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Effective Therapy for a Premenopausal Woman with
ER/PR Positive, HER2-Overexpressing Metastatic Breast Cancer
Diagnosis: Hormone receptor positive, HER2-overexpressing, metastatic breast cancer
History of Present Illness: This is a 36-year-old premenopausal woman who presented initially in 2002 with a 5-monthhistory of a growing lump in the upper outer quadrant of her right breast. Mammography showed a 2 cm mass. Biopsyconfirmed the presence of invasive adenocarcinoma. She had lumpectomy and sentinel lymph node mapping andsampling. She had a 1.5 cm, grade 3, invasive ductal cancer and there was one SLN that contained animmunohistochemical positive focus [T1c (1.5 cm) N0i+ (IHC+ SLN)]. The tumor was ER/PR+, HER2+, and grade 3.
She received adjuvant chemotherapy on CALGB 40101 (arm D) with six cycles of dose-dense paclitaxel (at the time,adjuvant trastuzumab was not standard). After chemotherapy, she received standard adjuvant radiation and thencompleted 5 years of tamoxifen. Her menses continued regularly during the 5 years of adjuvant tamoxifen.
Eleven months after stopping tamoxifen, she presented with a new lump in the base of her right neck. By physical exam,the lump was discovered to be tiny nodes in the low cervical node area, and she also had a 2 cm hard, right axillarymass. It was irregular, mobile, and nontender. She did not complain of it but said she noticed it after the physicianfound it. Right axillary node FNA was done and found cells consistent with fat necrosis. However, additional workupwas underway and included elevated serum markers with a CA27.29 at 70 units/ml and CA15.3 at 51.1 units/ml. A PETscan skull-base to mid-thigh showed abnormal uptake in the right breast, left proximal femur and femoral neck.
Bilateral mammograms and ultrasound of the right breast confirmed a 1.9 cm irregular mass in the right axillary tail atthe area of the lumpectomy bed. An additional right breast biopsy confirmed the presence of grade 3 invasiveadenocarcinoma with prominent lobular features, ER positive (Allred 8)/PR positive (Allred 8), HER2-overexpressing(3+ by IHC). FNA of the low right cervical node found lymphocytes and histiocytes consistent with a reactive lymphnode. Since PET scans can miss bone metastases, a bone scan was performed. This scan showed focal tracer uptake in theleft femoral neck, left iliac wing, and mild diffuse asymmetry in the left ilium and left hemipelvis. X-ray revealed anunstable bone lesion and the patient admitted pain in the area. Prophylactic intramedullary nailing of the left femur andexcisional biopsy and curettage found pathology consistent with metastatic adenocarcinoma of breast primary. Shereceived palliative radiation to the left hip and femur.
Past Medical/Surgical History: Anxiety disorder; Rhinoplasty about 20 years ago; Cleft palate surgery at age 16 months
Ob/Gyn History: Menarche at 14, G0 P0. Continues to have monthly menses. OCP for many years, discontinued inlate 2002
Medications: A multivitamin and escitalopram 20 mg po daily
Allergies and Adverse Drug Reactions: No known drug allergies
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Social History: She denies significant history of tobacco or alcohol use. She moved to town to be near her boyfriend. Shehas no children. She works in a daycare taking care of infants and toddlers.
Family History: Her paternal grandmother had lung cancer. There is no other known family history of breast, ovarian,uterine, colon, prostate, or other cancers. There is no known family history of thrombotic disorders.
Physical ExaminationGeneral appearance: Generally well-appearing, young woman.
Vital signs: Temperature–36.4 C; Pulse–81/min; Respiration–16/min; BP–118/76 mm (Hg); Height–159.00 cms;Weight–45.9 kg; Pain Assessment–0/10; Fatigue Score–4/10
Skin: No suspicious rashes or growths.
Head and neck: Sclerae are anicteric. Oropharynx has moist mucous membranes and is without lesions ordischarge. There is no adenopathy in the left neck. There is fullness in the right supraclavicular area.
Musculoskeletal: No tenderness to palpation over the spine.
Cardiovascular: No murmurs or gallops.
Soft with palpable nodules or thickening. There is a well-healed surgical incision.
There is a hard, 2 to 3 cm, axillary lump.
Soft without palpable nodules, thickening or skin changes. There is no lymphadenopathy.
Abdomen: Nondistended, nontender and without organomegaly or mass.
Extremities: No edema, palpable cords, or calf tenderness. Healing surgical site after left hip surgery.
Labs: All indices within CBC/diff and CMP were normal
Pathology: Image-guided biopsy of the right breast yielded a diagnosis of cancer recurrence and tissue adequate for IHC.
ER and PR were both strongly positive and HER2 was positive at 3+ by IHC.
Assessment and Plan: The patient is a young, premenopausal woman with hormone-receptor positive,HER2-overexpressing, metastatic breast cancer involving a recurrence in her right breast, nodes in her axilla and neck,and bone. Metastases to bone required stabilization of her left femur with placement of an intramedullary nail. She isrecovering from surgery without complications.
We recommended that she restart systemic therapy with tamoxifen, goserelin monthly, and trastuzumab every 3 weeks.
We also added zolendronate every 3-4 weeks to decrease complications from bone metastases. After release of long-termtoxicity data with bisphosphonates, she was weaned off zolendronate.
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Adequate cardiac function was documented and a port-a-cath was placed for IV access prior to starting treatment. Shereturned 3 months later for repeat imaging; physical exam found less prominent breast mass and neck nodes and CTscan confirmed response to treatment.
Teaching points: The selection of first line treatment for this young premenopausal woman is a little challenging. Giventhe fact that her tumor is strongly ER/PR positive, and she has no evidence of visceral crisis, a regimen with a hormonalbackbone is strongly preferred over chemotherapy. The reinitiation of tamoxifen as a single agent is one option.
However, the progression within a relatively short time of discontinuing tamoxifen, would give many clinicians pause.
Combining tamoxifen with goserilin may provide additional insurance of efficacy. Perhaps more compelling, though, isthe potential for HER2 targeted therapies for this woman whose disease has declared its aggressive biology with ametastatic recurrence. The data for use of tamoxifen in conjunction with trastuzumab is somewhat limited but otherantihormonal agents combined with trastuzumab have proven to be effective and well tolerated options for treatment ofmetastatic breast cancer. The literature contains reports of durable responses, with median time to progression of over 5months and median duration of response of at least 17 months.1 In addition, there is a randomized trial of anastrozoleplus trastuzumab versus anastrozole alone that showed longer progression free survival (median 4.8 vs 2.4 months,P
= 0.0016) with the combination.2 Although this patient presented and was treated before the approval of combinedletrozole and lapatinib for first-line treatment of metastatic disease, this might be an effective second-line treatment forher (with ongoing ovarian suppression, if required).3
References:1. Marcom PK, Isaacs C, Harris L, et al. The combination of letrozole and trastuzumab as first or second-line biological therapyproduces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat.
2. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment ofpostmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer:results from the randomized phase III TAnDEM study. J Clin Oncol.
3. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy forpostmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol.
Assessment of Protein-Ligand binding affinity with Molecular docking approach and Application. 1,2Computer-Chemie-Center, University of Erlangen-Nuremberg, Erlangen, 91052, Germany. Abstract Molecular docking determines the affinity of the ligand molecule towards a target whose 3D structure is known. The most important goals of molecular docking are: 1. Characterization of the bindin
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