, ductal lavage has the potential to identify early breast cancers before any mammography changes occur.

It can be used to study breast epithelial cells at the molecular level. Limitations of ductal lavage are its time-consuming nature, inability

to detect extra-ductal carcinoma, and uncertainty about its sensitivity and specificity.

Indices of proliferation : PCNA , Ki67 Indices of apoptosis : bcl2 , bcl2/bax

ratio Indices of Angiogenesis :VEGF ,

ANGIOGENESIS INDEX Growth factor receptors : EGFR ,

Her2/neu

The 21-Gene Recurrence Score (RS) (Oncotype DX) is an RT-PCR based gene expression profiling assay that includes 16 cancer genes and 5 reference genes

Mama print – another assay based on 70 genes

PROLIFERATIONKi-67STK15

SurvivinCyclin B1

MYBL2

ESTROGENERPR

Bcl2SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

BAG1GSTM1

REFERENCEBeta-actin

GAPDHRPLPOGUSTFRC

CD68

Category

RS (0 – 100)

Low risk RS < 18

Int risk RS ≥ 18 and < 31

High risk RS ≥ 31

Surgical management of breast cancer has shifted from extensive and highly morbid procedures, to the modern concept obtaining the best possible cosmetic result in tandem with the appropriate oncological resection.

William Halsted popularized radical mastectomy in 1894.Radical mastectomy (RM) resulted in a significant drop in the local recurrence rate, but the curative potential remained limited.

MRM is a less morbid procedure compared to RM, the patient will still require a loss of the breast. The attempt to preserve the breast without compromising survival brought up the use of Breast Conserving Therapy (BCT)

This includes breast conserving surgery and breast radiotherapy. BCS is an important part of the breast-conserving therapy, which

may be defined as a combination of conservative surgery for resection of the primary tumor with or without surgical staging of the axilla, followed by radiotherapy for the eradication of the residual microscopic disease of the breast, with or without adjuvant systemic therapy.

ELIGIBLITY CRIETERIA – Ability to obtain a margin negative lumpectomy - capability to deliver breast irradiation - likely hood of achieving a cosmetically acceptable result EXCLUSION CRIETERIA - multicentric disease - diffuse malignant appearing microcalcificaton - prior therapeutic chest irradiation - associated contraindication to radiation - positive margin on lumpectomy/reexcision specimen - history of collagen vascular disease - tumor size > 5 cm

The incision should be sited in such a way that if mastectomy is eventually required, it can be included in the mastectomy specimen. In the upper part of the breast, incisions should be curvilinear or transverse, while in the lower part, they should be either curvilinear or radial.

Resection of 0.5 to 1.0 cm of grossly normal tissue resulted in a histologically negative margin in 95% of patients.

In order to ascertain a negative margin, intraoperative margin assessment (IOMA) has been found to be useful. These include:

gross inspection in the operating room, with or without frozen section analysis, cytologic touch prep (CTP) analysis,

shaved margin (SM), intraoperative ultrasound (IOUS). Drainage of the lumpectomy cavity should be avoided and it

should be allowed to fill with serum and fibrin. This will give the best cosmetic result.

COMPLICATIONS : Seroma formation, arm morbidity (arm swelling, arm pain, arm

numbness, arm stiffness, shoulder stiffness, shoulder pain, and nerve injury),

phantom breast syndrome, delayed cellulitis pain syndromes of the chest wall, axilla, and

upper extremity

skin sparing mastectomy (SSM) was first used by Toth and Lappert in 1991

removes the breast, nipple-areola complex, previous biopsy incisions, and skin overlying superficial tumors

Preservation of the inframammary fold (IMF) and native skin greatly enhances the aesthetic result of breast reconstruction.

The thickness of the mastectomy flaps should be the same as in a conventional mastectomy.

In radiofrequency ablation, high-frequency alternating current is delivered via an electrode inserted into the tumor under ultrasound guidance. Pilot studies have shown that this technique have confirmed its efficacy to kill tumor cells. Similarly cryosurgery and focused ultrasound are currently under investigation in breast cancer. Percutaneous tumor excision is another novel technique in which small breast tumors are extracted via plastic cannulas attached to a circular blade. The lesion in question is targeted and retrieved with the assistance of mammographic stereotactic localization.

MammoSite involve a reasonably user-friendly inflatable balloon that is inserted into the lumpectomy cavity either in the operating room or postoperatively, under ultrasound guidance.

Radioactive sources in form of interstitial catheters are placed in the tumor bed intra-or post-operatively offers several advantages over traditional external beam radiation.

It reduces the treatment time from 5 to 7 weeks to 4 to 5 days. It allows restriction of the radiation dose to the tumor bed

compared with conventional radiation therapy Older brachytherapy catheters were bulky and cumbersome.

Newer devices, such

There are two required components for BCT. First, tumors must be resectable with a pathologically clear margin, that is, a surrounding margin of breast parenchyma without disease. Secondly, patients undergoing partial mastectomy typically receive whole breast irradiation to achieve local control in the breast.

Tumor size must be sufficiently small relative to the entire breast, such that the appearance of the breast is cosmetically acceptable following partial mastectomy. Additionally, all suspicious findings on imaging must be resectable with the partial mastectomy. The presence of diffuse highly concerning microcalcifications on mammography is a contraindication to BCT. Pregnancy and a history of previous chest irradiation do not allow BCT, as they are contraindications to the requisite postoperative radiotherapy. Positive margins after BCT require a repeat attempt at excision or completion mastectomy to achieve clear margins. Findings of involved margins with partial mastectomy significantly increase the chance of disease recurrence

A recent trend including surgery as cancer prevention has gained wide acceptance. Contralateral prophylactic mastectomy (CPM) has been found to decrease the risk of development of a cancer in the disease-free breast in women at high risk.

BRCA mutation or a strong family history of breast cancer

LCIS,

Bilateral prophylactic salpingo-oophorectomy is widely used for cancer risk reduction in premenopausal women with BRCA1/2 mutations.[47-49] Bilateral prophylactic salpingo-oophorectomy significantly reduces breast cancer risk by approximately 50% and ovarian cancer risk by 80% to 95% but may be accompanied by menopausal symptoms, increased cardiovascular risk, impaired quality of life, and accelerated bone loss

circulating tumor cells (CTCs) enrichment of CTCs by antibody-

mediated targeting of the epithelial cell adhesion marker (EpCAM)

greater than five CTCs is the breaking point for a poor prognosis in breast cancer

Breast Cancer Subtypes Have Distinct Treatment Options

Endocrine Therapy

Trastuzumab

Chemo

Luminal A Yes No Yes

Luminal B Yes Y/N Yes

HER2 No Yes Yes

Basal-like No No Yes

Advances in Her-2/neu overexpressed breast cancer

•Trastuzumab in adjuvant, neoadjuvant, and metastatic setting

•Lapatinib in neoadjuvant and metastatic settings

•Pertuzumab, TDM-1 (Katherine trial) in neoadjuvant, adjuvant and metastatic settings

• Combinations of Her-2/neu inhibitors

Neoadjuvant Chemotherapy (NACT)

•Goal is to optimize surgical outcomes

•Standard for larger, Stage 3 tumors

• Marginally resectable tumor

• Inflammatory breast cancer

• Best outcome is pathologic complete response path CR

• Surgery is ALWAYS perfomed, regardless of outcome of chemotherapy

SERM – tamoxifen , raloxifen AROMATASE INHIBITOR – Exemestane Anastrazole Leterazole

HER2/NEU – trastuzumab, ado-trastuzumab emtansin pertuzumab laptanib mToR inhibitor – everolimus PARP (poly ADP ribose polymerase) inhibitor -Iniparib BRCA MUTATION INHIBITORS Olaparib

veliparib

Lapatinib • Binds to intracellular ATP

binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation

• Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)

• Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab

1+1 2+2 1+2

Lapatinib

Downstream signaling cascade

Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263;Konecny et al. Cancer Res. 2006;66:1630-1639

Oncotype Dx: Genomic Stratification of Luminal Breast Cancers for Therapeutic

Benefit The 21-Gene

Recurrence Score (RS) (Oncotype DX) is an RT-PCR based gene expression profiling assay that includes 16 cancer genes and 5 reference genes.

PROLIFERATIONPROLIFERATIONKi-67Ki-67

STK15STK15SurvivinSurvivin

Cyclin B1Cyclin B1MYBL2MYBL2

ESTROGENESTROGENERERPRPR

Bcl2Bcl2SCUBE2SCUBE2

INVASIONINVASIONStromelysin 3Stromelysin 3Cathepsin L2Cathepsin L2

HER2HER2GRB7GRB7HER2HER2

BAG1BAG1GSTM1GSTM1

REFERENCE GENESREFERENCE GENESBeta-actin, GAPDH, RPLPOBeta-actin, GAPDH, RPLPOGUS, TFRCGUS, TFRC

CD68CD68

PROLIFERATIONKi-67

STK15Survivin

Cyclin B1MYBL2

ESTROGENER

PGRBcl2

SCUBE2

INVASIONStromolysin 3Cathepsin L2

HER2GRB7HER2

GSTM1

REFERENCEBeta-actinGAPDHRPLPO

GUSTFRC

CD68

BAG1