SHOULD TRIPLE-NEGATIVE

BREAST CANCER (TNBC)

SUBTYPE AFFECT LOCAL-

REGIONAL THERAPY DECISION

MAKING?

The answer

is

YES

What is Triple Negative

Breast cancer?

ER , PR negative

HER 2 neu negative

Aggressive pathologic

features a higher

histology grade and

mitotic index

No hormonal

treatment

NO

Trastuzumab

Higher rate of

&early recurrence

distant metastasis

to brain and lungs

Is There Hope ???!!!!!!!!!!!!!!

Understanding the biology

Basal-like 1 (BL-1) Basal-like 2 (BL-2)

Immunomodulatory (IM) Mesenchymal (M)

Mesenchymal stem-like (MSL) Luminal androgen receptor (LAR)

Triple Negative Breast

Cancer

EGFR & CK5/6 (Positive)

EGFR & CK5/6 (Negative)

Female patient 32 ys old , presented with mass in left breast (2*3) cm , tru cut biopsy was taken revealed , infiltrating duct carcinoma , ER , PR ,HER2 neu negative ( Triple Negative) . The patient has come to your office to discuss her treatment options , she talked to you about her chance for breast conserving surgery .What will be your advice?????????

*In order to determine whether surgical choice has an impact on locoregional recurrence in patients with TNBC, several studies have investigated outcomes following treatments in TNBC compared with the general breast cancer population.

*The aggressive nature of the TNBC subtype may appear to exclude such patients from treatment with breast-conservation therapy (BCT)

Parker et al* addressed this by carrying out a retrospective analysis of

patients with TNBC, comparing their outcomes based on the surgical

approach (BCT versus mastectomy).

In this study, out of a total of 220 patients with TNBC, 61 (30%) patients

underwent BCT and 141 (70%) patients underwent mastectomy. To

determine whether the type of operative therapy had an impact on the

outcome for patients with TNBC, overall survival (OS) and disease-free

survival (DFS) were compared.

The 5-year DFS rates for the BCT and mastectomy groups

were 68% and 57%, respectively (P = 0.14).

The 5-year OS was better for the BCT than for the

mastectomy group (89% versus 69%; P = 0.018).

Parker et al. concluded that selected

patients with TNBC should be given the

opportunity to benefit from the less

aggressive BCT.*Parker CC, Ampil F, Burton G et al. Is breast conservation therapy a viable option

for patients with triple-receptor negative breast cancer? Surgery 2010; 148.

Solin et al.* conducted a study of 519 women with breast

cancer, 90 with TNBC. After BCT with radiation, women with

TNBC showed a higher 8-year rate of any locoregional

recurrence (8% versus 4%; P = 0.041) and a lower 8-year

rate of freedom from distant metastases (81% versus 92%; P

= 0.0066). Although women with TNBC had a higher rate of

locoregional recurrence after breast reconstruction with RT, Following multivariate analysis, this difference was

not statistically significant.

*Solin LJ, Hwang WT, Vapiwala N. Outcome after breast conservation treatment with radiation for women with triple-

negative early-stage invasive breast carcinoma. Clin Breast Cancer 2009; 9: 96–100.

Voduc et al classified patients into six subtypes, which included

distinction of basal-like (ER/PR/HER2 negative, EFGR positive or CK5/6

positive) and TNBC-phenotype (ER/PR/HER2 negative, EGFR negative

and CK5/6 negative) for analysis of LRR outcomes.

LRR was highest among basal-like, but not nonbasal TNBC, and these

LRR patterns were also similarly high when the two subtypes

underwent BCT. These findings have also been *confirmed in recent

meta-analyses

Abdulkarim et al analyzed LRR outcomes of T1–2, N0 TNBC treated

with BCT compared with modified radical mastectomy and reported an

absolute reduction of LRR risk by 6% in their BCT cohort.**

**Abdulkarim BS, Cuartero J, Hanson J, et al. Increased risk of locoregional recurrence for women with T1-2N0 triple-

negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with

breast-conserving therapy. J Clin Oncol. 2011;29:2852-2858.

*Wang J, Xie X, Wang X, et al. Locoregional and distant recurrences after breast conserving

therapy in patients with triple-negative breast cancer: a meta-analysis. Surg Oncol.

2013;22:247-255

So, your patient has gone for breast conserving surgery with lumpectomy with negative margin and adequate axillary evacuation with pathological staging (pT2N0M0) then she has returned to you for further management .Here is the question , Does being triple negative will impact your descion about her adjuvant radiotherapy????

*Adjuvant radiotherapy is a key component in BCS

*Given the ongoing excitement generated by newer radiation delivery methods

that deliver shorter courses of radiation for early-stage breast cancer.

*APBI delivers radiation to a small area surrounding the lumpectomy

cavity (and not all breast tissue) using a variety of delivery methods, reducing

treatment from five to six and a half weeks with conventionally fractionated whole-

breast radiation to less than five days with APBI, thus, lower treatment costs,

increasing patient convenience, and potentially decreasing toxicity with smaller

radiated volumes.

BUT, patterns of recurrence after BCT by subtype suggest

more true recurrences

(around the tumor bed) for TNBC

Although there is a paucity of data on outcomes by subtype from

prospective APBI trials, one recent prospective APBI study found

an unacceptably high five-year actuarial in-breast failure rate of

33% in their TNBC subset *

*Sioshansi S, Ehdaivand S, Cramer C, et al. Triple negative breast cancer is associated with an increased risk of residual

invasive carcinoma after lumpectomy. Cancer. 2012;118:3893-3898

The rising question here , if this patient had done MRM , is there will be an indication for adjuvant radiotherapy???

Abdulkarim et al. compared the locoregional recurrence

risk following MRM without adjuvant RT with BCS in a

population of patients with TNBC and a subgroup of patients

with T1-2N0 TNBC.

At a median follow-up of 7.2 years,

%10 of patients with TNBC developed locoregional recurrence,

and MRM without RT represented the only independent

prognostic factor associated with increased risk of locoregional

recurrence in the T1-2N0 subgroup when compared with BCS

Other studies have also suggested that some T1-2N0 patients may

benefit from MRM plus adjuvant RT , which is not recommended in

the current guidelines.

There is a study found a decreased effect of PMRT for patients

with TNBC when compared with other breast cancer subtypes (ER-

positive/PR-positive and the ER-positive/PR-positive/HER2-

negative subtype).

Taken together, the authors suggested relative radioresistance of

the TNBC subtype as a consequence of the ER-negative receptor

status. ER expression results in a decrease in cell-cycle duration,

reducing the time available for the repair of DNA damage caused by

radiation.

It was suggested that ER-negative cells as found in TNBC and

basal-like breast cancer would thus exhibit radioresistance, as DNA

repair is allowed to progress during the slower cell cycle.

Do you think that genetic testing for this patient will make a sense in decision making for locoregional management??

*There is some notable overlap between the morphologic and

phenotypic features of breast cancer in BRCA1 carriers and

sporadic TNBC. These strong resemblances suggest a

commonality in one or more defects in the functions of the

BRCA1 pathway for both BRCA1-associated and sporadic

TNBC.

*Although much remains to be learned about the clinical

implications regarding the resemblances between BRCA1-

associated and sporadic TNBC, knowledge of germline BRCA

mutation status is an important component of local-regional

management decisions.

It is essential to recognize that the increased lifetime risk of

ipsilateral breast relapse and contralateral breast cancer after

BCT in BRCA carriers is not shared by sporadic TNBC.

Thus, all patients with TNBC should

undergo risk assessment for genetic

susceptibility

*Though mutation status alone should not direct local-regional

management, it guides recommendations for additional risk-reducing

surgical interventions, such as oophorectomy or contralateral

prophylactic mastectomy, which may be performed simultaneously

with definitive surgery.

*The presence of a BRCA mutation should not preclude BCT in

patients who are otherwise appropriate candidates, as the data

suggest that BC-specific survival and overall survival for hereditary

breast cancer is independent of local treatment choice.

Given the high long-term risks of new in-breast and contralateral

breast primaries, definitive mastectomy with simultaneous

contralateral prophylactic mastectomy is the local-regional

management pathway that is most commonly selected by

patients with hereditary breast cancer

Triple negative breast cancer represent a major obstacle regarding its aggressiveness and lack of targets to be targated .

TNBC is not contraindication for breast conserving surgery.

Following breast conservation , conventional radiotherapy with boost is recommended

Genetic risk assessment for TNBC is recommended

Searching for targets is the most important

rising hope in management of triple

negative breast cancer