breast%20cancer
BREAST CANCER
Breast cancer is the presence of malignant breast nodule, mass or abscess.
Most common symptom of breast cancer is a new lump or mass in the breast. The lump or mass is usually painless, hard & irregular but it can also be tender, soft, rounded or painful.
Other signs & symptoms include breast pain or nipple pain, nipple discharge, nipple retraction and presence of breast skin changes (eg peau d' orange, nipple excoriation, scaling, inflammation, skin tethering, ulceration, abscess).

Breast%20cancer Treatment

Preoperative Systemic Therapy

  • May be considered in patients with operable disease if patient opts for breast-conserving surgery but is not possible due to tumor size, and those with tumor subtypes known to be responsive to preoperative systemic therapy
  • Preferred for patients with operable locally advanced breast cancer with HER2-positive disease, triple negative breast cancer if ≥T2 or ≥N1, with large primary tumor relative to breast size in favor of breast conservation, node-positive patients likely to be highly responsive to neoadjuvant chemotherapy, or until commencement of surgical treatment 
  • Indicated for patients with inoperable locally advanced breast cancer, including inflammatory tumors, those with bulky or matted N2 axillary nodes, N3 regional lymph node nodal disease and/or T4 tumors
  • Not applicable in patients with extensive in situ disease with undefined disease extent, with poorly delineated extent of tumor, or with unpalpable or clinically unassessable tumors
  • Neoadjuvant chemotherapy aims to eradicate or control undiscovered distant metastasis
  • Neoadjuvant endocrine therapy may be considered in patients with strongly hormone receptor-positive tumors
  • Neoadjuvant chemotherapy and Trastuzumab + Pertuzumab-based therapy is the recommended treatment option for patients with HER2-positive breast cancer who are candidates for neoadjuvant therapy

Preoperative Chemotherapy

  • All chemotherapy administration before surgery is preferred
    • Modalities used in adjuvant therapy may also be used eg endocrine and targeted therapy
  • Purpose is to reduce tumor size which allows complete removal of the tumor with less extensive surgery
  • Can convert inoperable tumors to viably operable tumors 
  • Can predict how the cancer cells respond to chemotherapeutic drugs
  • Considered in women with large clinical stage IIA, IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size and those who wish to undergo breast-conserving therapy
  • Indications:
    • Tumor size >2 cm (T2, T3)
    • Cancer does not involve the surrounding skin or chest wall
    • LN enlarged but movable
  • Endocrine therapy alone, ie Tamoxifen or aromatase inhibitor (for postmenopausal women; administered with ovarian suppression to premenopausal women) may be given in hormone receptor-positive disease
  • Patients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating Trastuzumab with or without Pertuzumab for at least 9 weeks

Pharmacotherapy

Risk Reduction for Carcinoma In Situ

Tamoxifen

  • Competitively binds to cytoplasmic ER in breast, uterus, vagina, anterior pituitary and tumors containing high levels of ER
    • Competitive binding protects against development of breast cancer
  • Decreases breast cancer risk in healthy premenopausal and postmenopausal women ≥35 years old
  • More effective risk reduction agent for most menopausal women who want a non-surgical risk reduction therapy but has more toxic effects
  • May be considered as an adjuvant therapy in DCIS patients who underwent breast conservation therapy and radiation therapy in ER-positive DCIS; benefit of Tamoxifen in ER-negative DCIS is uncertain
    • Reduces the risk of cancer recurrence on the ipsilateral breast
  • Studies have shown that Tamoxifen can reduce the risk of invasive breast cancer in premenopausal and postmenopausal patients ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% or with history of LCIS
    • Used in ER-positive tumor
  • Advised to be taken for 5 years

Raloxifene

  • May be considered in postmenopausal patients with history of LCIS or ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen therapy 
  • Long-term use was shown to be less effective but a safer risk reduction agent compared to Tamoxifen in postmenopausal women, in pregnant women or those planning a pregnancy

Aromatase Inhibitors

  • Eg Anastrozole, Exemestrane
  • Alternative to Tamoxifen in postmenopausal women with DCIS
    • May be of advantage in postmenopausal patients <60 years old or with thromboembolism concerns
  • May be considered in postmenopausal patients with history of LCIS or ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen or Raloxifene therapy

Chemotherapeutic Agents for Invasive Breast Cancer

  • Several combination treatment regimens are used for adjuvant chemotherapy
    • Usually includes 4-8 cycles of taxane- and/or anthracycline-based regimen
  • Chemotherapy response depends on ER status
  • Platinum compounds may be given to BRCA1 patients; cells deficient of BRCA1 are hypersensitive to platinum compounds
  • Complete preoperative chemotherapy after surgery if not completed
  • Preferred time for initiation of adjuvant systemic therapy is within 3-6 weeks after surgery
  • May substitute Paclitaxel or Docetaxel with albumin-bound Paclitaxel if deemed medically necessary (eg hypersensitivity reactions)

Trastuzumab

  • Indicated for patients who are HER2 positive with (nonresponsive, incompletely or highly) endocrine-responsive tumors and low, intermediate or high-risk categories to decrease disease recurrence
    • Indicated for patients with early breast cancer who are HER2 positive, given after surgery, adjuvant or neoadjuvant chemotherapy, and radiotherapy (if applicable)
  • Can help slow cancer growth and may also stimulate the immune system to more effectively fight the cells
    • Reduces risk of recurrence by half and improves survival
  • Given to both premenopausal and postmenopausal patients
  • May be given concurrently with a taxane following anthracycline or after completion of all chemotherapy
  • One year is the accepted standard treatment duration
  • Contraindicated in patients with low left ventricular ejection fraction (<50%)
  • The antibody-linked Trastuzumab agent, Ado-trastuzumab or Trastuzumab emtansine, is used instead of Trastuzumab if with residual disease after preoperative therapy
  • Subcutaneous Trastuzumab plus Hyaluronidase-oysk may be used in place of Trastuzumab

Trastuzumab Combinations (HER2-positive Disease)

Preferred Adjuvant Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) plus Trastuzumab with or without Pertuzumab
  • Docetaxel, Carboplatin, Trastuzumab (TCH) with or without Pertuzumab
  • Paclitaxel plus Trastuzumab
    • May be considered for HER2-positive patients with low-risk T1N0M0 but with comorbidities not eligible for other adjuvant regimens
  • Ado-trastuzumab emtansine

Conditional Regimens:

  • Docetaxel plus Cyclophosphamide plus Trastuzumab

Other Adjuvant Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel plus Trastuzumab with or without Pertuzumab

Non-Trastuzumab Combinations (HER2-negative Disease)

Preferred Adjuvant Regimens:

  • Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) every 2 weeks
  • Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel
  • Docetaxel, Cyclophosphamide (TC)
  • Capecitabine: For triple-negative breast cancer with residual disease after surgery and taxane-/alkylator-/anthracycline-based chemotherapy

Conditional Regimens:

  • Cyclophosphamide, Methotrexate, Fluorouracil (CMF) 
  • Dose-dense Doxorubicin, Cyclophosphamide (AC)
  • Doxorubicin, Cyclophosphamide (AC) every 3 weeks
  • Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel

Other Recommended Regimens:

  • Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel every 3 weeks
  • Epirubicin, Cyclophosphamide (EC)
  • Docetaxel, Doxorubicin, Cyclophosphamide (TAC)
  • For triple-negative breast cancer: Weekly Paclitaxel + Carboplatin; Docetaxel + Carboplatin

Other Treatment Strategies

  • Extended adjuvant Neratinib should be considered in HR-positive, HER2-positive patients after treatment with Trastuzumab-containing regimen if at high-risk for disease recurrence
Adjuvant Endocrine Therapy
  • Offered to patients with detectable expression of HR (>1% invasive cancer cells)
  • Minimum duration of therapy is 5 years but recent data suggest that extending therapy for an additional 5 years reduces risk recurrence and improves disease-free survival
    • Discussion should be made with the patient regarding the benefits and risks of extended therapy
  • Sequential administration of hormone therapy after chemotherapy is recommended for patients with high-risk features (eg lymph node metastasis, unknown recurrence score, intermediate to high recurrence score)

Recommended Adjuvant Endocrine Therapy for Premenopausal Women

  • Any of the following:
    • Tamoxifen for 5 years with or without ovarian suppression or ablation or
    • Aromatase inhibitor for 5 years with ovarian suppression or ablation for 5 years
  • If patient becomes amenorrheic while on the 5-year Tamoxifen therapy, assessment of FSH, LH and estradiol levels should be done to confirm menopause
    • Aromatase inhibitor therapy should be started to be given for 5 years 
    • Consider continuing Tamoxifen therapy for another 5 years to complete 10 years
  • Continuation of Tamoxifen therapy for up to 10 years should be considered for patients who remain premenopausal 5 years after initiation of adjuvant endocrine therapy
  • Tamoxifen therapy is also recommended for men with breast cancer, and may use a GnRH analog with aromatase inhibitor if Tamoxifen use is contraindicated

Recommended Adjuvant Endocrine Therapy for Postmenopausal Women

  • Any of the following:
    • Aromatase inhibitor for 5 years or
      • May consider continuing treatment for another 3-5 years 
    • Aromatase inhibitor for 2-3 years followed by Tamoxifen to complete the 5-year treatment duration or
    • Tamoxifen for 2-3 years followed by 1 of the following: or
      • Aromatase inhibitor to complete the 5-year treatment duration
      • Aromatase inhibitor for 5 years
    • Tamoxifen for 4.5-6 years followed by aromatase inhibitor for 5 years or Tamoxifen therapy for additional 5 years to complete the 10-year duration or
    • Tamoxifen monotherapy of 5-10 years should only be considered in patients with contraindications to or opposed to aromatase inhibitor therapy

Aromatase Inhibitors

  • Eg Anastrozole, Exemestane, Letrozole 
  • Adjuvant treatment in postmenopausal patients with ER-positive, stages I and II (tumor size <5 cm) invasive carcinoma
  • Based on randomized controlled trials, relative to Tamoxifen, aromatase inhibitors improve clinical outcomes in patients with early ER-positive invasive breast cancer; however, treatment was associated with increased drug costs and slight decrease in follow-up costs compared to Tamoxifen
  • Have the same anti-tumor efficacy and toxicity profiles
  • Anastrozole is recommended for primary adjuvant therapy
  • Exemestane is used as adjuvant therapy following 2-3 years of adjuvant Tamoxifen therapy
  • Letrozole is recommended for primary and extended adjuvant therapy following standard Tamoxifen therapy

Tamoxifen

  • 1st-line adjuvant endocrine therapy in both pre- and post-menopausal breast cancer patients
Chemotherapy for Recurrent or Metastatic Breast Cancer
  • Consider a taxane- or anthracycline-based regimen
    • Sequential monotherapy rather than concomitant use is recommended
    • Considered as 1st-line agents for patients with HER2-negative metastatic breast cancer who have not yet been on these regimens as adjuvant therapy and for whom treatment with chemotherapy is appropriate
    • If taxane-naive and with history of resistance to anthracycline or with anthracycline maximum cumulative dose or toxicity but is being considered for further chemotherapy, single-agent taxane-based therapy is preferred
  • Monotherapy with Capecitabine, Vinorelbine or Eribulin may be considered in patients previously given a taxane- or anthracycline-based therapy without indications for combination regimens
  • No evidence states that combination regimens are superior to sequential single agents
  • HER2-directed therapy, either as a single agent, combined with chemotherapy or with endocrine therapy, should be proposed early to patients with HER2-positive metastatic breast cancer
    • If without contraindications, further anti-HER2 therapy should be considered in patients with HER2-positive metastatic breast cancer who relapsed following adjuvant or any line metastatic anti-HER2 treatment

HER2-Negative Disease

  • Combination regimen may be used for patients with high tumorburden, rapidly progressive disease, and visceral crisis

Preferred Single Agent Regimens

  • Anthracyclines: Doxorubicin, liposomal Doxorubicin
  • Anti-metabolites: Capecitabine, Gemcitabine
  • Microtubule inhibitors: Vinorelbine, Eribulin
  • Taxanes: Paclitaxel
  • PARP inhibitor: Olaparib, Talazoparib
    • Treatment option for HER2-negative, germline BRCA 1/2-mutation positive patients
  • Platinum agents: Carboplatin, Cisplatin
    • Treatment option for triple-negative, germline BRCA1/2-mutation positive patients
  • Atezolizumab plus albumin-bound Paclitaxel
    • Treatment option for patients with PD-L1-positive triple-negative breast cancer

Other Recommended Regimens

  • Cyclophosphamide, Docetaxel, albumin-bound Paclitaxel, Epirubicin, Ixabepilone, Sacituzumab govitecan-hziy (for patients with triple-negative breast cancer with history of at least 2 therapies for metastatic breast cancer)

Useful in Certain Conditions (Eg High Tumor Burden, Rapidly Progressing Disease, Visceral Crisis)

  • Doxorubicin, Cyclophosphamide (AC)
  • Epirubicin, Cyclophosphamide (EC)
  • Carboplatin and Paclitaxel or albumin-bound Paclitaxel
  • Cyclophosphamide, Methotrexate, Fluorouracil (CMF)
  • Docetaxel and Capecitabine
  • Gemcitabine and Paclitaxel (GT)
  • Gemcitabine and Carboplatin
  • Paclitaxel and Bevacizumab

HER2-Positive Disease

  • May substitute Trastuzumab with Trastuzumab plus Hyaluronidase-oysk injection for subcutaneous use
  • Combination of Trastuzumab and Pertuzumab with or without cytotoxic therapy may be considered in HER2-positive patients with recurrent or metastatic disease if without previous history of Pertuzumab treatment
  • Tucatinib + Trastuzumab + Capecitabine is a treatment option for patients with metastatic disease, including brain metastases) with history of ≥1 line of HER2-targeted therapy 
  • Fam-trastuzumab deruxtecan-nxki is indicated for patients with metastatic disease with history of ≥2 lines of HER2-targeted therapy
  • Combination of Lapatinib or Neratinib and Capecitabine may be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane and Trastuzumab
    • Study has shown that the combination was associated with 51% risk reduction of cancer progression

Preferred Regimens

  • Pertuzumab plus Trastuzumab plus Docetaxel
  • Pertuzumab plus Trastuzumab plus Paclitaxel

Other Recommended Regimens

  • Ado-trastuzumab emtansine (T-DM1)
  • Fam-trastuzumab deruxtecan-nxki
  • Lapatinib plus Capecitabine
  • Neratinib plus Capecitabine
  • Trastuzumab plus Capecitabine
  • Trastuzumab plus Docetaxel
  • Trastuzumab plus Lapatinib (without cytotoxic therapy)
  • Trastuzumab plus Paclitaxel with or without Carboplatin
  • Trastuzumab plus Vinorelbine
  • Trastuzumab plus other agents
  • Tucatinib + Trastuzumab + Capecitabine

Systemic Therapy for Recurrent or Metastatic Disease

HER2-negative Postmenopausal Patients or or Premenopausal Patients Receiving Ovarian Ablation/Suppression

Preferred Regimens - 1st-line Therapy

  • Aromatase inhibitor plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib)
  • Estrogen receptor down-regulator (eg Fulvestrant) with or without non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
  • Fulvestrant plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib)
  • Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
  • Serum estrogen receptor modulators (eg Tamoxifen, Toremifene)
  • Steroidal aromatase inactivator (eg Exemestane)

Preferred Regimens - 2nd-line and Subsequent-line Therapy

  • Estrogen receptor down-regulator (eg Fulvestrant)
  • Exemestane plus endocrine therapy (eg Exemestane, Fulvestrant, Tamoxifen)
  • Fulvestrant plus Alpelisib (for PIK3CA-mutated tumors)
  • Fulvestrant plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib) if not previously used
  • Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
  • Serum estrogen receptor modulators (eg Tamoxifen, Toremifene)
  • Steroidal aromatase inactivator (eg Exemestane)

Conditional Regimens

  • Abemaciclib
  • Ethinyl estradiol
  • Fluoxymesterone
  • Megestrol acetate 

HER2-positive Postmenopausal Patients or Premenopausal Patients Receiving Ovarian Ablation/Suppression

  • Aromatase inhibitor with or without Trastuzumab
  • Aromatase inhibitor with or without Lapatinib
  • Aromatase inhibitor with or without Lapatinib plus Trastuzumab
  • Fulvestrant with or without Trastuzumab
  • Tamoxifen with or without Trastuzumab

HER2-targeted Therapy

  • Treatment option for ER/PR-positive, HER2-positive patients, should be offered once diagnosis is confirmed
  • Includes any of the following:
    • Pertuzumab plus Trastuzumab plus taxane (preferred regimen)
    • Ado-Trastuzumab emtansine (T-DM1)
    • Trastuzumab plus chemotherapy

Aromatase Inhibitors

  • Eg Anastrozole, Letrozole 
  • Used in postmenopausal patients
  • Preferred 1st-line therapy for recurrent disease in postmenopausal women who have received previous antiestrogen therapy and are within 1 year of antiestrogen exposure
  • Used in postmenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with no prior endocrine therapy within 1 year 

Endocrine Therapy plus Ovarian Ablation or Suppression or Selective ER Modulators

  • Tamoxifen is a standard
    • Monotherapy with Tamoxifen may be considered in HER2-negative premenopausal women who declines ovarian ablation/suppression
  • Used in premenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with or without prior endocrine therapy within 1 year

CDK4/6 Inhibitors

  • Eg Abemaciclib, Palbociclib, Ribociclib
  • Highly selective inhibitors of CDK 4/6 kinase activity which are used to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer
  • Combination therapy of any CDK4/6 inhibitor with an aromatase inhibitor or Fulvestrant is a preferred 1st-line regimen option for hormone-receptor positive, HER2-negative postmenopausal patients or premenopausal patients receiving ovarian suppression or ablation with an LHRH agonist
  • Abemaciclib or Palbociclib combined with Fulvestrant is among the preferred regimens for hormone receptor-positive, HER2-negative postmenopausal breast cancer patients
  • Ribociclib with Tamoxifen may be considered as 1st-line treatment option, together with ovarian suppression, inpatients with hormone-receptor positive, HER2-negative metastatic breast cancer
  • Abemaciclib may be considered in the presence of disease progression despite endocrine therapy and chemotherapy for metastatic disease

Mammalian Target of Rapamycin (mTOR) Pathway Inhibitor

  • Inhibits protein in cells that promotes growth and division
  • Eg Everolimus
    • Used in addition to an aromatase inhibitor, Exemestane, Fulvestrant, or Tamoxifen in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer that had progressed or recurred during treatment with a non-steroidal aromatase inhibitor
    • May also stop angiogenesis which can help limit tumor growth

Monoclonal Antibody Therapy

Bevacizumab

  • May be used to treat metastatic breast cancer which is commonly used in combination with Paclitaxel
  • Prevents angiogenesis

Pembrolizumab

  • Approved for use in patients with any subtype of breast cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors with disease progression after 1st-line therapy or when no alternative therapy options are available

Pertuzumab

  • A human epidermal growth factor receptor (HER) dimerisation inhibitor preventing HER2 heterodimerisation with other HER receptors thereby inhibiting HER signalling pathway activation
  • Used in combination with Trastuzumab, a taxane, chemotherapeutic agents and HER2-targeted therapy in the treatment of HER2-positive premenopausal or postmenopausal patients with recurrent or metastatic disease, regardless if with history of endocrine therapy in the past 12 months
    • Also used for the treatment of locally advanced, inflammatory or early stage HER2-positive breast cancer
  • LVEF assessment should be done at baseline and during treatment; discontinue if with confirmed clinically significant decline in LV function

Trastuzumab

  • Indicated for high-risk, HER2-positive tumor
    • Added in preoperative chemotherapy regimens in patients with HER2-positive tumors
  • May be used to treat metastatic breast cancer, with or without chemotherapy
    • May be given as monotherapy to patients with HER2-overexpressing tumors who have received at least 2 regimens of chemotherapy for metastatic disease
  • May be used as adjuvant therapy along with chemotherapy in cancer recurrence risk reduction and as neoadjuvant therapy with chemotherapy to reduce the tumor size prior to surgical operation
  • Combination with an anthracycline is related to significant cardiac toxicity, except as part of the neoadjuvant Trastuzumab with Paclitaxel followed by CEF regimen
  • Ado-trastuzumab/Trastuzumab emtansine/T-DM1 is preferred over Trastuzumab for patients with disease progression after Trastuzumab-based treatment
  • Subcutaneous Trastuzumab plus Hyaluronidase-oysk may be used in place of Trastuzumab

Mutation-specific Therapies

  • PARP inhibitors Olaparib and Talazoparib are preferred options for patients with recurrent or metastatic breast cancer (any subtype) with BRCA1 and BRCA2 germline mutation, respectively
  • Alpelisib + Fulvestrant combination therapy is recommended for patients with ER- and/or PR-positive, HER2-negative recurrent or stage IV breast cancer with PIK3CA mutation
  • Atezolizumab + albumin-bound Paclitaxel combination therapy is recommended for ER- and/or PR-negative, HER2-negative recurrent or stage IV breast cancer with PD-L1 expression
  • Tropomyosin receptor kinase (TRK) inhibitors Larotrectinib and Entrectinib are recommended agents for patients with any subtype of breast cancer with neurotrophic tropomyosin receptor kinase (NTRK) gene fusions

Selective ER Down-Regulator

  • Eg Fulvestrant
  • Recommended regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer when given in combination with Palbociclib, Abemaciclib, or Everolimus
  • May also be considered in postmenopausal, HER2-positive patients with recurrent or metastatic breast cancer
    • Given with or without Trastuzumab

Selective ER Modulators

  • Eg Tamoxifen, Toremifene
  • Preferred regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer
  • Tamoxifen with or without Trastuzumab is an alternative option for postmenopausal, HER2-positive patients with recurrent or metastatic disease

Tyrosine Kinase Inhibitors

  • Eg Lapatinib, Neratinib
  • Combined with an aromatase inhibitor, Capecitabine, or Trastuzumab as a treatment option for HER2-positive patients with recurrent or metastatic disease
  • Combination of Lapatinib and Trastuzumab or Capecitabine may be considered in patients with disease progression after Trastuzumab-based therapy
  • Neratinib/Capecitabine combination is an option for patients with ≥2 lines of prior HER2-targeted treatment

Other Agents

Bisphosphonates and Denosumab

  • Given in addition to endocrine therapy or chemotherapy if bone metastasis is present
  • Ibandronic acid, Pamidronate or Zoledronic acid (with calcium citrate and vit D)
    • Help strengthen bones and decrease the risk of fractures and bone pains and prevent hypercalcemia of malignancy
  • Zoledronic acid may be more effective than Pamidronic acid in lytic breast metastasis
  • A randomized trial had shown Denosumab to have slightly better tolerability and efficacy when compared to Zoledronic acid
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