NCCN VERSION 2 2015

The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

MS-33

NCCN Guidelines Index

Breast Cancer Table of Contents

Discussion

NCCN Guidelines Version 2.2015

Breast Cancer

long-term (greater than 5-year) safety and efficacy of these agents are

still under investigation. The various studies are consistent in

demonstrating that the use of a third-generation aromatase inhibitor in

postmenopausal women with hormone receptor-positive breast cancer

lowers the risk of recurrence, including IBTR, contralateral breast

cancer, and distant metastatic disease when used as initial adjuvant

therapy, sequential therapy, or extended therapy. The panel finds no

compelling evidence that there is meaningful efficacy or toxicity

differences between the aromatase inhibitors, anastrozole, letrozole,

and exemestane. All three have shown similar anti-tumor efficacy and

toxicity profiles in randomized studies in the adjuvant settings. The

updated version of the

NCCN Guidelines for Breast Cancer

recommends the following adjuvant endocrine therapy options for

women with early breast cancer who are postmenopausal at diagnosis:

an aromatase inhibitor as initial adjuvant therapy for 5 years (category

1); tamoxifen for 2 to 3 years followed by one of the following options:

an aromatase inhibitor to complete 5 years of adjuvant endocrine

therapy (category 1) or 5 years of aromatase inhibitor therapy (category

2B); or tamoxifen for 4.5 to 6 years followed by 5 years of an aromatase

inhibitor (category 1) or consideration of tamoxifen for up to 10 years. In

postmenopausal women, the use of tamoxifen alone for 5 years

(category1) or up to 10 years is limited to those who decline or who

have a contraindication to aromatase inhibitors.

In premenopausal women, the aromatase inhibitors are associated with

the development of benign ovarian pathology and do not adequately

suppress ovarian estrogen synthesis. Premenopausal women should

not be given adjuvant initial therapy with an aromatase inhibitor outside

the confines of a clinical trial. Women who are premenopausal at

diagnosis and who become amenorrheic with chemotherapy may have

continued estrogen production from the ovaries without menses. Serial

assessment of circulating LH, FSH, and estradiol to assure a true

postmenopausal status is mandatory if this subset of women is to be

considered for therapy with an aromatase inhibitor.

309,310

After 5 years of

tamoxifen (category 1), for women postmenopausal at that time

(including those who have become postmenopausal during the 5 years

of tamoxifen therapy), the NCCN Panel recommends considering

extended therapy with an aromatase inhibitor for up to 5 years (category

1) or based on the data from the ATLAS trial considering tamoxifen for

an additional 5 years. For those who remain premenopausal after the

initial 5 years of tamoxifen, the panel recommends considering

continuing up to 10 years of tamoxifen therapy.

The measurement of the nuclear antigen, Ki-67 by IHC, gives an

estimate of the tumor cells in the proliferative phase (G1, G2, and M

phases) of the cell cycle. Studies have demonstrated the prognostic

value of Ki-67 as a biomarker and its usefulness in predicting response

and clinical outcome.

311

One small study suggests that measurement of

Ki-67 after short-term exposure to endocrine treatment may be useful to

select patients resistant to endocrine therapy and those who may

benefit from additional interventions.

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However, these data require

larger analytic and clinical validation. In addition, standardization of

tissue handling and processing is required to improve the reliability and

value of Ki-67 testing. At this time, there is no conclusive evidence that

Ki-67 alone, especially baseline Ki-67 as an individual biomarker, helps

to select the type of endocrine therapy for an individual patient.

Therefore, the NCCN Breast Cancer Panel does not currently

recommend assessment of Ki-67.

The

cytochrome P-450 (CYP450) enzyme

, CYP2D6, is involved in the

conversion of tamoxifen to endoxifen. Over 100 allelic variants of

CYP2D6

have been reported in the literature.

313

Individuals with

wild-type

CYP2D6

alleles are classified as extensive metabolizers of