CLINICAL ISSUES IN BREAST CANCER
| Breast Cancer and Pregnancy —Mindy Goldman, MD, Associate Clinical Professor, Department of Obstetrics
and Gynecology and Reproductive Sciences; Director, Cancer Survivorship Program, Carol Franc Buck Breast Care Center,
University of California, San Francisco, School of Medicine
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| General considerations: in general, parity protective for breast cancer; reduced risk for breast cancer if patient pregnant at
<30 yr of age; parity transiently increases risk, but overall reduced risk for greater number of full-term pregnancies; pregnancy
may promote existing breast cancer cells, but inhibits tumor initiation; breast cancer soon after pregnancy may have
worse prognosis; pregnancy-associated breast cancer (PABC)—breast cancer diagnosed during pregnancy or 1 yr postpartum;
breast cancer most common malignancy diagnosed during pregnancy; increasing because of delay in childbearing;
0.1% to 3% of new breast cancers diagnosed during pregnancy; typically, 1- to 2-mo delay in diagnosis; physiologic
changes of pregnancy make it difficult to diagnose small lumps; 2.5-fold increased risk for metastatic disease at diagnosis;
decreased survival believed related to delayed diagnosis; no data supporting termination of pregnancy with diagnosis of
PABC; survival related to stage of disease at diagnosis
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| Prognosis: higher incidence of inflammatory breast cancers during pregnancy; more likely node-positive; more high-grade
tumors; less likely to be hormone-receptor positive; increased vascular invasion; possibly higher incidence of human epidermal
growth factor receptor (HER-2/neu) positivity; possible explanations of poor outcome in pregnancy—estrogen
may affect tumor cells directly or cause overstimulation of growth factors; inhibition of immune rejection process during
pregnancy; presence of blocker and helper antibodies that promote tumor growth; increases in corticosteroids causing immune
suppression; adjuvant treatments may be less effective; other hormones may promote tumor growth; differences in
outcomes likely related to more adverse biologic factors in young women; higher risk for contralateral breast cancer and
incidence of second primary cancer in young women
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| Diagnostic issues: physical findings—enlarging mass (often painless), thickening or dimpling of breasts, spontaneous nipple
discharge (particularly bloody nipple discharge), axillary adenopathy, and nipple retraction; benign pregnancy lesions
often confused with breast cancer include lactational adenomas, galactoceles, mastitis, and infarction of hypertrophied
breast tissue; mammography—safe as long as fetus shielded; avoid in first trimester; increased water content and glandularity
of breast tissue in pregnancy decreases sensitivity; detection of contralateral abnormalities main role of mammography;
ultrasonography (US)—helpful in distinguishing solid from cystic masses; magnetic resonance imaging
(MRI)—safe, but effectiveness in pregnancy not known; biopsy—discrete mass requires biopsy; fine-needle aspiration
(FNA)—increases false positives in pregnancy due to proliferative changes; perform excisional or core biopsy if FNA inconclusive;
milk fistula may occur with core biopsy; staging work-up—chest x-ray with appropriate shielding to assess
for pulmonary metastasis; liver function tests to evaluate for liver metastasis; abdominal US for liver evaluation; avoid bone
scans and computed tomography (CT); obtain bone scan only with high suspicion for bony metastasis; MRI for evaluation
of visceral organs; echocardiography if anthracycline-based chemotherapy planned; estrogen and progesterone receptor status
on biopsy; little data on accuracy of hormone receptor testing in pregnancy
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| Treatment: little prospective data about treatment; surgery—little or no risk to fetus; intraoperative fetal monitoring if at
stage of viability; mastectomy treatment of choice because adjuvant irradiation contraindicated; data suggest similar long-
term outcomes for mastectomy and lumpectomy; breast-conserving surgery possible if irradiation delayed postpartum; sentinel
node biopsy—if sentinel nodes negative, then remaining nodes may be negative and can avoid full node dissection,
decreasing risk for lymphedema; lack of information about safety of sentinel node biopsy in pregnancy; minimal exposure
from radioisotopes used; full node dissection should be performed if nodes palpable; delay reconstruction postpartum; radiation
therapy—extent of damage based on dose and timing of pregnancy; preimplantation exposure associated with cell
death and possible increased risk for spontaneous abortion (SAB); first trimester exposure associated with intrauterine
growth retardation (IUGR), central nervous system (CNS) abnormalities, microcephaly, and ocular problems; second trimester
exposure associated with bone marrow, liver, and kidney abnormalities and sterility; theoretic risk for future childhood
cancers; chemotherapy—decisions about type and timing based on stage of disease, stage of gestation, and altered
drug metabolism in pregnancy; usually no dose modification; unclear whether there is third spacing of chemotherapeutic
agents into amniotic fluid; cyclophosphamide, 5-fluorouracil, and doxorubicin generally used; minimal data on taxanes in
pregnancy; trastuzumab (Herceptin) used in HER-2/neu-positive disease; recent report of reversible anhydramnios in patient
exposed to Herceptin; reports of congenital malformations for first trimester exposure and increased risk for stillbirths;
no malformations in second and third trimester; should be delayed until second trimester; follow-up to 8 yr showed normal
development; neoadjuvant chemotherapy—used in third trimester; delivery—should be planned when blood counts
maximal; main risks of myelosuppression are postpartum hemorrhage and infection; typically, induction at 34 wk if maternal
therapy needed; monitor fetal blood counts; children born to mothers receiving chemotherapy during pregnancy have
shown normal growth and development; hormonal therapy—little data; reports of teratogenic effects in animals from
tamoxifen exposure and one report of ambiguous genitalia in human; one case report of tamoxifen used in metastatic breast
cancer showed no adverse effects; aromatase inhibitors used only in postmenopausal women; used for ovulation induction
for breast cancer patients who desire in vitro fertilization (IVF) followed by cryopreservation of embryos
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| Recurrence during pregnancy: believed worse prognosis; same treatment issues, but options may be more limited because
of failed therapies; metastatic breast cancer—treatment goal palliation rather than cure; need to weigh risk for
toxicity to fetus; reports of placental metastases with widely metastatic disease; no known cases of fetal metastases
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| Breast-feeding: recommended to stop breast-feeding before biopsy to decrease risks for secondary infection, abscess, and
possible milk fistula; if mammography indicated, perform immediately after nursing or breast pumping; avoid if patient
receiving chemotherapy or radiation
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| Reproductive issues: chemotherapy-induced menopause—incidence of ovarian failure dependent on chemotherapy regimen,
cumulative dose, and age; mostly due to alkylating agents; more cyclophosphamide patient receives, greater risk for
ovarian failure; resumption of menses if <40 yr of age; >90% chance of permanent ovarian failure if patient >40 yr of age;
even patient who resumes menses has increased risk for premature ovarian failure; ovarian suppression and fertility—
ongoing study following ovarian function in women <40 yr of age given ovarian suppression before chemotherapy; fertility
treatments—no increased risk for primary breast cancer in women taking infertility drugs, except use of >6 cycles of injectable
gonadotropins; no clear increased risk with clomiphene; data show women with recent exposure to fertility drugs
who develop breast cancer may have worse prognosis; no data on fertility treatments in women with history of breast cancer;
studies have not shown worse outcomes for patients who become pregnant after breast cancer (studies may have selection
bias); minimal data on estrogen and progesterone receptor status during pregnancy; recommended to wait 2 yr after breast
cancer before getting pregnant; previous chemotherapy does not cause increased miscarriage rates or teratogenic effects
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| Delivery issues: patient can have cesarean delivery if indicated, even with previous tissue transfer surgery; breast-
feeding—most patients with breast-conserving surgery report inadequate lactation in affected breast; may have asymmetric
breasts due to inadequate hypertrophy; breast-conserving surgery may allow for lactation; breast-feeding less
likely with centrally located tumors or with previous irradiation (induces fibrosis of lobules and decreased milk production)
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| BRCA 1 and BRCA 2: risk for breast cancer 80% by 70 yr of age for women with mutations in either gene; 5% to 12%
chance of mutation if patient diagnosed at <35 yr of age; women with mutations becoming pregnant <40 yr of age at
higher risk for breast cancer, compared to nonmutation carriers; PABC more common in women with mutations, particularly
BRCA1; BRCA1 carriers have higher incidence of hormone receptor-negative disease
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| Primary Care Follow-up of Breast Cancer Survivors —Ruth E. Johnson, MD, Consultant, Department
of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
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| Epidemiology: >2 million breast cancer survivors in United States; increased incidence in last decade, but death rate stable;
200,000 American women diagnosed with invasive breast cancer annually
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| Evaluation: women at risk for recurrence for rest of life; most recurrences occur within first 5 yr, but may occur at anytime;
symptoms suggestive of recurrence—change in breast or chest wall and regional adenopathy, particularly in clavicular
and axillary areas; symptoms of metastatic disease—weight loss, cardiopulmonary symptoms, and
musculoskeletal pain; most symptoms nonspecific, but >75% of recurrences present with symptom or physical finding;
carefully evaluate symptoms, particularly if no good reason for symptom; physical examination may detect local or regional
recurrences in breast, chest wall, and lymph nodes; follow-up care—routine history, physical examination, and
mammography; may add chest x-ray, blood profile, and serum tumor markers; routine laboratory tests, chest x-ray, and
bone scan rarely identify metastases in asymptomatic woman; asymptomatic recurrences comprise only 15% to 25% of
metastatic disease; data show earlier detection of metastasis not associated with improved survival; no justification for
obtaining serum tumor markers in regular monitoring of asymptomatic patients; secondary primary breast cancer—
risk greater with early-onset first cancer (<50 yr of age and premenopausal) and strong genetic or family history; may be
slightly increased risk in woman <45 yr of age at time of radiation therapy for initial cancer; mammography important for
early detection of asymptomatic recurrence of first cancer or new second primary cancer in either breast
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| Recommendations for follow-up care after breast cancer: history, physical examination, mammography, and pelvic
examination; not recommended—routine laboratory testing and tumor markers; screening—screen for other cancers
according to recommended guidelines for general population, unless patient at risk for hereditary breast or ovarian cancer
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| Breast reconstruction: implants or tissue flaps option for most women after mastectomy; no data suggesting immediate or
delayed reconstruction alters long-term outcome of breast cancer, nor does it impede or delay local or regional recurrence;
examine reconstructed breast for nodular, erythematous, or rash-like skin changes or thickening of subcutaneous
tissue; no indication for mammography; US best diagnostic modality
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| Lymphedema: risk directly related to extent of axillary surgery and radiation therapy; obesity or significant weight gain
after surgery and postoperative infection risk factors; data show sentinel lymph node biopsy associated with lower risk
for lymphedema; usually responds to elevation, compression gloves and sleeves, physical therapy, and lymphatic massage;
protect affected arm from becoming infected by avoiding compression and venipuncture
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| Hormone replacement therapy (HRT): historically contraindicated due to epidemiologic relation of estrogen to breast
cancer and because antiestrogen therapy proven to prevent recurrences and decrease risk for contralateral breast cancer;
unknown whether HRT alters risk for recurrence
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| Osteoporosis: amenorrhea secondary to chemotherapy accompanied by loss of bone mineral density (BMD) similar to natural
menopause; proestrogenic effects of tamoxifen preserve BMD in postmenopausal women; may reduce osteoporotic
fractures; in premenopausal women, tamoxifen associated with varying degrees of decreased BMD; bisphosphonates
during or after chemotherapy may prevent bone loss associated with chemotherapy-induced menopause; weight-bearing
exercise and intake of adequate calcium and vitamin D recommended; bone mineral densitometry warranted in women
with chemotherapy-induced menopause and premenopausal women on tamoxifen; consider therapy for woman with BMD
1 to 2 SDs below mean BMD in young women
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| Cardiovascular factors: no data on whether prolonged estrogen deprivation puts breast cancer survivor at increased risk
for heart disease; aggressive management of cardiovascular risk factors warranted; tamoxifen—lowers total cholesterol
and low-density lipoprotein (LDL) cholesterol in postmenopausal women; does not affect high-density lipoprotein
(HDL) cholesterol; minimal effect on lipids of premenopausal women; Tamoxifen Prevention Trial did not find reduction
in risk for coronary event with use; known to increase risk for thromboembolic events; absolute risk small, but exercise
high level of suspicion if patient presents with symptoms; raloxifene—proestrogenic effects on bone and lipids in postmenopausal
women; no data about safety in women with history of breast cancer; clinical consequence of use >5-yr unknown;
use with caution in breast cancer survivors
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| Menopausal symptoms: hot flushes—venlafaxine (Effexor) recommended; start with 37.5 mg daily, titrating to 75 mg
daily; vaginal dryness—vaginal lubricants may relieve dryness and dyspareunia; nonhormonal treatments, eg, glycerin,
mineral oil, and methylparaben (Replens), glycerin, propylene glycol, and parabens (Astroglide); vaginal estrogen
creams, rings, tablets, eg, estradiol (Vagifem) used for relief of urogenital symptoms; psychosocial issues—distress and
adjustment problems most intense in first year after diagnosis and tend to improve over time
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Educational Objectives
| The goal of this program is to educate the listener about the management of breast cancer in pregnancy and the care of
women with a history of breast cancer. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Discuss factors influencing breast cancer in pregnancy.
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| 2. Identify the appropriate diagnostic modalities for the pregnant patient suspected of having breast cancer.
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| 3. Summarize the safety of conventional breast cancer treatment during pregnancy.
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| 4. List the symptoms suggestive of breast cancer recurrence.
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| 5. Provide care for the woman with a history of breast cancer.
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Discussed on This Program
Clomiphene citrate [Clomid, Milophene, Serophene]
Cyclophosphamide [Cytoxan, Cytoxan Lyophilized, Neosar] Fluorouracil (5-fluorouracil, 5-FU) [Adrucil, Carac, Efudex,
Fluoroplex]
Docetaxel [Taxotere]
Doxorubicin [Adriamycin PFS, Adriamycin RDF]
Estradiol hemihydrate [Vagifem. Estrasorb]
Glycerin, propylene glycol, and methylparaben (Replens)
Glycerin, propylene glycol, and parabens (Astroglide)
Paclitaxel [Onxol, Paxene, Taxol, Abraxane]
Raloxifene [Evista]
Tamoxifen citrate [Nolvadex]
Trastuzumab [Herceptin]
Venlafaxine HCl [Effexor, Effexor XR]
Estradiol hemihydrate [Vagifem]
Suggested Reading
Aguas F et al: Prophylaxis approach to a-symptomatic post-menopausal women: breast cancer. Maturitas 52 Suppl 1:S23,
Epub 2005; Batur P et al: Menopausal hormone therapy (HT) in patients with breast cancer. Maturitas 53(2):123, 2006;
Burstein HJ: Primary care for survivors of breast cancer. N Engl J Med 343(15):1086, 2000; Eedarapalli P et al: Breast
cancer in pregnancy. J Obstet Gynaecol 26(1):1, 2006; Ring AE et al: Breast cancer and pregnancy; Ann Oncol
16(12):1855, Epub 2005.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Dr. Johnson was recorded at OB/GYN Clinical Reviews, sponsored by Mayo Clinic College of Medicine and held on
November 10-11, 2005 in Rochester, Minnesota. Dr. Goldman was recorded at Antepartum & Intrapartum Management,
sponsored by the University of California, San Francisco, School of Medicine and held on June 9-11, 2005, in
San Francisco. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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