Post-graduate Lecture - Yousef El-Ayman

1. Hormonal&Neoadjuventtherapyin
BreastCancer

2. Introduction
 Global cancer statistics show that breast cancer
is the most frequently diagnosed cancer,
accounting for over a million cases each year
 The leading cause of cancer death in women
worldwide.
 In the United States, breast cancer is the most
common female cancer, the second most
common cause of cancer death in women, and
the main cause of death in women ages 20 to 59
years

3. Introduction
 The incidence rates are highest in North
America, Australia/New Zealand, and in
western and northern Europe, and lowest in
Asia and sub-Saharan Africa
 Variations are most likely due to socio-
economic factors

4. Introduction
 The incidence rates decreased from 1999 to
2007 by 1.8 percent per year.
 Trials & reports suggest that this drop was
due to discontinuation of HRT “Hormone
ReplacementTherapy”

5. Clinical presentation
 In countries with established breast cancer screening
programs, most patients present due to an abnormal
mammogram.
 Up to 15% of women are diagnosed with breast mass
that is not detected on mammogram
(mammographically occult disease)
 30% present with a breast mass in the interval
between mammograms (interval cancers)
 women without access to screening mammograms
and younger women under 40 years who may not be
undergoing routine screening mammograms may
present with a breast or axillary mass with or without
skin changes.

6. Clinical presentation
Presentations:
 Breast Mass: The “classic” characteristics of a
cancerous lesion include a hard, immovable,
single dominant lesion with irregular borders.
However, these features cannot reliably
distinguish a benign from a malignant tumor
 Locally advanced disease : axillary adenopathy
(suggesting locoregional disease), or skin
findings such as erythema, thickening, or
dimpling of the overlying skin (peau d’orange),
suggesting inflammatory breast cancer.

7. Clinical presentation
Presentations:
 Metastatic disease : depending on the organs
involved, most commonly the bone (back or
leg pain), liver (abdominal pain, nausea,
jaundice), and lungs (shortness of breath or
cough)

8. Imaging
 Classic mammographic findings of breast
cancer include the presence of a soft tissue
mass and clustered microcalcifications. The
most specific feature is a spiculated soft
tissue mass, with nearly 90 percent
representing an invasive cancer

9. Imaging

10. Imaging
 Breast ultrasound: is often used to distinguish
a benign versus malignant lesion.
Sonographic features of malignancy include
the presence of spiculation,
hypoechogenicity, microlobulation, internal
calcifications, shadowing, a lesion taller than
it is wide, and angular margins

11. Imaging

12. Imaging
 Magnetic resonance imaging (MRI): typically
used to screen women at high risk for breast
cancer. (known genetic or family
predisposition), or contralateral breast
(especially in lobular carcinoma)
 More accurate delineation of the extent of
the disease if breast conservative surgery is
considered
 Suspicious areas not otherwise defined by
other imaging modalities

13. Pathology
The most common histologic types:
 Infiltrating ductal carcinoma : 70 to 80% of
invasive lesions. These lesions are
characterized by cords and nests of cells
 Infiltrating lobular carcinoma : about 8%
 Mixed ductal/lobular carcinoma: about 7%
 Other types : metaplastic, mucinous, tubular,
medullary, and papillary carcinomas. <5% of
invasive cancers

14. Diagnosis
 The diagnosis requires obtaining a tissue
sample and requires pathologic, radiologic,
and clinical correlation (triple test)
 Women with abnormal imaging findings
alone should undergo biopsy guided by
mammography (stereotactic biopsy or wire
localization breast biopsy), ultrasound, or
breast MRI.
 Women with a breast mass should undergo a
fine needle aspiration or core needle biopsy.

15. Diagnosis
 Women presenting with signs of
inflammatory breast cancer (rapidly
progressing, tender, firm, and enlarged
breast with thickening of the underlying skin)
require two full thickness skin biopsies. The
presence of dermal lymphatic invasion is
pathognomonic for inflammatory breast
cancer

16. Receptortesting
 Newly diagnosed breast cancers must be
tested for by estrogen (ER) and progesterone
(PR) receptor expression and for
overexpression of human epidermal growth
factor 2 (HER2) receptors. This information is
critical for both prognostic and therapeutic
purposes.

17. Receptortesting
 ER and PR are prognostic factors for invasive
breast cancer. In addition, patients who are
ER and/or PR positive (75% of breast Cancer
cases) are candidates for endocrine therapy
as neoadjuvant or adjuvant treatment.
 HER2 overexpression is present in 20 percent
of patients and predicts those who will
benefit from HER2-directed therapy

18. Receptortesting
 Breast cancer can be characterized into
different subtypes by whether or not they
express ER, PR, and HER2
 ER and/or PR positive cancers comprise the
majority of cases (75%)
 HER2 is overexpressed in 23% of cases
 ER, PR, and HER2 negative (triple negative
breast cancer “TNBC”) cancers comprise 13%

19. Staging
 Breast cancer is staged using the American
Joint Committee on Cancer and the
International Union for Cancer Control (AJCC-
UICC) classification system for tumor, nodes,
and metastases (TNM)

20. Staging
 In the TNM system, patients are assigned a
clinical stage (cTNM) preoperatively.
Following surgery, the pathologic stage
(pTNM) is then determined. For patients who
undergo neoadjuvant treatment, the final
pathologic stage is designated by the letter y
(ypTNM)

25. Neoadjuvant therapy
 Neoadjuvant therapy refers to the systemic
treatment of breast cancer prior to definitive
surgical therapy
 the primary objective of neoadjuvant therapy is
to improve surgical outcomes where a primary
surgical approach is technically not feasible. Or
patients with operable breast cancer who desire
breast conservation, where a mastectomy is
required or a partial mastectomy would result in
a poor cosmetic outcome

26. Neoadjuvant therapy
 Neoadjuvant therapy also allows for an early
evaluation of the effectiveness of systemic
therapy. This may permit the clinician to
discontinue ineffective treatment.

27. Selection
 Inoperable disease : Patients with locally
advanced breast cancer (clinical stage IIIA-
IIIC) are ideal candidates.
 Many patients with tumors larger than 5 cm,
even if potentially operable, are considered to
have locally advanced breast cancer on
neoadjuvant therapy clinical trials

28. Selection
 Operable disease : Patients with early stage
breast cancer (stage I or II) if breast
conserving surgery is not possible due to a
high tumor-to-breast ratio or an expected
postoperative cosmetic outcome would be
suboptimal due to tumor location.
 In addition, patients with small tumors may
be offered neoadjuvant therapy if their breast
cancer subtype is associated with a high
likelihood of response

29. Selection
 Clinical status : Neoadjuvant systemic
therapy is a treatment option for patients
who have medical contraindications to
undergoing surgery at diagnosis, but in whom
surgery is anticipated at a later date, such as
women with breast cancer diagnosed during
pregnancy

30. Selection
 Subtypes: Neoadjuvant therapy is most
appropriate for patients likely to have a good
locoregional response, regardless of tumor
size at presentation. This includes those with
HER2-positive or (triple-negative breast
cancers”TNBC”)
 In contrast, HER2-negative, ER-positive
breast cancers are less likely to have a clinical
or pathologic complete response to
neoadjuvant chemotherapy

31. HER2-Positive
 Patients with HER2-positive cancers have a
relatively high rate of pathologic complete
response to neoadjuvant chemotherapy,
particularly if treatment includes a HER2-
directed agent chemotherapy
 The pathologic complete response (pCR) rate
following neoadjuvant chemotherapy alone
was 39% for patients with HER2-positive
disease, in comparison with 18% for those
with HER2-negative breast cancers.

32. HER2-Positive
 Studies also demonstrated a high rate of pCR
among HER2-positive patients, regardless of
the status of the hormone receptors:
 Among 24 patients with hormone receptor-
positive and HER2-positive disease, the pCR
rate was 33%
 Among patients with hormone receptor-
negative and HER2-positive disease, the pCR
rate was 45%

33. HER2-Positive
 Among HER2-positive patients treated with
neoadjuvant chemotherapy plus trastuzumab,
the pCR rate was 60%.
 For this reason, we recommend the addition of
targeted treatment against HER2 (ie,
trastuzumab) to neoadjuvant chemotherapy in
these patients

34. Triple-negativebreastcancer
 pCR rates to neoadjuvant chemotherapy
among triple-negative breast cancer (TNBC)
patients range from 27 to 45%, while the pCR
rate for HER2-negative, hormone receptor-
positive patients is generally less than 10%.
 TNBC patients with more than minimal
residual disease at surgery have a much
higher risk of early distant disease recurrence

35. Pre-treatmentevaluation
 Tumor evaluation: using U/S or MRI, with
radiopaque clips.
 L.N evaluation: if palpable  FNA
 If +ve  further evaluation after treatment
 If –ve  Sentinal Lymph Node Biopsy (SLNB)
 If non-palpable  SLNB
 If –ve  no further evaluation
 If +ve  further evaluation after treatment

36. Choiceoftherapy
 Patients with TNBC who are not candidates
for surgery or desire breast conserving
surgery. These patients have an excellent
chance of achieving a clinical and pathologic
complete response to treatment.

37. Choiceoftherapy
 For postmenopausal women with HER2-negative,
estrogen receptor (ER) and/or progesterone receptor
(PR) positive breast cancers who are not candidates
for initial resection, we suggest neoadjuvant
chemotherapy rather than endocrine therapy.
 While few of these patients will achieve a clinical or
pathologic complete response, tumor shrinkage may
permit some unresectable patients to undergo
surgery and some borderline patients to be offered
breast conservation.
 However, those who are medically unfit for or refuse
chemotherapy may be treated with neoadjuvant
endocrine therapy

38. Choiceoftherapy
 Premenopausal women with HER2-negative, ER-positive
and/or PR-positive breast cancers who are not candidates
for initial resection.
 While few of these patients will achieve a clinical or
pathologic complete response, tumor shrinkage may
permit some unresectable patients to undergo surgery and
some borderline patients to be offered breast conservation.
 Patients who refuse neoadjuvant chemotherapy should
undergo primary surgery.
 patients who refuse both neoadjuvant chemotherapy and
primary surgery may be offered neoadjuvant endocrine
therapy, but must be informed of the absence of data
regarding the risks and benefits of such an approach

39. Choiceoftherapy
 For patients with HER2-positive breast cancer
who are not candidates for surgery or have
larger tumors and desire breast conserving
surgery, The addition of trastuzumab to
neoadjuvant chemotherapy is recommended
over chemotherapy alone.

40. NACT VsACT
 locally advanced breast cancer, neoadjuvant
chemotherapy (NACT) is associated with high
rates of clinical response and a higher
likelihood for allowing cosmetically
acceptable surgery. However, NACT does not
improve disease-free or overall survival
compared to adjuvant chemotherapy.

41. Regimens
 Anthracycline-taxane based regimens
 Carboplatin + paclitaxel

42. Neoadjuvantendocrinetherapy
 At the present time, neoadjuvant endocrine
therapy is restricted to postmenopausal
patients who are not medically fit to receive
or refuse chemotherapy.
 For postmenopausal women, we suggest the
administration of an aromatase inhibitor (AI)
rather than tamoxifen.
 There is no preferred agent among the
different AIs (exemestane, letrozole, or
anastrozole)

43. Durationof endocrinetherapy
 A response to endocrine therapy may not be
evident for at least three to four months and
maximal response may not be achieved until
much later. Thus, the duration of treatment
prior to surgery must be individualized based
on the patient’s clinical status and the clinical
response.

44. Durationof endocrinetherapy
 If the tumor is amenable to surgery after three to
four months, definitive surgical treatment is
recommended.
 However, if the tumor is responding to endocrine
therapy, extending treatment to six months or
longer, with clinical monitoring of response, may
permit a higher percentage of patients to
undergo breast conserving surgery.
 If at any time there is evidence of progression or
non-response, we recommend surgery.

45. HER2directedtherapy
 Trastuzumab: a monoclonal antibody that
binds the extracellular domain of HER2.
 Lapatinib: an orally available tyrosine kinase
inhibitor of epidermal growth factor and
HER2.
 Pertuzumab: is a humanized monoclonal
antibody that blocks the dimerization domain
of HER2.

46. HER2directedtherapy
 No current evidence suggest advantage of
replacing Trastuzumab with Lapatinib,
However, combining two anti HER2 agents is
a promising strategy but still under
investigation.

47. TreatmentEvaluation
 Patients undergoing neoadjuvant systemic
therapy should undergo periodic clinical
evaluations during treatment to assess
response and ensure that their tumor is not
progressing.
 There are no formal guidelines regarding the
ideal assessment strategy during
neoadjuvant treatment

48. TreatmentEvaluation
 For patients on neoadjuvant chemotherapy (NACT),
clinical examination is performed every two to four
weeks (prior to each cycle of treatment). This should
include evaluation of the affected breast and
ipsilateral axilla.
 For patients undergoing neoadjuvant endocrine
therapy, clinical evaluations is performed every four
to eight weeks. Their response to treatment is
expected to take a longer time to become evident.
 Imaging studies (U/S or MRI) should only be
performed if disease progression is suspected based
on clinical exam.

49. Timeforsurgery
 proceeding with definitive surgery is
recommended as soon as the patient has
recovered from toxicities due to neoadjuvant
treatment. This typically takes three to six
weeks after completing neoadjuvant
chemotherapy.
 Patients treated with endocrine therapy
typically do not need to discontinue
treatment prior to proceeding with surgery.

50. Hormone Therapy
 patients who are ER and/or PR positive (75%
of breast Cancer cases) are candidates for
endocrine therapy as neoadjuvant or
adjuvant treatment.

51. Hormone Therapy
Treatment options are:
 Tamoxifen (20 mg daily) in premenopausal and
postmenopausal women
 Aromatase inhibitors in postmenopausal women
only. Drugs in this class include anastrazole (1 mg
daily), letrozole (2.5 mg daily), and exemestane (25
mg daily)
 Ovarian suppression or ablation: Blocking
production of estrogens at the level of the ovaries in
premenopausal women. Either by radiation therapy,
oophorectomy or the use of gonadotropin releasing
hormones (goserelin , buserelin)

52. Choice of treatment
 Postmenopausal women: AI is used rather than for
five years because there is no data to support
extendedAI treatment beyond this duration.
 Women who prefer to take tamoxifen should be
offered subsequent treatment with an AI at one of two
opportunities:
 Following completion of a two to three year course of
tamoxifen, AI is given for three or two years to complete
a planned five year course
 Following completion of a five year course of
tamoxifen , we treat with an AI is given for an
additional five years.

53. Choice of treatment
 Women who refuse to take an AI or cannot tolerate
an AI due to side effects, are given tamoxifen for at
least a five year treatment course.
 A further five years of tamoxifen should be offered
to women with a relatively poor prognosis
(pathologically involved lymph nodes at diagnosis,
large tumor size, higher tumor grade) and those who
are tolerating treatment.
 For women experiencing more serious side effects
from tamoxifen, stopping tamoxifen after five years
is reasonable, particularly if they had a tumor with
relatively good prognostic features (small tumor, no
evidence of nodal involvement, low tumor grade)

54. Choice of treatment
 premenopausal women: options include
tamoxifen , ovarian ablation/suppression,
or a combination of ovarian suppression
plus tamoxifen treatment.
 Treatment with Tamoxifen is given for at
least five years (see before)

55. Choice of treatment
 Aromatase inhibitors are contraindicated
because reduced feedback of estrogen to the
hypothalamus and pituitary may increase
gonadotropin secretion and stimulate the ovary,
leading to an increase in androgen substrate and
aromatase. Even in chemotherapy-induced
amenorrhea, since an AI can promote re-
activation and estrogen production by the
ovaries

56. Choice of treatment
 Women who are permanently postmenopausal
by prior treatment should be treated as
described for postmenopausal women
 we consider women less than 60 years to be
postmenopausal if they underwent a bilateral
oophorectomy, have not had menstrual periods
for 12 months or more in the absence of
tamoxifen , chemotherapy, or ovarian
suppression

57. Choice of treatment
 Men: The majority of male breast cancers are
hormone-positive and as such, they are
candidates for adjuvant endocrine therapy as
well. For most men with breast cancer,
tamoxifen is the preferred agent

58. Side effects
 Tamoxifen: Hot flashes, vaginal discharge, sexual
dysfunction, menstrual irregularities & increased
risk of thrombo-embolic events and uterine
cancer
 AIs: Osteoporosis and increased risk of future
fractures, cardiovascular disease and
hypercholesterolaemia, & reactivation of
ovaries.

59. Timing with other treatments
 Hormonal Therapy can be initiated
concomitantly with chemo- or radiotherapy or
can be initiated after completion, there is no
strong evidence suggesting an advantage of one
approach over the other

60. ThankYou